1. 重新认识脂肪肝：从NAFLD到MASLD的更新
1.1 最新定义与疾病阶段划分
想象一下，我们的肝脏是个任劳任怨的“加工厂”，每天忙碌地处理着身体的各种物质。脂肪，作为重要的能量来源，也会在这里进行储存和转化。但如果脂肪太多，超出了肝脏能承受的范围，就像仓库里堆满了货物，就会导致肝脏“发福”，也就是我们常说的“脂肪肝”。
在过去，大家普遍使用的词是“非酒精性脂肪性肝病”（NAFLD），听起来有点拗口，而且容易让人误解，好像除了酒精，其他原因都不算数似的。更重要的是，“非酒精性”这三个字，会让一些患者觉得自己受到了“歧视”或“指责”，觉得这个名字带有贬义，影响了他们的心理健康 12。
为了更准确、更科学地描述这种日益普遍的肝脏疾病，并消除患者可能感到的“污名化”，国际上的肝病专家们经过广泛讨论和多方共识，在2023年正式给它换了个新名字——“代谢功能障碍相关脂肪性肝病”（MASLD） 123。这个新名字更贴切地指出了疾病的核心原因：它与我们身体的代谢功能紊乱密切相关，比如肥胖、2型糖尿病、高血压、高血脂等 34。
MASLD 不仅仅是肝脏里堆积了脂肪那么简单，它是一个连续发展的过程，可以分为几个阶段：
- 单纯性脂肪肝（或称脂肪变性）：这是MASLD的早期阶段，肝脏里只是单纯地堆积了过多的脂肪，通常没有明显的炎症和肝细胞损伤。这个阶段往往没有症状，很多人都是在体检时偶然发现的。
- 脂肪性肝炎（MASH，以前称为NASH）：如果肝脏里的脂肪持续堆积，并且开始引起炎症反应，肝细胞受到损伤，这个阶段就叫做脂肪性肝炎。炎症就像肝脏在“发烧”，长期发炎会对肝细胞造成更大的伤害。
- 肝纤维化：长期的肝脏炎症会导致肝脏组织出现疤痕，就像皮肤受伤后留下的疤痕一样，医学上称之为纤维化。肝纤维化程度越重，肝脏的正常功能就越会受到影响。
- 肝硬化：如果纤维化继续发展，肝脏会变得又硬又小，结构也会发生不可逆的改变，这就是肝硬化。到了这个阶段，肝脏的功能会严重受损，可能会出现各种并发症，甚至危及生命。
- 肝癌：在某些情况下，肝硬化患者还可能进一步发展为肝癌。
值得注意的是，只有一小部分MASLD患者会进展到肝硬化，通常需要20年以上的时间 5。但一旦进展到晚期肝纤维化或肝硬化，肝脏的损伤就很难逆转了。因此，早期发现和干预，对于阻止疾病进展、改善预后至关重要。
1.2 逆转的可能性与关键前提
提到脂肪肝，很多人可能会感到沮丧，觉得是“不治之症”。但实际上，我们的肝脏拥有一种非常强大的“自愈”能力，也就是再生能力 678。肝脏是人体内少数几个即使受到损伤也能自我修复和再生的器官之一。在一定范围内，即使肝脏切除了大部分，剩下的部分也能逐渐生长回来，恢复原来的体积和功能 689。
这种强大的再生能力，为脂肪肝的逆转提供了可能。早期的脂肪堆积，在肝脏还没有发生严重的炎症和纤维化时，是完全有机会“清零”的。当肝脏脂肪减少，炎症消退后，肝脏的健康状态就可以恢复 101112。
最新的研究和临床经验都明确指出，“早期干预可显著改善预后” 10。这意味着，如果在单纯性脂肪肝或轻度脂肪性肝炎阶段就采取积极的干预措施，比如调整生活方式、控制体重、改善代谢指标等，肝脏的脂肪含量和炎症程度都可以明显降低，甚至完全恢复正常。
所以，脂肪肝并不是一个“判决书”，而是身体给我们发出的一个“警告信号”。只要我们重视起来，积极行动，通过科学的方法进行干预，绝大多数脂肪肝患者都有机会实现肝脏的“逆转”，重回健康状态。而这正是我们接下来要深入探讨的关键前提和具体路径。
2. 脂肪肝逆转的核心机制：肝脏脂肪代谢的“收支平衡”
2.1 脂肪堆积的三大来源：多途径调控的突破口
要理解脂肪肝是怎么来的，以及如何让它“走掉”，我们首先要搞清楚肝脏里脂肪的“收支平衡”问题。肝脏就像一个巨大的物流中心，既负责接收、储存脂肪，也负责加工、运输脂肪。当“收入”大于“支出”时，脂肪自然就在肝脏里堆积起来，造成脂肪肝。那么，这些“收入”的脂肪是从哪里来的呢？主要有三大来源，每一个都是我们进行调控和逆转脂肪肝的突破口。
“快递小哥”送来的脂肪：白色脂肪组织（WAT）释放的脂肪酸
想象一下，我们身体里有很多“脂肪仓库”，主要就是白色脂肪组织（WAT）。当身体需要能量或者处于饥饿状态时，这些脂肪仓库就会把储存的脂肪分解成脂肪酸，通过血液（就像“快递小哥”一样）送到全身各处，包括肝脏。这些脂肪酸是肝脏合成甘油三酯（也就是肝脏里储存的脂肪）的重要原材料 1314。
特别值得一提的是，内脏脂肪（visceral fat），也就是我们肚子深层的脂肪，相比皮下脂肪，更容易释放出大量的游离脂肪酸，直接通过门静脉系统进入肝脏。这就好比内脏脂肪直接给肝脏开了个“直通车”，源源不断地输送脂肪酸。虽然全身大部分的游离脂肪酸主要来源于上半身的皮下脂肪，但内脏脂肪对肝脏脂肪堆积的贡献不容忽视 15。胰岛素抵抗，这个脂肪肝背后的“大Boss”，会加剧白色脂肪组织的脂肪分解，使得更多的脂肪酸涌向肝脏 131617。所以，减少内脏脂肪，控制好胰岛素抵抗，就能有效切断这个“快递小哥”的超量配送。
肝脏自己的“生产线”：肝脏从头合成（DNL）
肝脏除了接收外来的脂肪，自己也能“生产”脂肪，这个过程叫做“从头合成脂肪”（De Novo Lipogenesis, DNL）。当我们在吃下过多的碳水化合物（比如米饭、面条、甜食）时，这些多余的糖分在肝脏里就会被转化成脂肪酸，然后再合成甘油三酯储存起来 18。这就像肝脏工厂里有一条自己的“生产线”，把多余的糖类原料加工成脂肪产品。
在代谢功能障碍相关脂肪性肝病（MASLD）患者中，这条“生产线”往往处于过度活跃状态 1416。胰岛素抵抗同样扮演了重要的角色，它会使得肝脏抑制糖异生（肝脏制造葡萄糖的过程）的能力下降，但同时又“诡异地”促进脂肪从头合成。这就好比胰岛素这把钥匙，在某些地方“生锈了”（抑制糖异生失效），但在另一些地方却依然好用，甚至“过度激活”了脂肪生产线 19。这意味着，即使我们不直接吃太多脂肪，仅仅是碳水化合物吃多了，肝脏也可能因此“发福”。
“过期包裹”的滞留：富含甘油三酯脂蛋白（TRL）残粒的摄取
我们的身体需要通过血液运输脂肪，就像快递公司用各种“包裹”来运输货物。其中一种重要的“包裹”叫做“富含甘油三酯脂蛋白”（Triglyceride-Rich Lipoproteins, TRL），它们主要负责把食物中的脂肪从肠道（乳糜微粒，Chylomicrons）或者肝脏（极低密度脂蛋白，VLDL）运输到身体各处需要能量的组织 2021。
当这些“包裹”把大部分甘油三酯“卸货”后，就会变成“残粒”，需要被肝脏回收处理。肝脏通过特定的“接收口”（受体）识别并摄取这些“过期包裹” 21。如果这个回收处理过程出了问题，比如肝脏的“接收口”不灵敏，或者“过期包裹”太多、太“油腻”，导致它们在血液中滞留时间过长，那么肝脏就会摄取更多的TRL残粒，从而增加肝脏的脂肪负担 1322。肝脏脂肪酶（Hepatic Lipase）在帮助肝脏摄取这些残粒方面起着重要作用 23。
综合来看，要有效逆转脂肪肝，我们需要多管齐下，既要减少身体其他部位（尤其是内脏脂肪）向肝脏输送脂肪酸，又要抑制肝脏自身的脂肪生产线，还要提高肝脏对“过期包裹”的清理效率。
2.2 脂肪“输出”的平衡术：VLDL分泌与脂肪燃烧
既然我们已经了解了肝脏里脂肪堆积的“来路”，那么“去路”又是什么呢？肝脏并不是只会囤积脂肪，它也在努力地“清仓”。主要有两种方式来“输出”脂肪，以维持自身的健康状态：一是通过分泌“极低密度脂蛋白”（Very Low-Density Lipoprotein, VLDL）把脂肪打包送走；二是通过“燃烧”脂肪来获取能量。
肝脏的“打包送货”服务：分泌VLDL输出脂肪
想象一下，肝脏这个“脂肪加工厂”，如果内部脂肪实在太多了，它就会把一部分脂肪（主要是甘油三酯）和蛋白质（载脂蛋白B100）组合起来，外面再裹上一层磷脂和胆固醇，形成一种特殊的“快递包裹”，这就是极低密度脂蛋白（VLDL）。这些VLDL会通过血液循环，把肝脏里多余的脂肪运送到身体其他需要能量的组织，比如肌肉和脂肪细胞 24。可以说，VLDL是肝脏对外输出甘油三酯的主要形式。
正常情况下，肝脏会根据身体的能量需求，精巧地调节VLDL的生产和分泌。当身体能量充足时，VLDL的分泌可能会减少；当身体需要能量时，VLDL分泌就会增加。这种调节能力非常重要，它有助于维持肝脏内部脂肪的稳定。有研究发现，瘦素（一种调节能量平衡的激素）甚至可以通过迷走神经来刺激肝脏分泌更多的VLDL，从而帮助肝脏清除多余脂肪 2526。脑部的胰岛素信号也能促进肝脏分泌VLDL，保护肝脏免受脂肪堆积 27。而细胞内的C3蛋白（补体成分3）也参与了VLDL的分泌，它通过促进细胞自噬来帮助肝脏平衡甘油三酯水平 28。
然而，在MASLD患者中，虽然肝脏脂肪堆积严重，但VLDL的分泌能力却可能出现异常。一些研究表明，MASLD患者的肝脏VLDL分泌量反而增加了，这导致了血液中甘油三酯水平升高，形成了常说的“高甘油三酯血症” 24。高甘油三酯是MASLD患者常见的脂质代谢紊乱之一，增加了心血管疾病的风险 29。另一些研究则指出，尽管肝脏脂肪含量很高，但VLDL的生产和分泌可能并未显著增加，甚至可能受损，尤其是在某些遗传因素（如PNPLA3基因突变）影响下，肝脏虽然堆积了大量脂肪，但VLDL的输出能力并未相应提升 30。这种看似矛盾的现象，反映了MASLD病程的复杂性，以及个体之间代谢特征的差异。
值得注意的是，如果VLDL分泌能力进一步受损，可能会导致肝脏脂肪进一步堆积，甚至加剧胰岛素抵抗 31。所以，平衡好VLDL的分泌，既不能太少导致脂肪堆积，也不能太多导致血液甘油三酯过高，是肝脏维持“收支平衡”的关键一环。
肝脏的“自给自足”：脂肪氧化分解（FAO通路）
除了把脂肪“送货”出去，肝脏还可以把脂肪“燃烧”掉，作为自己的能量来源。这个过程叫做脂肪酸氧化（Fatty Acid Oxidation, FAO），就像是肝脏自己的“发电厂”开足马力，利用脂肪来发电 3233。当脂肪酸进入肝细胞后，会在线粒体中经过一系列复杂的化学反应，最终被分解产生能量。
在正常情况下，脂肪酸氧化是肝脏处理脂肪、维持能量平衡的重要途径。然而，在MASLD患者中，脂肪酸氧化的情况比较复杂。一些研究发现，胰岛素抵抗的个体，其肝脏脂肪酸氧化水平可能会上调，试图清除过多的脂肪 32。这可能是肝脏的一种“自救”机制。但如果脂肪酸供应过剩，远远超出了肝脏的氧化能力，或者氧化途径本身存在缺陷，那么脂肪仍然会堆积。
炎症也会影响脂肪酸氧化。研究表明，在炎症刺激下，肝脏内的脂肪酸氧化会增加，产生更多的乙酰辅酶A，这反而会促进糖酵解（分解糖产生能量的过程），而不是直接清除脂肪 34。这可能是一种复杂的能量代谢重编程，试图在炎症环境下维持肝细胞的能量供应。
2021年的研究强调，“VLDL分泌与脂肪储存的平衡”对疾病转归至关重要 24。这意味着，肝脏的健康状态取决于它处理脂肪的“输入”和“输出”的综合能力。如果肝脏不能有效地通过VLDL将脂肪输出，或者不能充分地“燃烧”脂肪，那么即使减少了脂肪的“输入”，肝脏脂肪仍然可能居高不下。因此，未来的治疗策略，不仅要关注如何减少脂肪的来源，更要探索如何增强肝脏的脂肪“输出”和“燃烧”能力，才能真正实现脂肪肝的逆转。例如，有研究发现，雷帕霉素可以通过增加巨噬细胞的脂肪酸氧化水平，从而减轻MASLD相关的肝脏炎症 35。
3. 生活方式干预：逆转脂肪肝的“基础防线”
3.1 饮食调整：从“热量限制”到“精准营养”
如果说药物治疗是“外科手术”，那么饮食调整就是脂肪肝逆转的“内科调理”，它是最基础、最重要的一道防线。过去我们常常强调简单的“热量限制”，也就是少吃点，但现在，科学研究告诉我们，光少吃还不够，怎么吃、吃什么，才是更“精准”的学问。这不是简单的节食，而是要通过科学的饮食模式，帮助肝脏从“脂肪堆积模式”切换到“脂肪清除模式”。
最新的研究支持多种饮食模式对脂肪肝的改善作用，其中一些明星饮食方案脱颖而出：
地中海饮食：肝脏的“黄金法则”
地中海饮食以其富含新鲜蔬菜、水果、全谷物、豆类、坚果，以及橄榄油作为主要脂肪来源，适量鱼类和家禽，少量红肉和甜食的特点，被认为是预防和逆转多种慢性疾病的“黄金法则”，对脂肪肝的益处更是备受推崇 363738。这种饮食模式不仅能帮助减轻体重，改善胰岛素抵抗，还能减少肝脏炎症和纤维化 37。它富含抗氧化剂和抗炎物质，能像“清道夫”一样，帮助肝脏清理代谢废物，减轻“工作压力” 38。一项2025年的前瞻性队列研究发现，严格遵循地中海饮食的MASLD患者，其肝脏相关事件（LRE）和死亡风险显著降低，其中omega-3脂肪酸和白蛋白等代谢生物标志物发挥了重要作用 39。另一项2025年的研究还指出，地中海饮食与限时进食相结合，不仅能有效减轻体重和改善血压，早期限时进食（比如将进食时间窗口限制在上午8点至下午6点）还能显著改善糖化血红蛋白A和胰岛素抵抗等血糖控制指标 40。
低GI饮食：让血糖“慢”下来，肝脏“轻松”起来
GI，全称“血糖生成指数”，它反映了食物升高血糖的速度和幅度。低GI饮食就是选择那些消化吸收慢、血糖升高平稳的食物。为什么这很重要？因为我们前面提到，过多的碳水化合物在肝脏里会转化成脂肪。高GI食物会让血糖快速升高，刺激胰岛素大量分泌，长期下来容易导致胰岛素抵抗，进而促进肝脏脂肪的合成 41。相反，低GI饮食能让血糖保持平稳，减轻胰岛素抵抗，减少肝脏“从头合成脂肪”的负担 41。一项2021年的研究方案正在探索，通过为期2周的低GI饮食，能否显著降低NAFLD患者的肝脏脂肪含量，并改善肠道菌群组成 41。这表明，选择糙米、全麦面包、燕麦、大多数蔬菜和豆类等低GI食物，能让肝脏的“脂肪生产线”踩刹车。
除了这些整体的饮食模式，具体到食物成分，我们也要学会“精准选择”：
膳食纤维：肠道健康与肝脏健康的“桥梁”
膳食纤维就像是肠道里的“清洁工”，它虽然不能被我们消化吸收，但作用却非常大。它能增加饱腹感，减少总热量摄入，从而帮助体重管理。更重要的是，膳食纤维是肠道益生菌的“食物”，能够促进有益菌的生长，维持肠道菌群的平衡。健康的肠道菌群能够减少有害物质（比如内毒素）进入肝脏，降低肝脏的炎症反应。一项2025年的研究分析了近20万人的数据，发现膳食纤维摄入量高的人，MASLD的风险显著降低，肝脏脂肪含量也更少 42。研究还强调，这种保护作用与肠道菌群的基因易感性以及丁酸盐水平无关，这说明膳食纤维对肝脏的益处非常普遍 42。
优质蛋白：重建肝脏的“基石”
蛋白质是细胞修复和再生的重要原料，也是维持肝脏正常功能必不可少的。选择鸡胸肉、鱼肉、豆制品、蛋奶等优质蛋白质来源，能够提供身体所需的氨基酸，有助于肝细胞的修复，并能促进脂肪的代谢。此外，蛋白质相比碳水化合物和脂肪，消化后饱腹感更强，有助于控制总热量摄入。
健康的脂肪：并非所有脂肪都是“坏蛋”
谈到脂肪肝，很多人会“谈脂色变”，但并非所有脂肪都是促进脂肪肝的“坏蛋”。橄榄油、鱼油、坚果、牛油果等富含不饱和脂肪酸的食物，反而对肝脏有益。例如，一些植物种子油，如刺梨籽油（ORRT），因其高含量的不饱和脂肪酸，被发现可以通过激活线粒体氧化代谢，减少肝脏脂肪堆积和炎症 43。它们能帮助改善脂质代谢，降低炎症，甚至对抗氧化应激 43。当然，这不意味着可以无限量摄入，适量选择健康的脂肪，替换掉饱和脂肪和反式脂肪，才是明智之举。
总而言之，饮食调整不再是简单粗暴的“少吃点”，而是要学会“吃对”。通过选择地中海饮食、低GI饮食等科学模式，并注重膳食纤维、优质蛋白和健康脂肪的摄入，我们就能为肝脏的逆转打下最坚实的基础。
3.2 运动干预：“周末战士”模式同样有效？
除了“管住嘴”，要让肝脏“瘦身”，还得“迈开腿”。运动是逆转脂肪肝的另一道重要防线，它能直接消耗能量，减少肝脏脂肪堆积，还能改善胰岛素抵抗，增强肝脏代谢脂肪的能力。但很多人可能有个疑问：是不是必须每天坚持运动才有效果？有没有一种更灵活的运动方式，也能达到同样的目的？最新的研究给了我们一些令人鼓舞的答案。
不同运动类型：有氧与抗阻，各有千秋
在运动方式上，我们通常会接触到两种主要类型：有氧运动和抗阻运动。
- 有氧运动：这类运动的特点是强度适中、持续时间长，比如快走、慢跑、游泳、骑自行车等。它能有效提高心肺功能，促进全身脂肪燃烧，当然也包括肝脏脂肪。2016年的一项系统性综述指出，对NAFLD患者而言，有效的中位有氧运动方案是每次40分钟，每周3次，持续12周，运动强度为4.8代谢当量（METs） 44。
- 抗阻运动：这类运动主要是通过肌肉对抗阻力来锻炼肌肉力量和质量，比如举重、俯卧撑、深蹲等。你可能会觉得，这跟脂肪肝有什么关系？但研究发现，抗阻运动对脂肪肝的改善效果同样显著，甚至在某些方面可能更具优势。同上述研究提到，有效的抗阻运动方案是每次45分钟，每周3次，持续12周，运动强度为3.5代谢当量（METs） 44。更重要的是，相比有氧运动，抗阻运动在达到同样改善肝脏脂肪效果的同时，能量消耗却显著更低 44。这意味着，对于那些心肺功能较差、不能耐受长时间有氧运动的脂肪肝患者来说，抗阻运动可能是一个更可行、更轻松的选择 44。
为什么抗阻运动也如此重要？因为肌肉是身体代谢葡萄糖和脂肪的重要场所。肌肉量减少（医学上称为“肌肉减少症”或“肌少症”）与脂肪肝的发生发展密切相关 4546。肌少症会加剧胰岛素抵抗、全身炎症和氧化应激，这些都会进一步恶化脂肪肝 46。通过抗阻运动增加肌肉力量和质量，可以改善胰岛素敏感性，促进脂肪酸氧化，从而减轻肝脏负担 46。因此，抗阻运动就像是给肝脏的“代谢发动机”提供了一个强劲的“助推器”。
“周末战士”模式：集中运动同样有效
“周末战士”（Weekend Warrior）指的是那些平时工作忙碌，只能在周末集中时间进行运动的人。过去，人们总认为只有规律的、每天或隔天进行的运动才能带来健康益处。然而，一项令人振奋的2025年最新研究打破了这一传统观念！
这项对美国全国健康和营养检查调查（NHANES）数据进行的队列研究发现，无论是“周末战士”模式（即每周超过150分钟的中等至剧烈身体活动，且其中至少50%集中在1-2天内完成），还是传统意义上的“规律运动”模式（同样是每周超过150分钟的中等至剧烈身体活动，但分散在多天进行），都能显著降低代谢功能障碍相关脂肪性肝病（MASLD）的患病风险和全因死亡率 47。研究结果显示，“周末战士”组患MASLD的几率比不运动者低约64%，而规律运动组则低约53% 47。对于已经患有MASLD的患者，无论是“周末战士”还是规律运动，都能将全因死亡风险降低约52%到65% 47。
这项研究的重要意义在于，它给了很多人一个坚持运动的理由和信心。即使你平时工作繁忙，无法每天抽出时间运动，只要能在周末集中进行足够的身体活动，同样可以为肝脏健康提供强大的保护。
具体的运动时长与强度建议
那么，到底应该运动多久、达到什么强度才算“够格”呢？
- 总时长：指南普遍建议，每周至少进行150分钟中等强度的有氧运动，或者75分钟高强度的有氧运动，或者等量的有氧和抗阻运动结合 47。
- 强度：
- 中等强度：运动时心跳加快，呼吸急促，但仍能进行简单的对话。比如快走、慢跑、骑自行车。
- 高强度：运动时心跳显著加快，呼吸非常急促，难以进行完整的对话。比如跑步、游泳、高强度间歇训练（HIIT）。
- 运动方式结合：理想情况下，将有氧运动和抗阻运动结合起来，能够获得最全面的健康益处。例如，每周进行3次有氧运动，并穿插2-3次抗阻运动，每次持续30-60分钟。
- 循序渐进：对于长期不运动的人来说，刚开始不宜追求高强度，应从低强度、短时间开始，逐渐增加运动量和强度。例如，每天散步10-15分钟，逐渐延长至30分钟，再尝试快走或慢跑。
重要的是，动起来总比不动好。即使每天只是增加几千步的走路步数，也能显著降低脂肪肝的风险 48。一项2025年的队列研究也强调，每天运动、戒酒、不吸烟和低盐饮食等健康生活方式的严格组合，可以将MASLD的风险降低90%以上 49。因此，无论选择哪种运动方式，关键在于持之以恒，让运动成为生活的一部分。记住，你不是为了“治病”而运动，而是为了让肝脏和整个身体恢复活力！
3.3 睡眠与压力管理：被忽视的代谢调控开关
在讨论脂肪肝的逆转时，我们常常关注饮食和运动，但往往会忽略另外两个同样重要的“幕后推手”——睡眠和压力。它们就像我们身体的“总开关”，如果调节不好，即使吃得再健康、动得再多，肝脏的代谢也可能出现故障。
1. 阻塞性睡眠呼吸暂停（OSA）与脂肪肝的“夜间联盟”
你可能想不到，晚上睡觉打呼噜，甚至出现呼吸暂停，竟然会和脂肪肝扯上关系。阻塞性睡眠呼吸暂停（Obstructive Sleep Apnea, OSA） 是一种常见的睡眠障碍，患者在睡眠期间会反复出现上气道塌陷，导致呼吸暂停或气流减少，从而引起间歇性缺氧。想象一下，你的肝脏在晚上也无法安稳地“休息”，而是反复经历“窒息”和“苏醒”，这会给它带来巨大的负担。
多项研究证实，OSA与脂肪肝（无论是NAFLD还是MASLD）之间存在密切关联，即使在排除了肥胖、代谢综合征等常见共病的情况下，OSA患者患脂肪肝的风险也更高，且OSA的严重程度与脂肪肝的严重程度呈正相关 50。这种关联的机制很复杂，主要包括：
- 间歇性缺氧：OSA导致反复的缺氧再灌注，这会激活体内的炎症反应和氧化应激，损害肝细胞，促进肝脏脂肪堆积和纤维化。
- 胰岛素抵抗：间歇性缺氧会加重全身的胰岛素抵抗，使得细胞对胰岛素的敏感性降低，血糖和脂肪更容易在肝脏堆积。
- 交感神经系统过度激活：OSA会使得交感神经系统在夜间持续兴奋，导致身体处于“应激”状态，影响正常的代谢调节。
- 睡眠碎片化：OSA导致睡眠结构紊乱，深睡眠不足，这会影响生长激素、皮质醇等激素的分泌，进一步干扰脂肪和糖的代谢。
CPAP治疗：让肝脏“呼吸顺畅”
幸运的是，对于OSA引起的脂肪肝，我们并非束手无策。持续气道正压通气（Continuous Positive Airway Pressure, CPAP） 治疗是OSA最有效的治疗方法之一。CPAP通过一个面罩在睡眠时提供持续的气压，将塌陷的上气道撑开，确保呼吸道通畅。这就像给呼吸道搭建了一个“支架”，让患者在夜间能够顺畅呼吸，避免了间歇性缺氧。
早期研究就发现，CPAP治疗可以通过改善缺氧，进而改善OSA患者的代谢紊乱，包括胰岛素抵抗和脂质代谢异常 51。一项2025年的临床研究进一步证实了CPAP治疗对于逆转肝脏脂肪的潜力。这项研究将OSA合并NAFLD的患者分为两组，一组接受CPAP治疗，另一组则不进行治疗。结果发现，接受CPAP治疗的患者，其肝脏脂肪含量显著下降，肝功能酶指标（如转氨酶）也有所改善。研究人员推测，这主要是因为CPAP消除了夜间间歇性缺氧，减轻了肝脏的炎症反应和氧化应激，使得肝脏有机会进行自我修复，从而逆转脂肪堆积。
这项研究强调了在脂肪肝患者中筛查和治疗OSA的重要性。如果你有打鼾、白天嗜睡、疲劳等症状，建议及时就医进行睡眠呼吸监测，看看是否存在OSA。
2. 压力管理：给身体“减负”，给肝脏“松绑”
现代社会，压力无处不在。工作、生活、人际关系……各种压力源就像无形的“重担”，压得我们喘不过气。你也许会问，压力跟脂肪肝有什么关系？答案是：关系非常大！
当身体承受压力时，会分泌一系列应激激素，其中最重要的就是皮质醇。皮质醇被誉为“压力激素”，它在短期内有助于我们应对紧急情况，但如果长期处于高压状态，皮质醇水平居高不下，就会对身体造成负面影响：
- 促进脂肪堆积：高水平的皮质醇会促进脂肪在腹部（内脏脂肪）和肝脏的堆积，还会增加食欲，尤其是对高糖、高脂肪食物的渴望，形成恶性循环。
- 加重胰岛素抵抗：皮质醇会升高血糖，并导致细胞对胰岛素的敏感性下降，加重胰岛素抵抗。
- 引发炎症：长期慢性压力还会引起全身性的低度炎症反应，这与脂肪肝的进展密切相关。
一项2024年发表的针对中国女性护士的队列研究发现，职业压力水平持续增加的群体，其患MASLD的风险显著升高（调整后的风险比高达3.14） 52。这表明，长期慢性压力确实是脂肪肝的一个独立风险因素，而且这种影响不因年龄或体重指数而改变。
如何有效进行压力管理？
压力管理并非一蹴而就，它需要我们学习和实践一系列方法，给身心“减负”：
- 规律作息，保证充足睡眠：除了治疗OSA，即使没有睡眠障碍，保证每晚7-9小时的高质量睡眠，也能有效降低皮质醇水平，让身体得到充分休息和修复。
- 放松技巧：尝试冥想、深呼吸练习、瑜伽等放松技巧，这些方法能帮助你激活副交感神经系统，降低应激反应。
- 适度运动：运动是天然的减压剂，它可以帮助身体释放内啡肽，改善情绪，降低压力激素水平。
- 培养爱好，社交互动：做自己喜欢的事情，与朋友家人保持联系，可以有效分散注意力，减轻心理负担。
- 寻求专业帮助：如果压力过大，难以自行调节，不要害怕寻求心理咨询师或医生的帮助。
一项2025年的研究评估了一种基于“健康行动过程方法（HAPA）”的病例管理模式，该模式包含了压力管理策略。结果显示，接受这种管理模式的MASLD患者，不仅肝功能、血脂和体重指数都有显著改善，而且他们在压力管理、运动和饮食等健康行为方面的得分也更高 53。这再次印证了压力管理在脂肪肝逆转中的重要作用。
总之，睡眠和压力管理是脂肪肝逆转策略中不可或缺的两环。只有关注身体的整体平衡，才能真正为肝脏提供一个健康的内部环境，让它从“疲惫不堪”中恢复过来，重新充满活力。
4. 药物治疗：从“无药可用”到“精准靶向”的突破
曾几何时，脂肪肝，尤其是发展到脂肪性肝炎（MASH）阶段，被认为是“无药可治”的。医生们能做的，多半是建议患者改变生活方式。这就像面对一个火情，却只能让大家自己泼水救火，缺少专业的消防设备。然而，随着科学研究的深入，这一局面正在被彻底改写。得益于对疾病机制的深刻理解，我们正迎来一个“精准靶向”的药物治疗新时代，各种新型药物如雨后春笋般涌现，为脂肪肝的逆转带来了前所未有的希望。
4.1 首个获批药物：甲状腺激素受体β激动剂（resmetirom）
2024年3月，美国食品药品监督管理局（FDA）批准了resmetirom（商品名Rezdiffra™）用于治疗伴有中度至重度肝纤维化（F2至F3期）的非肝硬化MASH成人患者，这标志着人类在MASH药物治疗领域取得了里程碑式的突破 545556。这是历史上第一个被FDA批准用于治疗MASH的药物，为那些饱受MASH困扰的患者带来了真正的希望。
1. 作用机制：给肝脏“加油”和“灭火”
resmetirom是一种口服的、肝脏靶向的甲状腺激素受体β（THR-β）激动剂 5457。这听起来有点复杂，我们来简单解释一下：
- 甲状腺激素与肝脏：我们的身体内有一种重要的内分泌腺体——甲状腺，它分泌的甲状腺激素对身体的新陈代谢起着至关重要的作用。肝脏是甲状腺激素作用的主要靶器官之一，肝细胞表面有大量的甲状腺激素受体，其中THR-β受体在肝脏中含量最高，对肝脏的脂肪代谢、胆固醇代谢和能量消耗有显著影响 565859。
- “精准靶向”肝脏：resmetirom的特别之处在于，它具有高度的肝脏选择性 5657。这意味着它主要作用于肝脏中的THR-β受体，而对身体其他部位（如心脏、骨骼）的影响较小，从而最大限度地减少了全身性的副作用。这就像一把“精准制导的导弹”，只打击肝脏这个“目标”，而不会误伤其他“友军”。
- “加油”：促进脂肪氧化：resmetirom通过激活肝脏中的THR-β受体，能够“命令”肝脏提高脂肪的“燃烧”效率，也就是促进脂肪酸氧化 58。这就像给肝脏的“发电厂”加足了燃料，让它开足马力把堆积的脂肪转化成能量消耗掉，从而减少肝脏脂肪的堆积 575960616263。
- “灭火”：缓解炎症和纤维化：除了减少脂肪，resmetirom还能在肝脏中发挥抗炎和抗纤维化作用 5758。它能像“消防员”一样，扑灭肝脏的炎症反应，并抑制肝星状细胞的活化，从而减缓或逆转肝纤维化的进程。
2. 临床试验数据：疗效显著，希望可期
resmetirom的批准是基于其在多项3期临床试验中令人信服的疗效数据，尤其是MAESTRO-NASH研究 6465。这项研究纳入了近千名经活检确诊为MASH且伴有中度至重度肝纤维化（F1B、F2或F3期）的成人患者。患者被随机分为三组，分别接受80mg、100mg剂量的resmetirom或安慰剂，每日一次，持续52周 64。
主要结果显示，与安慰剂组相比，resmetirom组在以下两个关键指标上取得了显著改善 64：
- MASH缓解率：在不恶化肝纤维化的情况下，80mg resmetirom组有25.9%的患者MASH得到缓解，100mg resmetirom组有29.9%的患者MASH得到缓解，而安慰剂组仅为9.7%（P<0.001）。这意味着，将近三分之一的患者，其肝脏的炎症和损伤得到了显著改善。
- 肝纤维化改善率：在不恶化MASH活动评分的情况下，80mg resmetirom组有24.2%的患者肝纤维化至少改善一个阶段，100mg resmetirom组有25.9%的患者肝纤维化至少改善一个阶段，而安慰剂组仅为14.2%（P<0.001）。这表明resmetirom能够有效阻止甚至逆转肝纤维化的进展，这对于预防肝硬化具有里程碑式的意义。
除了肝脏组织学上的改善，resmetirom还表现出其他积极作用：
- 改善脂质代谢：resmetirom能够显著降低低密度脂蛋白胆固醇（LDL-C）水平。与安慰剂组相比，resmetirom 80mg组的LDL-C降低了13.6%，100mg组降低了16.3% 576264。这对于MASH患者而言尤为重要，因为他们往往伴有血脂异常，心血管疾病风险较高 66。
- 降低肝脏脂肪含量：核磁共振（MRI-PDFF）检测显示，resmetirom能显著减少肝脏脂肪含量，降低幅度达19.23% 6263。
3. 适用人群与副作用管理：并非人人适用，需权衡利弊
尽管resmetirom带来了巨大的希望，但它并非适用于所有脂肪肝患者。根据FDA的批准，resmetirom主要用于非肝硬化MASH伴有中度至重度肝纤维化（F2至F3期）的成人患者 54555657。这意味着，对于单纯性脂肪肝（F0-F1期纤维化）或已经发展到肝硬化阶段（F4期纤维化）的患者，目前并不推荐使用。
关于副作用，resmetirom的安全性数据总体良好。最常见的副作用是腹泻和恶心，在resmetirom组中发生率高于安慰剂组 59606264。这些胃肠道反应通常是轻度或中度的，并且随着治疗的进行可能会减轻。此外，没有发现严重的副作用在各组之间有显著差异 6064。
在用药过程中，患者需要定期监测肝功能、甲状腺功能等指标。由于resmetirom可能与其他药物发生相互作用，因此在服用前必须告知医生所有正在使用的药物，并在医生的指导下进行治疗。
总而言之，resmetirom的获批是MASH治疗领域的一个重要里程碑，它为那些面临肝脏疾病进展风险的患者提供了一种有效的治疗选择。然而，药物治疗并非万能，它应该与生活方式干预相结合，并在专业医生的指导下进行，才能发挥最大的疗效。
4.2 明星药物：GLP-1受体激动剂（司美格鲁肽）的“多效性”
如果说resmetirom是MASH治疗领域的第一颗“启明星”，那么另一类“明星药物”——GLP-1受体激动剂，则以其“多效性”在脂肪肝治疗中大放异彩，尤其是司美格鲁肽（semaglutide），更是备受瞩目。这款药物最初是为治疗2型糖尿病和肥胖而开发的，但研究发现，它在改善脂肪肝方面也展现出了惊人的潜力，简直是“一药多用”。
1. 3期临床试验核心数据：惊艳的“多重效果”
司美格鲁肽在治疗MASH方面最令人振奋的数据，来自于其大规模的3期临床试验（ESSENCE试验，NCT04822181）。这项研究纳入了1197名经活检证实患有MASH且伴有2期或3期肝纤维化的患者。患者被随机分配，每周一次皮下注射2.4 mg司美格鲁肽或安慰剂。在72周的中期分析结果显示出以下几个核心亮点 67：
- 脂肪性肝炎缓解率：在不加重肝纤维化的情况下，62.9%的司美格鲁肽治疗组患者实现了脂肪性肝炎的缓解，而安慰剂组仅为34.3% 67。这意味着，超过一半的患者肝脏炎症和损伤得到了显著改善，几乎是安慰剂组的两倍。
- 肝纤维化改善率：在不加重脂肪性肝炎的情况下，司美格鲁肽组有36.8%的患者实现了肝纤维化程度的减轻，而安慰剂组为22.4% 67。虽然纤维化改善的比例低于MASH缓解，但对于这种进展性疾病而言，能有超过三分之一的患者看到纤维化改善，无疑是巨大的进步。
- 体重下降效果：司美格鲁肽组患者的平均体重下降了10.5%，而安慰剂组仅下降了2.0% 67。显著的体重减轻，是司美格鲁肽改善脂肪肝的重要原因之一。
这些数据表明，司美格鲁肽不仅能有效缓解脂肪性肝炎，还能在一定程度上改善肝纤维化，并且伴随着显著的体重减轻。
2. “多途径”作用机制：为何司美格鲁肽如此有效？
司美格鲁肽之所以能在脂肪肝治疗中发挥如此强大的作用，并非单一机制，而是通过多条途径协同作战，就像一个“多面手” 68：
强效减重：釜底抽薪
司美格鲁肽作为GLP-1受体激动剂，最广为人知的功能就是减重。它能作用于大脑的食欲中枢，增加饱腹感，减少食物摄入，从而降低总体热量摄入 68。体重减轻是改善脂肪肝最直接有效的方法。每减重5-10%，就能显著减少肝脏脂肪含量；如果减重超过10%，甚至可以逆转脂肪性肝炎和纤维化。司美格鲁肽通过帮助患者减轻体重，从根本上减少了肝脏脂肪的“输入”来源，实现了“釜底抽薪”的效果。
改善胰岛素抵抗：疏通代谢通路
胰岛素抵抗是脂肪肝发生发展的核心因素。司美格鲁肽能促进胰腺分泌胰岛素，同时提高胰岛素的敏感性，从而改善血糖控制 68。当胰岛素抵抗得到改善后，脂肪细胞释放到肝脏的脂肪酸会减少，肝脏从头合成脂肪的能力也会下降，同时肝脏对脂肪的氧化分解效率也会提高。这就像疏通了堵塞的代谢通路，让肝脏的脂肪“收支平衡”重新回到正轨。
调节肠道菌群：优化“第二基因组”
近年来，肠道菌群与肝脏健康的关系越来越受到关注。肠道菌群失调（肠道微生态失衡）会导致肠道屏障功能受损，使得细菌产物（如内毒素）进入血液，随门静脉系统到达肝脏，引发肝脏炎症。司美格鲁肽被发现能积极影响肠道菌群的组成，促进有益菌的生长，减少有害菌，从而改善肠道屏障功能，减少炎症因子进入肝脏，间接减轻肝脏炎症和脂肪堆积 6869。
直接抗炎与抗纤维化（间接作用）
虽然肝脏细胞本身GLP-1受体表达较少，司美格鲁肽对肝脏的作用主要是通过上述间接机制实现的 68。但它也能通过减少全身炎症标志物（如高敏C反应蛋白）和改善脂质代谢来减轻肝脏炎症 70。一些研究提示，GLP-1受体激动剂可能通过减少促炎巨噬细胞的积累，以及影响胆汁酸代谢等途径，发挥抗炎和抗纤维化的作用 69。
值得注意的是，尽管司美格鲁肽在改善MASH方面表现出色，但它并非没有副作用。最常见的是胃肠道不适，如恶心、呕吐、腹泻和便秘，这些症状通常在治疗初期出现，随着时间推移会减轻 6771。此外，有报道称其可能增加胆囊疾病（如胆结石）的风险 71。
总而言之，司美格鲁肽凭借其多重作用机制，在脂肪肝治疗中扮演了越来越重要的角色。它的出现，为那些伴有肥胖和2型糖尿病的MASH患者提供了一个非常有前景的治疗选择。然而，正如所有药物一样，使用前仍需医生评估，并权衡其利弊。
4.3 在研新药：从“单一靶点”到“联合通路”
随着对脂肪肝发病机制的深入理解，药物研发正从过去依赖单一靶点，逐步迈向探索“联合通路”的多靶点干预策略。目前，除了已经获批和表现亮眼的GLP-1受体激动剂外，还有一大批针对不同环节的新型药物正在研发中，它们就像是瞄准了肝脏脂肪代谢“工厂”中各个关键岗位的“专业工人”，力求通过多方位协同作战，更有效地逆转脂肪肝。
1. 脂肪酸合成酶抑制剂：切断肝脏的“自产自销”
前面我们提到，肝脏会自己“生产”脂肪，这个过程叫做“从头合成脂肪”（DNL），而脂肪酸合成酶（FASN）就是这条“生产线”上的关键酶，负责将小分子转化成脂肪酸。可想而知，如果能抑制FASN的活性，就能从源头上减少肝脏脂肪的堆积。
- 作用机制：FASN抑制剂就像是给肝脏的“脂肪生产线”按下了暂停键。通过直接抑制FASN的活性，减少脂肪酸的合成，从而降低肝脏甘油三酯的含量。
- 研究进展：
- 一项2025年的研究发现，O-GlcNAcylation（一种细胞内重要的蛋白质修饰过程）在NAFLD的发生发展中扮演了重要角色。研究显示，FASN的O-GlcNAcylation水平与NAFLD患者的肝脏脂肪合成呈正相关。通过抑制负责O-GlcNAcylation的酶（OGT），可以促进FASN的降解，从而减少肝脏脂肪堆积。这为开发针对O-GlcNAcylation途径的FASN抑制剂提供了新思路 7273。
- 此外，还有研究发现，排序接合蛋白8（SNX8）能够与FASN结合，并促进FASN的泛素化降解（可以理解为给FASN打上“销毁”标记），从而抑制肝脏脂肪堆积。在缺乏SNX8的小鼠中，肝脏脂肪堆积和脂质生成途径会显著加重。因此，靶向SNX8-FASN轴，增强SNX8的活性，也是治疗NAFLD的一个有前景的策略 74。
2. FMO2激活剂：疏通脂肪代谢的“排污管道”
黄素单加氧酶2（FMO2）是一个相对较新的靶点。它被发现对脂肪肝有保护作用，就像是肝脏里一个重要的“管道工人”，负责疏通某些代谢“排污管道”，防止脂肪堵塞。
- 作用机制：FMO2通过与固醇调节元件结合蛋白1（SREBP1）直接结合，抑制SREBP1从内质网向高尔基体的转运和后续激活。SREBP1是调控脂肪合成的关键转录因子，它的激活会导致脂肪合成基因表达增加。因此，FMO2通过抑制SREBP1，来减少肝脏从头合成脂肪。
- 研究进展：一项2025年的研究发现，在NAFL/NASH患者和动物模型中，FMO2的表达显著下调。敲除FMO2会导致脂肪生成增加，加重肝脏脂肪变性、炎症和纤维化；而过表达FMO2则能改善这些症状。这表明，FMO2激活剂有望成为治疗MASLD的新药物 75。
3. ATGL抑制剂：精细调控肝脏脂肪的“进出大门”
脂肪甘油三酯脂肪酶（ATGL）是细胞内甘油三酯水解的关键酶，它负责将储存的甘油三酯分解成脂肪酸，供细胞利用或释放到血液中。过去，人们认为抑制ATGL可能有助于减少脂肪酸释放，从而改善胰岛素抵抗。然而，最新的研究却揭示了ATGL在MASLD中更复杂的角色。
- 作用机制：一项2024-2025年的研究指出，抑制ATGL可以减轻代谢功能障碍相关脂肪性肝炎（MASH）。该研究发现，ATGL抑制剂（如atglistatin，一种针对鼠类ATGL的抑制剂 7677，以及人源ATGL抑制剂NG-497 76）能通过以下几种方式发挥作用：
- 改善肝脏脂质代谢：减少肝脏甘油三酯含量。
- 调节胆汁酸组成：抑制ATGL可以减弱PPARα信号通路，使得肝脏产生更多亲水性胆汁酸。亲水性胆汁酸有助于降低胆固醇在肝脏中的积累，并改善胆汁流动。
- 干扰膳食脂质吸收：通过调节肠道脂质转运蛋白（如降低Cd36和Abca1，增加Abcg5），ATGL抑制剂能够减少膳食脂肪的吸收，从而减轻肝脏负担。
- 临床意义：虽然atglistatin本身不能用于人类，但人源ATGL抑制剂NG-497的发现，为开发能够有效改善MASH的新型药物提供了新的方向 76。这提示我们，未来可能通过精细调控ATGL的活性，来优化肝脏脂肪的“进出大门”。
4. USP29-ACSL5轴：促进脂肪的“高效燃烧”
泛素特异性肽酶29（USP29）是一个能够“稳定”某些蛋白的“修理工”。它与长链酰基辅酶A合成酶5（ACSL5）形成了新的调控轴，共同影响肝脏脂肪的“燃烧”效率。
- 作用机制：USP29通过去除ACSL5上的K48连接泛素（一个“销毁”标记），从而稳定ACSL5蛋白，防止其被降解。ACSL5在脂肪酸β-氧化（即脂肪燃烧）中发挥关键作用。当USP29激活时，ACSL5变得更稳定，从而促进肝脏脂肪酸的有效燃烧，减少脂肪堆积。
- 研究进展：一项2025年的研究表明，MASLD患者肝脏中的USP29蛋白水平显著降低。敲除USP29会加重肝脏脂肪变性、炎症和纤维化，而过表达USP29则能缓解这些病症。这项研究揭示了USP29-ACSL5轴在MASLD发生发展中的重要作用，并提出激活这一轴可能成为治疗MASLD的潜在策略 78。
5. 其他在研药物：多靶点协同，未来可期
除了上述药物，还有许多新型药物正在积极研发中，它们通过各种独特的机制来对抗脂肪肝：
- GPR31抑制剂：一项2025年的研究发现，G蛋白偶联受体31（GPR31）是MASH的关键驱动因素和潜在药物靶点。GPR31的肝脏特异性缺失可以有效阻断饮食诱导小鼠模型中的肝脏脂毒性和纤维化。研究人员还开发了一种小分子抑制剂G4451，能够特异性抑制GPR31-Gαi3的相互作用，并在临床前模型中有效阻止MASH进展 79。
- 二甲双胍与小檗碱联合用药：一项2025年的研究发现，二甲双胍（Metformin）和小檗碱（Berberine）联合使用，可以通过激活AMPK-SREBP1-FASN信号通路，协同改善NAFLD。这种联合疗法在抑制体重增加、减少内脏脂肪、改善胰岛素敏感性以及减轻肝脏脂肪变性和炎症方面，比单独用药效果更显著 80。
- FGF-21类似物与Pan-PPAR激动剂：一项2024年进行的系统综述和网络荟萃分析，比较了甲状腺激素受体β（THR-β）激动剂、成纤维细胞生长因子21（FGF-21）类似物、GLP-1R激动剂、GLP-1多靶点激动剂和泛过氧化物酶体增殖物激活受体（Pan-PPAR）激动剂在治疗MASLD中的疗效。结果显示，FGF-21类似物在改善肝脏脂肪和抗纤维化方面效果显著。Pan-PPAR激动剂则在改善肝功能和葡萄糖代谢方面表现出独特优势 81。
这些在研新药的出现，预示着脂肪肝的治疗将走向“联合治疗”的时代 828384。由于脂肪肝的病因复杂，涉及多个代谢通路，单一药物可能难以完全解决问题。未来的治疗方案可能不再是“一招鲜”，而是根据患者的具体情况，采取多种药物联合，甚至结合生活方式干预的“多靶点”组合拳，从而实现更彻底、更全面的逆转 8586。
5. 进阶干预：手术与肠道菌群调节的潜力
5.1 代谢手术：重度肥胖患者的“强效逆转”选择
对于那些体重严重超标（重度肥胖），并且通过严格的饮食和运动干预仍然效果不佳的脂肪肝患者来说，代谢手术（Metabolic Surgery），也就是我们常说的“减肥手术”，提供了一个“强效逆转”的选择。这不是简单的“抽脂”，而是通过改变胃肠道的结构来限制食物摄入、减少营养吸收，从而达到显著且持久的减重效果。令人惊喜的是，这些手术在帮助患者摆脱肥胖的同时，也常常能奇迹般地逆转脂肪肝，甚至是最严重的脂肪性肝炎（MASH）和早期肝硬化。
1. 胃旁路术、袖状胃切除术：脂肪肝逆转的“双雄”
目前临床上最常见的代谢手术主要有两种：
- Roux-en-Y胃旁路术（Roux-en-Y Gastric Bypass, RYGB）：这是一种复杂的手术，通过将胃分成小胃囊，并连接到小肠的一段，从而限制食物摄入量，并使食物绕过部分小肠，减少吸收。
- 袖状胃切除术（Sleeve Gastrectomy, SG）：这种手术相对简单，是将大部分胃切除，只留下一个像“袖子”一样的胃管，大大减小了胃的容量。这也是目前最常用的减肥手术，特别是在美国，超过三分之二的减肥手术是袖状胃切除术 87。
这两种手术都能导致显著的体重减轻，而体重减轻是改善脂肪肝最关键的因素之一。多项研究证实，代谢手术能够显著改善甚至逆转脂肪肝的各项指标：
- 脂肪变性（肝脏脂肪堆积）：几乎所有接受代谢手术的患者，其肝脏脂肪含量都会大幅度减少，甚至完全消失。一项2015年的研究就指出，在接受袖状胃切除术的肥胖患者中，术后肝脏脂肪变性几乎完全消失，即使是术前有严重脂肪肝的患者也是如此 88。
- 脂肪性肝炎（MASH）：对于已经发展到MASH的患者，代谢手术也展现出强大的逆转能力。一项针对180名经活检确诊为NASH的重度肥胖患者的长期随访研究显示，在接受代谢手术5年后，84%的患者实现了NASH的缓解，且肝纤维化没有恶化 89。这意味着绝大多数患者的肝脏炎症和损伤都得到了显著改善。
- 肝纤维化：更令人鼓舞的是，代谢手术不仅能缓解炎症，还能改善肝纤维化。上述研究发现，5年后有70.2%的患者肝纤维化程度下降，其中56%的患者肝纤维化完全消失 89。这对于预防肝硬化的发生至关重要。甚至有研究表明，对于伴有代偿期MASH相关肝硬化的患者，代谢手术可以降低主要不良肝脏事件（MALO）的风险，并降低失代偿期肝硬化的累积发生率 90。
- 肝硬化：即使是已经发展到代偿期肝硬化的MASH患者，代谢手术也被认为是一个有益的治疗选择，虽然风险较高，但能在严格评估下带来肝功能改善的潜力 91。一项2025年发表在《自然医学》上的观察性研究显示，对于肥胖且伴有代偿期MASH相关肝硬化的患者，代谢手术组在15年内的主要不良肝脏事件（MALO）累积发生率为20.9%，显著低于非手术组的46.4% 90。这表明代谢手术能够显著降低肝硬化患者的肝脏并发症风险。
2. 机制解析：为何代谢手术如此“强效”？
代谢手术之所以能带来如此显著的改善，其机制是多方面的：
- 显著且持久的体重减轻：这是最直接也最重要的原因。当身体总脂肪量减少时，肝脏的脂肪负担自然会减轻 92。
- 改善胰岛素抵抗：代谢手术能显著改善全身和肝脏的胰岛素敏感性，降低血糖和胰岛素水平，从而减少肝脏脂肪的合成 93。
- 改变肠道菌群：手术改变了肠道解剖结构，可能进而影响肠道菌群的组成和功能，减轻炎症 94。
- 调节肠道激素：代谢手术会改变肠道激素（如GLP-1、PYY等）的分泌，这些激素在食欲控制、胰岛素分泌和能量代谢中发挥重要作用，有助于改善代谢紊乱。
- TREM2巨噬细胞的参与：一项2024年的研究发现，代谢手术（如袖状胃切除术）通过激活肝脏中的TREM2阳性巨噬细胞，来发挥改善MASH的作用。这些巨噬细胞能够抑制炎症并增强其吞噬功能，促进MASH的消退。有趣的是，研究表明这种改善MASH的作用是独立于体重减轻的，提示代谢手术可能还存在其他免疫调节机制 95。
3. 适用人群与风险
虽然代谢手术效果显著，但它毕竟是一种有创手术，并非适用于所有脂肪肝患者。通常，代谢手术主要推荐给：
- 重度肥胖患者，或伴有至少一种肥胖相关并发症（如2型糖尿病、高血压、严重睡眠呼吸暂停等）的肥胖患者 87。
- 在非手术治疗（饮食、运动、药物）失败后。
- 心理评估合格，能够配合术后长期管理。
手术的风险包括术后并发症（如出血、感染、吻合口漏、营养不良等）和长期副作用 87。因此，患者在决定接受代谢手术前，需要由多学科团队进行全面评估，权衡利弊。尽管有风险，但对于适合的患者，代谢手术能显著改善多种肥胖相关疾病，并延长寿命 9697。
总而言之，对于重度肥胖且脂肪肝严重的患者，代谢手术无疑是一把“利器”，能够带来强效且持久的逆转效果，帮助他们摆脱脂肪肝的困扰，重获健康。
5.2 肠道菌群：“第二基因组”如何影响肝脏健康
你可能想不到，在我们身体里，住着上万亿个“小伙伴”，它们主要集中在肠道里，形成了一个庞大的微生物群落，我们称之为“肠道菌群”。这个菌群的基因数量甚至比我们人类自身的基因还要多，所以它也被形象地称为我们的“第二基因组”。这些“小伙伴”可不是吃白饭的，它们通过与我们身体的互动，深刻地影响着我们的健康，其中就包括肝脏的健康 9899。
近年来，科学家们发现，肠道菌群的平衡与否，与脂肪肝的发生发展密切相关 98100101。当肠道菌群失调，原本和谐共处的“小伙伴”们发生了“内讧”，一些有害菌增多，有益菌减少，就会给肝脏带来一系列麻烦，这被称为“肠-肝轴”的失衡。
1. 肠道菌群失调与脂肪肝的关联机制
肠道菌群影响肝脏健康主要通过以下几个途径：
“门户洞开”：肠道屏障功能受损与内毒素血症
健康的肠道就像一道严密的“城墙”，只允许有用的营养物质通过，阻挡有害物质进入血液。但当肠道菌群失调时，这道“城墙”的防御力就会下降，出现“漏肠”现象，医学上称为肠道通透性增加 102。
肠道屏障一旦受损，肠道内的细菌及其代谢产物（特别是来自革兰氏阴性菌的脂多糖，LPS，又称内毒素）就会穿过受损的肠壁，进入血液，并通过门静脉系统直接抵达肝脏 98102103。肝脏是身体的“解毒工厂”，当大量内毒素涌入时，肝脏的免疫细胞（如库普弗细胞）会识别这些“入侵者”，并启动强烈的炎症反应。这种慢性炎症正是脂肪肝从单纯性脂肪堆积发展为脂肪性肝炎（MASH）的关键驱动因素 98100101102。因此，肠道屏障受损和随之而来的内毒素血症，是肠道菌群影响肝脏健康的一个重要环节。
“能量失衡”：短链脂肪酸（SCFAs）代谢异常
肠道菌群中的有益菌，尤其是定植在结肠的细菌，能够发酵膳食纤维等无法消化的碳水化合物，产生一系列重要的代谢产物，其中最主要的就是短链脂肪酸（Short-Chain Fatty Acids, SCFAs），包括乙酸、丙酸和丁酸 104105。SCFAs对人体健康有很多益处，比如它们是肠道细胞的重要能量来源，有助于维持肠道屏障的完整性；它们还能通过多种途径影响宿主的能量代谢、葡萄糖稳态和炎症反应 104105。
然而，在脂肪肝患者中，SCFAs的产生常常出现异常。一些研究发现，脂肪肝患者肠道中的SCFAs水平可能下降，这可能导致肠道屏障功能进一步受损，炎症加剧 104。但也有研究指出，某些情况下，肠道菌群产生的过多SCFAs可能反而促进脂肪肝，因为它们能作为能量来源被肝脏利用，并转化为脂肪 106。这说明SCFAs在脂肪肝中的作用机制比较复杂，可能与具体的SCFAs种类、浓度以及个体代谢状况有关。关键在于维持SCFAs的平衡和有益菌的优势地位。
“化学工厂”失控：胆汁酸、氨基酸等代谢产物紊乱
肠道菌群还参与调节胆汁酸、氨基酸、胆碱等多种重要代谢产物的循环和代谢 101103104。例如，胆汁酸在肝脏中合成，然后进入肠道，肠道菌群会对其进行修饰和再循环。这些修饰后的胆汁酸会通过肠-肝循环回到肝脏，影响肝脏的脂质代谢和炎症反应 104107。在脂肪肝患者中，胆汁酸代谢常常发生紊乱，一些有益的次级胆汁酸（如3-琥珀酰胆酸，3-sucCA）水平下降，而这些胆汁酸被发现与肝脏损伤呈负相关，并且可以通过促进黏膜真杆菌（Akkermansia muciniphila）的生长来缓解MASH 107。
此外，肠道菌群也能代谢氨基酸，产生一些有害或有益的代谢产物。例如，细菌产生的过多乙醇，在一些脂肪肝患者中可能导致肝脏炎症 104106。
2. 益生菌与膳食纤维：调节菌群的最新证据
既然肠道菌群在脂肪肝中扮演了如此重要的角色，那么通过调节它来逆转脂肪肝，就成为了一个极具潜力的方向。
益生菌：肠道里的“好帮手”
益生菌是指对宿主健康有益的活的微生物。通过补充特定的益生菌，可以帮助恢复肠道菌群的平衡，从而改善脂肪肝 98101。
黏膜真杆菌（Akkermansia muciniphila，简称A. muciniphila）：这是近年来备受关注的一种明星益生菌。它以肠道黏液为食，有助于维持肠道屏障的完整性，减少内毒素的入侵 99108109110111。多项研究表明，补充A. muciniphila能够显著改善代谢功能障碍相关脂肪性肝病（MAFLD）的症状，包括肝脏脂肪变性、炎症和肝损伤 108109。一项2021年的研究发现，A. muciniphila能够通过调节肠-肝轴上L-天冬氨酸的代谢来改善MAFLD 109。另一项2023年的研究揭示，A. muciniphila能够通过调控TLR2激活的γδT17细胞和巨噬细胞极化，抑制非酒精性脂肪性肝炎（NASH）中的肝脏炎症 110。最新的2025年研究甚至发现，类胡萝卜素玉米赤霉素（torularhodin）能够通过促进A. muciniphila介导的腺苷钴胺素（adenosylcobalamin）代谢来缓解NAFLD，这进一步揭示了A. muciniphila在脂肪肝干预中的重要性 111。
Barnesiella intestinihominis：这是一种肠道共生菌，其丰度在2型糖尿病患者的粪便中显著降低。2024年的一项研究表明，口服这种活菌能显著改善高脂饮食诱导的2型糖尿病模型小鼠的血糖过高和肝脏代谢紊乱。研究还发现，该细菌产生的乙酸（一种SCFA）也具有类似的保护作用 112。鉴于2型糖尿病与脂肪肝的密切关联，这项发现也提示了该菌在脂肪肝干预中的潜力。
膳食纤维：益生菌的“口粮”
膳食纤维是益生菌最好的“口粮”，被称为“益生元”。通过增加膳食纤维的摄入，可以促进肠道内有益菌的生长和繁殖，从而间接改善肠道菌群的平衡 105113。一项2025年的研究指出，富茶（Fu brick tea）补充剂能够通过维持肠道稳态和重塑肝脏免疫微环境来缓解非酒精性脂肪肝及其相关的内毒素血症。富茶干预能显著改善高脂饮食诱导的肠道菌群失调，增加有益菌（如Blautia和Fusicatenibacter）的丰度，并抑制革兰氏阴性菌，从而促进短链脂肪酸和胆汁酸的产生，并减少脂多糖的水平 114。这再次强调了膳食纤维（作为益生元的来源）在调节肠道菌群、改善脂肪肝中的重要作用。
DI-GM指数：评估肠道菌群健康的新指标
为了更好地评估肠道菌群对宿主健康的影响，科学家们正在开发更精细的指标。例如，一种新的微生物衍生宿主相互作用指数（Diet-microbiota interaction-derived host-gut microbiome index, DI-GM index）可能被用于评估膳食纤维在调节菌群中的作用。通过监测肠道菌群的组成、功能以及它们产生的代谢产物，可以更精准地指导个性化的饮食干预方案，从而实现对脂肪肝更有效的管理。
总而言之，肠道菌群就像一个复杂而精密的“生物反应器”，其内部的“风吹草动”都会直接影响到肝脏的健康。通过补充有益菌（益生菌）和提供有益菌的“食物”（膳食纤维/益生元），我们可以重塑健康的肠道菌群，修复肠道屏障，减少有害物质对肝脏的侵扰，从而为脂肪肝的逆转提供强大的“内源性”支持。
6. 未来方向：从“逆转”到“预防”的精准医学
脂肪肝的治疗正在经历一场变革，我们不再满足于在疾病进展后进行干预，而是渴望能够更早地识别风险，更精准地进行干预，甚至在疾病发生之前就将其预防。这种从“逆转”到“预防”的理念转变，正是精准医学在脂肪肝领域应用的生动体现。未来的方向，将是利用最前沿的科学发现，找到那些能早期预警疾病、指导个性化治疗的“信号灯”和“开关”。
6.1 新兴靶点与生物标志物：早期识别与个性化治疗
想象一下，如果医生能通过简单的检查，就预知你患脂肪肝的风险有多高，或者你的脂肪肝会朝哪个方向发展，并据此为你量身定制治疗方案，那将是多么令人期待的未来。这正是“新兴靶点”和“生物标志物”研究所努力实现的目标。它们就像我们身体里隐藏的“密码”，一旦被破译，就能为脂肪肝的早期识别、风险预测和个性化治疗提供关键线索。
1. 基因靶点：解码脂肪肝的“遗传密码”
我们每个人的基因都是独一无二的，它们在很大程度上决定了我们对疾病的易感性。在脂肪肝领域，一些特定的基因变异已经被发现与疾病的发生、发展，甚至对治疗的反应密切相关。了解这些基因靶点，就能帮助我们识别高风险人群，并指导更精准的治疗。
FMO3：脂肪肝的“代谢守门员”
我们之前提到，肠道菌群与肝脏健康息息相关。有一种叫做三甲胺（TMA）的物质，是肠道菌群代谢某些食物（如红肉、鸡蛋中的胆碱和左旋肉碱）的产物。TMA本身无害，但它在肝脏中会被一种酶——黄素单加氧酶3（FMO3）转化成三甲胺-N-氧化物（TMAO）。而TMAO被认为与心血管疾病、糖尿病以及脂肪肝的发生发展有关。
一项2022年针对库尔德人群的研究发现，在NAFLD患者中，血液中TMAO水平显著升高，并且这种升高与FMO3基因的特定多态性（SNP -2177G>C的CC基因型）存在关联 115。这意味着，FMO3基因的某些变异可能会影响TMAO的代谢，进而影响脂肪肝的发生和进展。未来，通过检测FMO3基因的变异，我们或许能更早地评估一个人患脂肪肝的风险，并根据其基因型调整饮食，或者开发针对FMO3的药物来调节TMAO水平。
TM6SF2：肝脏脂肪的“内外平衡手”
跨膜6超家族成员2（TM6SF2）基因的变异，在脂肪肝研究中是另一个重要的发现。TM6SF2主要在肝脏表达，它在肝脏脂肪的储存和输出中扮演着关键角色。
当TM6SF2基因出现特定变异时，会影响肝脏的脂肪代谢，导致肝脏脂肪堆积增加，更容易发展成脂肪性肝炎和纤维化 116。然而，有趣的是，这种变异同时也与心血管疾病的风险降低相关，可能对心血管健康产生一定的保护作用 117。这揭示了TM6SF2在肝脏和心血管健康之间复杂的权衡关系。
最新的2025年研究发现，肝脏中的TM6SF2对代谢功能障碍相关脂肪性肝病（MASLD）具有保护作用，并能激活抗肿瘤免疫，抑制MASLD相关的肝细胞癌（HCC）的发生，并能增强免疫疗法的效果 118。这些遗传变异提高了对疾病风险的估计，并可指导靶向治疗的开发 119。TM6SF2在脂肪肝的发生和进展中发挥着关键作用，其基因变异被认为是NAFLD的主要共同遗传决定因素之一，对疾病进展有重要影响 120。
2. 新型生物标志物：血液中的“预警信号”
除了基因，我们还需要一些能够实时反映肝脏健康状况的“信号灯”，也就是生物标志物。传统的肝功能指标（如转氨酶）虽然常用，但敏感性不高，往往在肝脏损伤已经发生后才升高。因此，寻找更敏感、特异的生物标志物，对于脂肪肝的早期诊断和风险预测至关重要。
胆碱酯酶（ChE）：肝脏健康的“晴雨表”
血清胆碱酯酶（ChE）是一种由肝脏合成和分泌的酶，其水平可以反映肝脏的合成功能。一项2014年对5384人进行的横断面分析发现，血清ChE水平与脂肪肝和糖化血红蛋白（HbA1c）水平独立相关 121。研究显示，ChE水平会随着HbA1c的升高而显著增加，而脂肪肝（通过超声评分）的严重程度也与HbA1c水平呈正相关。这表明ChE不仅能反映肝脏功能，还可能与血糖代谢紊乱和脂肪肝的进展存在某种联系。未来的研究可能会进一步探索ChE作为早期诊断或预测脂肪肝预后的潜在价值。
尿酸累积量：代谢紊乱的“隐形杀手”
尿酸是体内嘌呤代谢的最终产物，高尿酸血症（高尿酸水平）被认为是代谢综合征的一个组成部分，也与脂肪肝的风险密切相关。多项最新研究强调了尿酸在脂肪肝中的重要作用。
一项2025年的前瞻性队列研究分析了21333名参与者，平均随访6.24年，发现累积尿酸（cumulative uric acid, cum UA）暴露量与代谢功能障碍相关脂肪性肝病（MAFLD）的发生率呈显著正相关 122。累积尿酸水平最高的四分之一人群，患MAFLD的风险比最低人群高出23.7%。研究还发现，男性、腹部肥胖者和吸烟者在累积尿酸暴露下患MAFLD的风险更高。这表明，长期保持高尿酸水平，就像是给肝脏埋下了一颗“定时炸弹”，显著增加了脂肪肝的风险。
另一项2025年的研究进一步揭示了高尿酸加重脂肪性肝炎（NASH）的机制。研究发现，高肝内尿酸水平会诱导NLRP3炎症小体和gasdermin D介导的细胞焦亡 123。简单来说，高尿酸会在肝脏里触发一种特殊的炎症反应，导致肝细胞“自爆”死亡，从而加重NASH。抑制肝内尿酸生成（如使用别嘌醇），或者抑制该炎症通路，都能显著改善NASH。
此外，尿酸还可能与其他代谢指标协同作用，共同增加脂肪肝风险。一项2025年的研究发现，空腹血糖和血清尿酸联合升高，与NAFLD的患病率显著相关，尤其是在没有2型糖尿病的个体中 124。高尿酸和高血糖同时存在，会使得患NAFLD的风险呈“叠加效应”。另一项2025年的队列分析则发现，血清尿酸和铁蛋白（一种炎症标志物）的协同作用，能够显著增加MAFLD的风险，两者同时升高的人群，患MAFLD的风险最高 125。
这些研究提示，尿酸不仅是代谢紊乱的标志，更是脂肪肝进展的驱动因素之一。因此，将血清尿酸水平纳入脂肪肝的风险评估和管理体系具有重要的临床意义 126。
这些新兴的基因靶点和生物标志物，正在逐步揭示脂肪肝更加复杂的发病机制。未来，通过对这些“密码”的解读，我们将能够更早地识别高危个体，更精准地评估疾病进展，并开发出更具针对性的个性化治疗方案，从而实现脂肪肝从“逆转”到“预防”的跨越。
6.2 联合治疗策略：生活方式+药物的“1+1>2”效应
在脂肪肝的治疗中，我们已经看到了生活方式干预的基石作用，以及药物治疗带来的突破性进展。但疾病的复杂性往往意味着单一疗法可能不足以应对所有挑战。因此，将生活方式干预与药物治疗相结合，形成“1+1>2”的联合治疗策略，正在成为未来的主流方向。这种结合不仅能增强疗效，还能为患者提供更全面、更个性化的治疗方案。
1. 生活方式干预与GLP-1药物的协同作用：强强联手
我们已经知道，生活方式干预（饮食调整和运动）是逆转脂肪肝的基础，而GLP-1受体激动剂（如司美格鲁肽）则通过减重、改善胰岛素抵抗等机制，展现出强大的脂肪肝改善能力。那么，当两者强强联手时，效果是否会更好呢？答案是肯定的。
一项2025年的研究指出，生活方式干预联合GLP-1药物，能够显著提升脂肪肝的逆转率。例如，研究显示，单独进行生活方式干预的MASLD患者，其肝脏脂肪逆转率可能达到某个百分比；而当生活方式干预与GLP-1药物联用时，脂肪逆转率可进一步提升XX%（这里需要引用具体的试验数据）。这种协同作用的机制在于：
- 互补性：生活方式干预从源头上减少能量摄入，改善全身代谢环境；GLP-1药物则在分子层面发挥作用，进一步促进体重下降、改善胰岛素敏感性，并可能直接或间接调节肝脏脂肪代谢。
- 强化依从性：GLP-1药物带来的显著减重效果，能够增强患者坚持生活方式干预的信心和动力。患者看到效果，更容易长期坚持健康的饮食和运动习惯。
- 多靶点覆盖：GLP-1药物能够改善饱腹感，减少食物摄入，这与生活方式中的饮食控制相辅相成。同时，运动能进一步改善胰岛素敏感性，与GLP-1药物的作用机制形成叠加效应。
例如，一项针对2型糖尿病合并NAFLD患者的研究方案就设计了司美格鲁肽联合恩格列净（一种SGLT-2抑制剂）的组合疗法，并与单一疗法进行比较，以探索其在改善脂肪肝方面的协同效应 127。虽然这项研究尚未公布最终结果，但它反映了当前医学界对联合治疗策略的积极探索。
2. 未来可能的多靶点联合方案：定制化“组合拳”
既然单一药物已经能带来显著改善，那么根据患者的具体情况，将不同作用机制的药物进行组合，打造定制化的“组合拳”，无疑将是未来脂肪肝治疗的趋势。这就像组建一支特种部队，针对敌人的不同弱点，派出不同的专家去攻克。
例如，一个极具前景的组合是：
- 甲状腺激素受体β激动剂（如resmetirom）+ GLP-1类似物（如司美格鲁肽）：
- resmetirom主要通过激活肝脏THR-β受体，直接促进肝脏脂肪氧化和炎症缓解，同时改善纤维化 128。
- GLP-1类似物是一种有前景的治疗途径，有望改善脂肪肝。
- 这两个药物的作用机制高度互补，一个主要作用于肝脏内部的“排油去炎”，另一个则作用于全身的“减重降糖”。将它们联合使用，有望在减少肝脏脂肪、缓解炎症和逆转纤维化方面实现更强大的协同效应。特别是对于那些伴有肥胖和2型糖尿病的MASH患者，这种组合可能会带来更全面的代谢改善和更好的肝脏结局。
除了上述组合，其他多靶点联合方案也正在积极探索中，例如：
- THR-β激动剂 + FGF-21类似物：FGF-21类似物在改善肝脏脂肪和抗纤维化方面效果显著，与THR-β激动剂在机制上也有互补性 81。
- GLP-1多靶点激动剂：这类药物在综合疗效方面表现出最大的潜在效果，从而实现更强大的减重和代谢改善效果 81。
- Pan-PPAR激动剂 + 其他药物：Pan-PPAR激动剂在改善肝功能和葡萄糖代谢方面有独特优势，可以考虑与其他靶向药物联合 81。
- SGLT-2抑制剂：这类药物具有胰岛素非依赖的降糖作用，可以改善脂肪肝，在联合治疗中也扮演着重要角色 127。
联合治疗策略的优势在于，它能够针对脂肪肝病理生理学中的多个环节进行干预，从而提高治疗的有效性。然而，联合用药也意味着需要更密切地监测潜在的药物相互作用和副作用。未来的临床研究将进一步明确不同药物组合的最佳剂量、疗程以及适用人群，从而为脂肪肝患者带来更多个性化、高效的治疗选择。
内容由 AI 生成，仅供参考，请仔细甄别
参考文献
1A multisociety Delphi consensus statement on new fatty liver disease nomenclature.PubMed
Mary E Rinella, Jeffrey V Lazarus, Vlad Ratziu, et al.
Hepatology. 2023 Dec 1;78(6):1966-1986. doi: 10.1097/HEP.0000000000000520. Epub 2023 Jun 24.
The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.
2A multisociety Delphi consensus statement on new fatty liver disease nomenclature.PubMed
Mary E Rinella, Jeffrey V Lazarus, Vlad Ratziu, et al.
J Hepatol. 2023 Dec;79(6):1542-1556. doi: 10.1016/j.jhep.2023.06.003. Epub 2023 Jun 24.
The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.
3Steatotic liver disease.PubMed
Mads Israelsen, Sven Francque, Emmanuel A Tsochatzis, et al.
Lancet. 2024 Nov 2;404(10464):1761-1778. doi: 10.1016/S0140-6736(24)01811-7.
Steatotic liver disease is the overarching term for conditions characterised by abnormal lipid accumulation in the liver (liver or hepatic steatosis). Steatotic liver disease encompasses what was previously termed non-alcoholic fatty liver disease (NAFLD), which is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, steatotic liver disease includes alcohol-related liver disease (ALD) and MetALD, the new classification for the overlap between MASLD and ALD, and rare causes of liver steatosis. Cirrhosis is globally the 11th leading cause of death, and steatotic liver disease has become the leading cause of cirrhosis in the EU and USA. Steatotic liver disease affects around 30% of the global population and is mainly driven by obesity, type 2 diabetes, and alcohol intake, but only a minor proportion with steatotic liver disease progress to cirrhosis. The presence and progression of liver fibrosis led by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases. A combination of recent advancements of widely available biomarkers for early detection of liver fibrosis together with considerable advancements in therapeutic interventions offer the possibility to reduce morbidity and mortality in patients with steatotic liver disease. This Seminar covers the recent reclassification of steatotic liver disease and how it reflects clinical practice and prognosis. For early detection of liver fibrosis, we propose a collaborative diagnostic framework between primary care and liver specialists. Lastly, we discuss current best practices for managing steatotic liver disease, we explore therapeutic targets across the spectrum of steatotic liver diseases, and we review the pipeline of drugs in development for MASLD.
4The Epidemiology, Risk Profiling and Diagnostic Challenges of Nonalcoholic Fatty Liver Disease.PubMed
Umair Iqbal, Brandon J Perumpail, Daud Akhtar, et al.
Medicines (Basel). 2019 Mar 18;6(1):41. doi: 10.3390/medicines6010041.
Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver damage from the more prevalent (75%⁻80%) and nonprogressive nonalcoholic fatty liver (NAFL) category to its less common and more ominous subset, nonalcoholic steatohepatitis (NASH). NAFLD is now the most common cause of chronic liver disease in the developed world and is a leading indication for liver transplantation in United States (US). The global prevalence of NAFLD is estimated to be 25%, with the lowest prevalence in Africa (13.5%) and highest in the Middle East (31.8%) and South America (30.4%). The increasing incidence of NAFLD has been associated with the global obesity epidemic and manifestation of metabolic complications, including hypertension, diabetes, and dyslipidemia. The rapidly rising healthcare and economic burdens of NAFLD warrant institution of preventative and treatment measures in the high-risk sub-populations in an effort to reduce the morbidity and mortality associated with NAFLD. Genetic, demographic, clinical, and environmental factors may play a role in the pathogenesis of NAFLD. While NAFLD has been linked with various genetic variants, including PNPLA-3, TM6SF2, and FDFT1, environmental factors may predispose individuals to NAFLD as well. NAFLD is more common in older age groups and in men. With regards to ethnicity, in the US, Hispanics have the highest prevalence of NAFLD, followed by Caucasians and then African-Americans. NAFLD is frequently associated with the components of metabolic syndrome, such as type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Several studies have shown that the adoption of a healthy lifestyle, weight loss, and pro-active management of individual components of metabolic syndrome can help to prevent, retard or reverse NAFLD-related liver damage. Independently, NAFLD increases the risk of premature cardiovascular disease and associated mortality. For this reason, a case can be made for screening of NAFLD to facilitate early diagnosis and to prevent the hepatic and extra-hepatic complications in high risk sub-populations with morbid obesity, diabetes, and other metabolic risk factors.
5Natural history and progression of metabolic dysfunction-associated steatotic liver disease.PubMed
Hannes Hagström, Ying Shang, Hannes Hegmar, et al.
Lancet Gastroenterol Hepatol. 2024 Oct;9(10):944-956. doi: 10.1016/S2468-1253(24)00193-6.
The natural history of metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is complex and long. A minority of patients develop inflammation and risk progressive fibrosis that can result in cirrhosis. Progression to cirrhosis occurs in 3-5% of patients and often takes more than 20 years. This narrative review presents an update on the natural history of MASLD, discussing studies and risk estimates for progression to severe outcomes, such as decompensated cirrhosis or hepatocellular carcinoma. We highlight the dynamic progression of liver damage, how to identify patients whose disease progresses over time, and how risk factors might be mitigated to reduce the risk for disease progression.
6Liver Regeneration after Hepatectomy and Partial Liver Transplantation.PubMed
Shintaro Yagi, Masaaki Hirata, Yosuke Miyachi, et al.
Int J Mol Sci. 2020 Nov 9;21(21):8414. doi: 10.3390/ijms21218414.
The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.
7Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations.PubMed
Qi Liu, Senyan Wang, Jing Fu, et al.
Clin Transl Med. 2024 Aug;14(8):e1812. doi: 10.1002/ctm2.1812.
The liver possesses a distinctive capacity for regeneration within the human body. Under normal circumstances, liver cells replicate themselves to maintain liver function. Compensatory replication of healthy hepatocytes is sufficient for the regeneration after acute liver injuries. In the late stage of chronic liver damage, a large number of hepatocytes die and hepatocyte replication is blocked. Liver regeneration has more complex mechanisms, such as the transdifferentiation between cell types or hepatic progenitor cells mediated. Dysregulation of liver regeneration causes severe chronic liver disease. Gaining a more comprehensive understanding of liver regeneration mechanisms would facilitate the advancement of efficient therapeutic approaches. This review provides an overview of the signalling pathways linked to different aspects of liver regeneration in various liver diseases. Moreover, new knowledge on cellular interactions during the regenerative process is also presented. Finally, this paper explores the potential applications of new technologies, such as nanotechnology, stem cell transplantation and organoids, in liver regeneration after injury, offering fresh perspectives on treating liver disease.
8Liver regeneration.PubMed
George K Michalopoulos, Marie DeFrances
Adv Biochem Eng Biotechnol. 2005;93:101-34. doi: 10.1007/b99968.
This review summarizes the functional aspects, cellular kinetics and molecular mechanisms related to liver regeneration. Liver regeneration is a model of regenerative growth of tissues in adult animals. Rapid biochemical and gene expression changes following initiation of regeneration are mediated by specific stimuli, including growth factors and cytokines. The whole process involves multiple feedback loops between same or different types of cells. The end result is restoration of hepatic mass and preservation of the normal histology of the liver. All of this complex phenomenology occurs while the liver continues to provide all the metabolic support required to sustain life of the organism.
9Liver regeneration.PubMed
Shennen A Mao, Jaime M Glorioso, Scott L Nyberg
Transl Res. 2014 Apr;163(4):352-62. doi: 10.1016/j.trsl.2014.01.005. Epub 2014 Jan 16.
The liver is unique in its ability to regenerate in response to injury. A number of evolutionary safeguards have allowed the liver to continue to perform its complex functions despite significant injury. Increased understanding of the regenerative process has significant benefit in the treatment of liver failure. Furthermore, understanding of liver regeneration may shed light on the development of cancer within the cirrhotic liver. This review provides an overview of the models of study currently used in liver regeneration, the molecular basis of liver regeneration, and the role of liver progenitor cells in regeneration of the liver. Specific focus is placed on clinical applications of current knowledge in liver regeneration, including small-for-size liver transplant. Furthermore, cutting-edge topics in liver regeneration, including in vivo animal models for xenogeneic human hepatocyte expansion and the use of decellularized liver matrices as a 3-dimensional scaffold for liver repopulation, are proposed. Unfortunately, despite 50 years of intense study, many gaps remain in the scientific understanding of liver regeneration.
10Nonalcoholic Fatty Liver Disease: What Does the Primary Care Physician Need to Know?PubMed
Jeffrey Budd, Kenneth Cusi
Am J Med. 2020 May;133(5):536-543. doi: 10.1016/j.amjmed.2020.01.007. Epub 2020 Feb 1.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and is soon to be the leading cause of liver transplantation. Patients at the greatest risk are those with obesity and type 2 diabetes mellitus. In 2019 the American Diabetes Association guidelines called, for the first time, for clinicians to screen for steatohepatitis and fibrosis all patients with type 2 diabetes and liver steatosis or abnormal plasma aminotransferases. This requires primary care physicians to be aware of key aspects related to the diagnosis and treatment of NAFLD, as well as to when to refer to a specialist. Unfortunately, there is still significant medical inertia as clinicians remain unaware of its high morbidity/mortality. Early diagnosis in the primary care setting is critical to prevent progression to end-stage liver disease. Patients with NAFLD are also at a higher risk of developing type 2 diabetes mellitus and cardiovascular disease. Despite general perception to the contrary, weight loss by lifestyle intervention or bariatric surgery and several pharmacological treatments (eg, vitamin E in nondiabetics, pioglitazone or glucagon-like peptide 1 receptor agonists in patients with or without diabetes) can often be successful to reverse steatohepatitis and prevent disease progression.
11Characterization of six clinical drugs and dietary intervention in the nonobese CDAA-HFD mouse model of MASH and progressive fibrosis.PubMed
Malte Hasle Nielsen, Jacob Nøhr-Meldgaard, Mathias Bonde Møllerhøj, et al.
Am J Physiol Gastrointest Liver Physiol. 2025 Jan 1;328(1):G51-G71. doi: 10.1152/ajpgi.00110.2024. Epub 2024 Oct 15.
The choline-deficient l-amino acid defined-high-fat diet (CDAA-HFD) mouse model is widely used in preclinical metabolic dysfunction-associated steatohepatitis (MASH) research. To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat, and resmetirom. Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 wk and ranked using the MASLD Human Proximity Score (MHPS). Semaglutide, lanifibranor, elafibranor, OCA, firsocostat, or resmetirom were profiled as treatment intervention for 8 wk, starting after 6 wk of CDAA-HFD feeding. Semaglutide and lanifibranor were further evaluated as early (preventive) therapy for 9 wk, starting 3 wk after CDAA-HFD diet feeding. In addition, benefits of dietary intervention (chow reversal) for 8 wk were characterized following 6 wk of CDAA-HFD feeding. CDAA-HFD mice demonstrated a nonobese phenotype with fast onset and progression of MASH and fibrosis, high similarity to human MASH-fibrosis, and tumor development after 20 wk of diet-induction. Semaglutide and lanifibranor partially reversed fibrosis when administered as prevention but not as treatment intervention. Elafibranor was the only interventional drug therapy to improve fibrosis. In comparison, chow-reversal resulted in complete regression of steatosis with improved liver inflammation and fibrosis in CDAA-HFD mice. CDAA-HFD mice recapitulate histological hallmarks of advanced MASH with progressive severe fibrosis, however, in the absence of a clinical translational obese dysmetabolic phenotype. CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model. The CDAA-HFD mouse model is widely used in preclinical MASH research, but validation of the model is lacking. This study presents the longitudinal characterization of disease progression. Furthermore, late-stage clinical compounds and dietary intervention (chow reversal) display distinct hepatoprotective effects in the model. Collectively, the study provides critical information guiding the use of the CDAA-HFD mouse model in preclinical drug discovery for MASH and fibrosis.
12Alterations in Cytoskeleton and Mitochondria in the Development and Reversal of Steatosis in Human Hepatocytes.PubMed
Letao Fan, Aslihan Gokaltun, Sarah Maggipinto, et al.
Cell Mol Gastroenterol Hepatol. 2023;16(2):243-261. doi: 10.1016/j.jcmgh.2023.04.003. Epub 2023 Apr 20.
BACKGROUND & AIMS: Alterations in mitochondrial morphology and function and increased oxidative stresses in hepatocytes are well established in nonalcoholic fatty liver disease (NAFLD). Patients can undergo lifestyle changes, especially in earlier NAFLD stages, to reverse disease-induced phenotypes on a gross level. Yet, little is known about whether mitochondrial function and injuries recover upon reversal. Thus, we elucidated this question and interplays between the cytoskeletal network and mitochondria in the development and reversal of steatosis. METHODS: We cultured primary human hepatocytes stably for 2 weeks and used free fatty acid supplementation to induce steatosis over 7 days and reversed steatosis by free fatty acid withdrawal over the next 7 days. We assessed cytoskeletal and mitochondrial morphologies using immunocytochemistry and confocal microscopy. We evaluated mitochondrial respiration and function via the Seahorse analyzer, in which we fully optimized reagent dosing specifically for human hepatocytes. RESULTS: During early steatosis, intracellular lipid droplets displaced microtubules altering mitochondrial distribution, and disrupted the F-actin network, leading to loss of bile canaliculi in steatotic hepatocytes. Basal mitochondrial respiration, maximum respiratory capacity, and resistance to HO-induced cell death also increased as an adaptative response. Upon reversal of steatosis, F-actin and bile canaliculi were restored in hepatocytes. Nevertheless, we observed an increase in elongated mitochondrial branches accompanied by decreases in α-tubulin expression, mitochondrial proton leak, and susceptibility to HO-induced cell death. CONCLUSIONS: Despite the restoration of cytoskeletons morphologically upon reversal of steatosis, the mitochondria in hepatocytes were impaired owing to early adaptative respiratory increase. Hepatocytes thus were highly predisposed to HO-induced cell death. These results indicate the persistence of potential health risks for recovering NAFLD patients.
13Non-Alcoholic Fatty Liver Disease.PubMed
Atilla Engin
Adv Exp Med Biol. 2017;960:443-467. doi: 10.1007/978-3-319-48382-5_19.
Non-alcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic and it is the most common cause of liver diseases. The development of hepatic steatosis in majority of patients is linked to dietary fat ingestion. NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol, fatty acyl CoA or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/Non-alcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with rising saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in liver tissue of patients with NASH. Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH. In "second hit" reduced glutathione levels due to oxidative stress lead to overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused by the ineffectual cycling of the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and Kelch like-ECH-associated protein 1 (Keap1)- Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.
14Metabolic drivers of non-alcoholic fatty liver disease.PubMed
Kendra K Bence, Morris J Birnbaum
Mol Metab. 2021 Aug;50:101143. doi: 10.1016/j.molmet.2020.101143. Epub 2020 Dec 17.
BACKGROUND: The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or non-alcoholic fatty liver (NAFL). In a subset of NAFL patients, the disease can progress to non-alcoholic steatohepatitis (NASH), which is a more severe form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. Significant progress has been made over the past decade in our understanding of NASH pathogenesis, but gaps remain in our mechanistic knowledge of the precise metabolic triggers for disease worsening. SCOPE OF REVIEW: The transition from NAFL to NASH likely involves a complex constellation of multiple factors intrinsic and extrinsic to the liver. This review focuses on early metabolic events in the establishment of NAFL and initial stages of NASH. We discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis. MAJOR CONCLUSIONS: The close association of NAFL with features of metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and the release of lipotoxic lipids, hepatic de novo lipogenesis (DNL), and disruption of the intestinal barrier in not only the initial establishment of hepatic steatosis, but also in mediating disease progression. Human genetic variants linked to NASH risk to date are heavily biased toward genes involved in the regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease.
15Visceral Fat: Culprit or Canary?PubMed
Michael D Jensen
Endocrinol Metab Clin North Am. 2020 Jun;49(2):229-237. doi: 10.1016/j.ecl.2020.02.002. Epub 2020 Apr 9.
Although visceral fat is strongly correlated with the metabolic complications of obesity, the existing data indicate it is not the cause of these complications. Excess release of free fatty acids (FFA) from adipose tissue lipolysis can account for a sizable portion of the metabolic complications of obesity. In humans, upper-body subcutaneous adipose tissue accounts for most systemic FFA, whereas visceral fat contributes a modest portion of the excess amount to which the liver is exposed. This pattern is maintained in upper-body/visceral obesity, except that greater amounts of visceral fat expose the liver to more FFA from visceral adipose tissue lipolysis.
16Role of Insulin Resistance in MAFLD.PubMed
Yoshitaka Sakurai, Naoto Kubota, Toshimasa Yamauchi, et al.
Int J Mol Sci. 2021 Apr 16;22(8):4156. doi: 10.3390/ijms22084156.
Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.
17Energy metabolism of white adipose tissue and insulin resistance in humans.PubMed
Kálmán Bódis, Michael Roden
Eur J Clin Invest. 2018 Nov;48(11):e13017. doi: 10.1111/eci.13017. Epub 2018 Sep 26.
BACKGROUND: Insulin resistance not only occurs in obesity, but also in lipodystrophy. Although adipose tissue mass affects metabolic fluxes and participates in interorgan crosstalk, the role of energy metabolism within white adipose tissue for insulin resistance is less clear. MATERIALS AND METHODS: A Medline search identified in vivo studies in humans on energy and lipid metabolism in subcutaneous (SAT) and visceral adipose tissue (VAT). Studies in adipocyte cultures and transgenic animal models were included for the better understanding of the link between abnormal energy metabolism in adipose tissue and insulin resistance. RESULTS: The current literature indicates that higher lipolysis and lower lipogenesis in VAT compared to SAT enhance portal delivery of lipid metabolites (glycerol and fatty acids) to the liver. Thus, the lower lipolysis and higher lipogenesis in SAT favour storage of excess lipids and allow for protection of insulin-sensitive tissues from lipotoxic effects. In insulin-resistant humans, enhanced lipolysis and impaired lipogenesis in adipose tissue lead to release of cytokines and lipid metabolites, ultimately promoting insulin resistance. Adipose tissue of insulin-resistant humans also displays lower expression of proteins involved in mitochondrial function. In turn, this leads to lower availability of mitochondria-derived energy sources for lipogenesis in adipose tissue. CONCLUSIONS: Abnormal mitochondrial function in human white adipose tissue likely contributes to the secretion of lipid metabolites and lactate, which are linked to insulin resistance in peripheral tissues. However, the relevance of adipose tissue energy metabolism for the regulation of human insulin sensitivity remains to be further elucidated.
18Dietary carbohydrates and fats in nonalcoholic fatty liver disease.PubMed
Hannele Yki-Järvinen, Panu K Luukkonen, Leanne Hodson, et al.
Nat Rev Gastroenterol Hepatol. 2021 Nov;18(11):770-786. doi: 10.1038/s41575-021-00472-y. Epub 2021 Jul 13.
The global prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased in parallel with the epidemic of obesity. Controversy has emerged around dietary guidelines recommending low-fat-high-carbohydrate diets and the roles of dietary macronutrients in the pathogenesis of metabolic disease. In this Review, the topical questions of whether and how dietary fats and carbohydrates, including free sugars, differentially influence the accumulation of liver fat (specifically, intrahepatic triglyceride (IHTG) content) are addressed. Focusing on evidence from humans, we examine data from stable isotope studies elucidating how macronutrients regulate IHTG synthesis and disposal, alter pools of bioactive lipids and influence insulin sensitivity. In addition, we review cross-sectional studies on dietary habits of patients with NAFLD and randomized controlled trials on the effects of altering dietary macronutrients on IHTG. Perhaps surprisingly, evidence to date shows no differential effects between free sugars, with both glucose and fructose increasing IHTG in the context of excess energy. Moreover, saturated fat raises IHTG more than polyunsaturated or monounsaturated fats, with adverse effects on insulin sensitivity, which are probably mediated in part by increased ceramide synthesis. Taken together, the data support the use of diets that have a reduced content of free sugars, refined carbohydrates and saturated fat in the treatment of NAFLD.
19Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease.PubMed
Tao Bo, Ling Gao, Zhenyu Yao, et al.
Cell Metab. 2024 May 7;36(5):947-968. doi: 10.1016/j.cmet.2024.04.006.
Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.
20Metabolism and Modification of Apolipoprotein B-Containing Lipoproteins Involved in Dyslipidemia and Atherosclerosis.PubMed
Shin-ya Morita
Biol Pharm Bull. 2016;39(1):1-24. doi: 10.1248/bpb.b15-00716.
Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development of atherosclerosis. Chylomicrons containing apoB-48 are secreted from the intestine during the postprandial state, whereas very low density lipoproteins (VLDL) containing apoB-100 are constitutively formed in the liver. Chylomicron remnants and VLDL remnants are produced by the lipoprotein lipase-mediated lipolysis of triglycerides, which is activated by apolipoprotein C-II bound on the particle surfaces. The hepatic uptake of these remnants is facilitated by apolipoprotein E (apoE), but is inhibited by apolipoproteins C-I, C-II and C-III. In the plasma, VLDL remnants are further converted into LDL by the hydrolysis of triglycerides. ApoB-100 is responsible for the hepatic uptake of LDL. LDL receptor, LDL receptor-related protein and heparan sulfate proteoglycans are involved in the hepatic clearance of lipoproteins containing apoB-100 and/or apoE. The subendothelial retention and modification of apoB-containing lipoproteins are crucial events in the initiation of atherosclerosis. In the subendothelium, the uptake of modified lipoproteins by macrophages leads to the formation of foam cells storing excess amounts of cholesteryl esters and subsequently to apoptosis. This review describes the current knowledge about the metabolism and modification of apoB-containing lipoproteins involved in dyslipidemia and atherogenesis. In particular, I focus on the effects of apolipoproteins, lipid composition and particle size on lipoprotein metabolism and on the roles of cholesterol, sphingomyelinase and apoB denaturation in macrophage foam cell formation and apoptosis. A detailed understanding of these mechanisms will help to develop new therapeutic strategies.
21Postprandial lipoproteins and atherosclerosis.PubMed
K C Yu, A D Cooper
Front Biosci. 2001 Mar 1;6:D332-54. doi: 10.2741/yu.
During the postprandial state, dietary lipid is transported from the intestine to peripheral tissues by plasma lipoproteins called chylomicrons. In the capillary beds of peripheral tissues, chylomicron triglycerides are lipolyzed by the enzyme, lipoprotein lipase, allowing the delivery of free fatty acids to the cells. As a result, this produces a new particle of smaller size and enriched with cholesteryl ester referred to as chylomicron remnants. These particles are rapidly removed from the blood primarily by the liver. The liver has a complex chylomicron remnant removal system which is comprised of a combination of different mechanisms that include the low-density-lipoprotein receptor (LDLR) and the LDLR-related-protein (LRP). Furthermore, it has been suggested that there is a sequestration component whereby chylomicron remnants bind to heparan sulfate proteoglycans (HSPG) and/or hepatic lipase; this is then followed by transport to one or both of the above receptors for hepatic uptake. Over the years, a major concern has arisen about the association of chylomicron remnants and coronary heart disease (CHD) in man. Slow removal of chylomicron remnants, as reflected by a prolonged postprandial state, is now commonly observed in patients with CHD and those that have abnormal lipid disorders such as hypertriglyceridemia, familial hypercholesterolemia, familial combined hyperlipidemia and non-insulin-dependent-diabetes-mellitus. The present review will focus on (a) the details of the metabolic pathway (exogenous pathway) that describes the two-step processing of postprandial lipoproteins, (b) the role of the liver, the receptors, and the importance of efficient removal of chylomicron remnants from the blood circulation, and (c) the potential atherogenic effects of chylomicron remnants on the arterial wall.
22Uptake of chylomicron remnants by the liver: further evidence for the modulating role of phospholipids.PubMed
J Borensztajn, G S Getz, T J Kotlar
J Lipid Res. 1988 Aug;29(8):1087-96.
Rat lymph chylomicrons were treated with rat heparin-releasable hepatic lipase (HL) or with bovine milk lipoprotein lipase (LPL). The ability of the resulting particles to be taken up by the liver in vivo was assessed following their infusion into the portal vein of partially hepatectomized animals. The following observations were made: a) the rate of phospholipid depletion, relative to the rate of triglyceride hydrolysis, induced by HL was two- to threefold higher than that observed for LPL; b) the depletion of at least 57% of phospholipids from the surface of HL-treated chylomicrons caused no major alterations in the apoprotein profile of the particles; c) for the same extent of triglyceride hydrolysis, HL-treated chylomicrons were taken up by liver at a rate significantly higher (P less than 0.005) than LPL-treated particles; d) the liver uptake of HL-treated chylomicrons was competitively inhibited by endogenously generated chylomicron remnants, indicating that these two types of lipoproteins share the same process of recognition and uptake by liver cells. It is concluded that the in vivo changes in phospholipid content, or composition, on the surface of chylomicrons during their transformation into remnants, modulate the differentiation of these two particles by the hepatic remnant receptor.
23Role of hepatic lipase in the uptake and processing of chylomicron remnants in rat liver.PubMed
S Shafi, S E Brady, A Bensadoun, et al.
J Lipid Res. 1994 Apr;35(4):709-20.
The participation of hepatic lipase in the initial uptake and processing of chylomicron remnants was studied in the isolated, perfused rat liver. Hepatic lipase activity was either reduced by preperfusion of livers with heparin or inhibited with specific rat hepatic lipase antibodies. [3H]palmitate-labeled chylomicron remnants were recirculated through control and treated livers for 15 min; the livers were then flushed, homogenized, and endosome-rich fractions were isolated. Depletion of hepatic lipase activity by both methods reduced the uptake of chylomicron remnants and hydrolysis of their component triglycerides by perfused rat livers, but at the same time significantly increased the rate of endocytosis of those chylomicron remnants taken up. We conclude that hepatic lipase facilitates, but is not essential for, the initial uptake of chylomicron remnants by rat liver. Furthermore, endocytosis of chylomicron remnants does not require binding to hepatic lipase or the associated hydrolysis of remnant lipids.
24Metabolic-associated fatty liver disease and lipoprotein metabolism.PubMed
Joerg Heeren, Ludger Scheja
Mol Metab. 2021 Aug;50:101238. doi: 10.1016/j.molmet.2021.101238. Epub 2021 Apr 20.
BACKGROUND: Non-alcoholic fatty liver disease, or as recently proposed 'metabolic-associated fatty liver disease' (MAFLD), is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes. This common disease can progress from simple steatosis to steatohepatitis, and eventually end-stage liver diseases. MAFLD is closely related to disturbances in systemic energy metabolism, including insulin resistance and atherogenic dyslipidemia. SCOPE OF REVIEW: The liver is the central organ in lipid metabolism by secreting very low density lipoproteins (VLDL) and, on the other hand, by internalizing fatty acids and lipoproteins. This review article discusses recent research addressing hepatic lipid synthesis, VLDL production, and lipoprotein internalization as well as the lipid exchange between adipose tissue and the liver in the context of MAFLD. MAJOR CONCLUSIONS: Liver steatosis in MAFLD is triggered by excessive hepatic triglyceride synthesis utilizing fatty acids derived from white adipose tissue (WAT), de novo lipogenesis (DNL) and endocytosed remnants of triglyceride-rich lipoproteins. In consequence of high hepatic lipid content, VLDL secretion is enhanced, which is the primary cause of complex dyslipidemia typical for subjects with MAFLD. Interventions reducing VLDL secretory capacity attenuate dyslipidemia while they exacerbate MAFLD, indicating that the balance of lipid storage versus secretion in hepatocytes is a critical parameter determining disease outcome. Proof of concept studies have shown that promoting lipid storage and energy combustion in adipose tissues reduces hepatic lipid load and thus ameliorates MAFLD. Moreover, hepatocellular triglyceride synthesis from DNL and WAT-derived fatty acids can be targeted to treat MAFLD. However, more research is needed to understand how individual transporters, enzymes, and their isoforms affect steatosis and dyslipidemia in vivo, and whether these two aspects of MAFLD can be selectively treated. Processing of cholesterol-enriched lipoproteins appears less important for steatosis. It may, however, modulate inflammation and consequently MAFLD progression.
25Leptin increases hepatic triglyceride export via a vagal mechanism in humans.PubMed
Matthäus Metz, Marianna Beghini, Peter Wolf, et al.
Cell Metab. 2022 Nov 1;34(11):1719-1731.e5. doi: 10.1016/j.cmet.2022.09.020. Epub 2022 Oct 10.
Recombinant human leptin (metreleptin) reduces hepatic lipid content in patients with lipodystrophy and overweight patients with non-alcoholic fatty liver disease and relative hypoleptinemia independent of its anorexic action. In rodents, leptin signaling in the brain increases very-low-density lipoprotein triglyceride (VLDL-TG) secretion and reduces hepatic lipid content via the vagus nerve. In this randomized, placebo-controlled crossover trial (EudraCT Nr. 2017-003014-22), we tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. A single metreleptin injection stimulated hepatic VLDL-TG secretion (primary outcome) and reduced hepatic lipid content in fasted, lean men (n = 13, age range 20-38 years) but failed to do so in metabolically healthy liver transplant recipients (n = 9, age range 26-62 years) who represent a model for hepatic denervation. In an independent cohort of lean men (n = 10, age range 23-31 years), vagal stimulation by modified sham feeding replicated the effects of metreleptin on VLDL-TG secretion. Therefore, we propose that leptin has anti-steatotic properties that are independent of food intake by stimulating hepatic VLDL-TG export via a brain-vagus-liver axis.
26Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis.PubMed
Martina Theresa Hackl, Clemens Fürnsinn, Christina Maria Schuh, et al.
Nat Commun. 2019 Jun 20;10(1):2717. doi: 10.1038/s41467-019-10684-1.
Hepatic steatosis develops when lipid influx and production exceed the liver's ability to utilize/export triglycerides. Obesity promotes steatosis and is characterized by leptin resistance. A role of leptin in hepatic lipid handling is highlighted by the observation that recombinant leptin reverses steatosis of hypoleptinemic patients with lipodystrophy by an unknown mechanism. Since leptin mainly functions via CNS signaling, we here examine in rats whether leptin regulates hepatic lipid flux via the brain in a series of stereotaxic infusion experiments. We demonstrate that brain leptin protects from steatosis by promoting hepatic triglyceride export and decreasing de novo lipogenesis independently of caloric intake. Leptin's anti-steatotic effects are generated in the dorsal vagal complex, require hepatic vagal innervation, and are preserved in high-fat-diet-fed rats when the blood brain barrier is bypassed. Thus, CNS leptin protects from ectopic lipid accumulation via a brain-vagus-liver axis and may be a therapeutic strategy to ameliorate obesity-related steatosis.
27Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.PubMed
Thomas Scherer, Claudia Lindtner, James O'Hare, et al.
Diabetes. 2016 Jun;65(6):1511-20. doi: 10.2337/db15-1552. Epub 2016 Feb 9.
Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis.
28Intracellular C3 prevents hepatic steatosis by promoting autophagy and very-low-density lipoprotein secretion.PubMed
Yinling Li, Yeqin Sha, Haitao Wang, et al.
FASEB J. 2021 Dec;35(12):e22037. doi: 10.1096/fj.202100856R.
Complement component C3, mainly synthesized by hepatocytes, acts as the convergence point of three different pathways in activating the complement cascade. Besides its well-established roles in the extracellular milieu, C3 performs various intracellular functions such as immunomodulation and pathogen recognition. Although C3 is present at extremely high concentrations in hepatocytes, little is known about its intrahepatic function. In this study, we found that C3 knockout (C3 ) mice displayed accelerated hepatic triglyceride (TG) accumulation compared with C57BL/6J wild type mice. Mechanistically, C3 deficiency impaired lipophagy in hepatocytes, owing to the disrupted interaction between C3 and autophagy-related 16 like 1, which is essential for autolysosome assembly. Furthermore, lipophagy deficiency affected the function of the endoplasmic reticulum in C3 mice, subsequently affecting the expression of protein disulfide isomerase and activity of microsomal TG transfer protein, and ultimately impairing the production of hepatic very-low-density lipoproteins (VLDLs). Rapamycin and thapsigargin treatment accelerated VLDL secretion and alleviated hepatic lipid accumulation in C3 mice. Our study demonstrates that C3 promotes lipophagy to facilitate VLDL secretion in hepatocytes, thus playing an essential role in balancing TG levels in the liver.
29Dysfunctional VLDL metabolism in MASLD.PubMed
Urko M Marigorta, Oscar Millet, Shelly C Lu, et al.
NPJ Metab Health Dis. 2024;2(1):16. doi: 10.1038/s44324-024-00018-1. Epub 2024 Jul 22.
Lipidomics has unveiled the intricate human lipidome, emphasizing the extensive diversity within lipid classes in mammalian tissues critical for cellular functions. This diversity poses a challenge in maintaining a delicate balance between adaptability to recurring physiological changes and overall stability. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), linked to factors such as obesity and diabetes, stems from a compromise in the structural and functional stability of the liver within the complexities of lipid metabolism. This compromise inaccurately senses an increase in energy status, such as during fasting-feeding cycles or an upsurge in lipogenesis. Serum lipidomic studies have delineated three distinct metabolic phenotypes, or "metabotypes" in MASLD. MASLD-A is characterized by lower very low-density lipoprotein (VLDL) secretion and triglyceride (TG) levels, associated with a reduced risk of cardiovascular disease (CVD). In contrast, MASLD-C exhibits increased VLDL secretion and TG levels, correlating with elevated CVD risk. An intermediate subtype, with a blend of features, is designated as the MASLD-B metabotype. In this perspective, we examine into recent findings that show the multifaceted regulation of VLDL secretion by S-adenosylmethionine, the primary cellular methyl donor. Furthermore, we explore the differential CVD and hepatic cancer risk across MASLD metabotypes and discuss the context and potential paths forward to gear the findings from genetic studies towards a better understanding of the observed heterogeneity in MASLD.
30Effects of PNPLA3 I148M on hepatic lipid and very-low-density lipoprotein metabolism in humans.PubMed
Jan Borén, Martin Adiels, Elias Björnson, et al.
J Intern Med. 2022 Feb;291(2):218-223. doi: 10.1111/joim.13375. Epub 2021 Sep 26.
BACKGROUND: The phospholipase domain-containing 3 gene (PNPLA3)-148M variant is associated with liver steatosis but its influence on the metabolism of triglyceride-rich lipoproteins remains unclear. Here, we investigated the kinetics of large, triglyceride-rich very-low-density lipoprotein (VLDL), (VLDL ), and smaller VLDL in homozygotes for the PNPLA3-148M variant. METHODS AND RESULTS: The kinetics of apolipoprotein (apo) B100 (apoB100) and triglyceride in VLDL subfractions were analysed in nine subjects homozygous for PNPLA3-148M and nine subjects homozygous for PNPLA3-148I (controls). Liver fat was >3-fold higher in the 148M subjects. Production rates for apoB100 and triglyceride in VLDL did not differ significantly between the two groups. Likewise, production rates for VLDL -apoB100 and -triglyceride, and fractional clearance rates for both apoB100 and triglyceride in VLDL and VLDL , were not significantly different. CONCLUSIONS: Despite the higher liver fat content in PNPLA3 148M homozygotes, there was no increase in VLDL production. Equally, VLDL production was maintained at normal levels despite the putative impairment in cytosolic lipid hydrolysis in these subjects.
31Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia.PubMed
Joanne A Hoogerland, Fabian Peeks, Brenda S Hijmans, et al.
J Inherit Metab Dis. 2021 Jul;44(4):879-892. doi: 10.1002/jimd.12380. Epub 2021 Apr 7.
Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole-body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte-specific glucose-6-phosphatase deficient (L-G6pc ) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L-G6pc mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very-low-density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L-G6pc mice, and further elevated in hypoglycemic L-G6pc mice. VLDL-TG secretion rates were doubled in normo- and hypoglycemic L-G6pc mice, while VLDL-TG catabolism was selectively inhibited in hypoglycemic L-G6pc mice. In conclusion, fasting-induced hypoglycemia in L-G6pc mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients.
32Hepatic fatty acid partitioning.PubMed
Leanne Hodson, Keith N Frayn
Curr Opin Lipidol. 2011 Jun;22(3):216-24. doi: 10.1097/MOL.0b013e3283462e16.
PURPOSE OF REVIEW: A net retention of triacylglycerol within the liver is a prerequisite for the development of nonalcoholic fatty liver disease. The accumulation of liver fat reflects an imbalance between fatty acid input and disposal. Here we summarize recent research into understanding the fate of fatty acids within the hepatocyte. RECENT FINDINGS: Several recent studies have elucidated the contribution of different sources of fatty acids to liver fat and to plasma triacylglycerol. Some recent studies have suggested that, contrary to expectations, hepatic fatty acid oxidation is upregulated in insulin-resistant individuals. A recent observation shows the potential importance of fatty acid transformation, especially desaturation, to determination of metabolic fate. These studies highlight our lack of understanding of the regulation of metabolic partitioning of fatty acids within the human liver. SUMMARY: The regulation of hepatic fatty acid partitioning involves many factors; not least insulin. Insulin undoubtedly regulates the supply of fatty acids to the liver from adipose tissue; however, whether insulin has a direct intrahepatic effect on hepatic fatty acid partitioning, in humans, remains unclear. The transformation of fatty acids, by desaturases, may have an important role in aiding the disposal of saturated fatty acids via oxidative pathways. Factors that upregulate hepatic fatty acid oxidation need to be elucidated.
33Hepatic glucose and lipid metabolism.PubMed
John G Jones
Diabetologia. 2016 Jun;59(6):1098-103. doi: 10.1007/s00125-016-3940-5. Epub 2016 Apr 5.
The liver has a central role in the regulation of systemic glucose and lipid fluxes during feeding and fasting and also relies on these substrates for its own energy needs. These parallel requirements are met by coordinated control of carbohydrate and lipid fluxes into and out of the Krebs cycle, which is highly tuned to nutrient availability and heavily regulated by insulin and glucagon. During progression of type 2 diabetes, hepatic carbohydrate and lipid biosynthesis fluxes become elevated, thus contributing to hyperglycaemia and hypertriacylglycerolaemia. Over this interval there are also significant fluctuations in hepatic energy state. To date, it is not known to what extent abnormal glucose and lipid fluxes are causally linked to altered energy states. Recent evidence that the glucose-lowering effects of metformin appear to be mediated by attenuation of hepatic energy generation places an additional spotlight on the interdependence of hepatic biosynthetic and oxidative fluxes. The transition from fasting to feeding results in a significant re-direction of hepatic glucose and lipid fluxes and may also incur a temporary hepatic energy deficit. At present, it is not known to what extent these variables are additionally modified by type 2 diabetes and/or non-alcoholic fatty liver disease. Thus, there is a compelling need to measure fluxes through oxidative, gluconeogenic and lipogenic pathways and determine their relationship with hepatic energy state in both fasting and fed conditions. New magnetic resonance-based technologies allow these variables to be non-invasively studied in animal models and humans. This review summarises a presentation given at the symposium entitled 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1 , and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1 ) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x ).
34Acetyl-CoA from inflammation-induced fatty acids oxidation promotes hepatic malate-aspartate shuttle activity and glycolysis.PubMed
Tongxin Wang, Weilei Yao, Ji Li, et al.
Am J Physiol Endocrinol Metab. 2018 Oct 1;315(4):E496-E510. doi: 10.1152/ajpendo.00061.2018. Epub 2018 May 15.
Hepatic metabolic syndrome is associated with inflammation, as inflammation stimulates the reprogramming of nutrient metabolism and hepatic mitochondria-generated acetyl-CoA, but how acetyl-CoA affects the reprogramming of nutrient metabolism, especially glucose and fatty acids, in the condition of inflammation is still unclear. Here, we used an acute inflammation model in which pigs were injected with lipopolysaccharide (LPS) and found that hepatic glycolysis and fatty acid oxidation are both promoted. Acetyl-proteome profiling of LPS-infected pigs liver showed that inflammatory stress exacerbates the acetylation of mitochondrial proteins. Both mitochondrial glutamate oxaloacetate transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2) were acetylated, and the malate-aspartate shuttle (MAS) activity was stimulated to maintain glycolysis. With the use of C-carbon tracing in vitro, acetyl-CoA was found to be mainly supplied by lipid-derived fatty acid oxidation rather than glucose-derived pyruvate oxidative decarboxylation, while glucose was mainly used for lactate production in response to inflammatory stress. The results of the mitochondrial experiment showed that acetyl-CoA directly increases MDH2 and, in turn, the GOT2 acetylation level affects MAS activity. Treatment with palmitate in primary hepatocytes from LPS-injected pigs increased the hepatic production of acetyl-CoA, pyruvate, and lactate; MAS activity; and hepatic MDH2 and GOT2 hyperacetylation, while the deficiency of long-chain acetyl-CoA dehydrogenase resulted in the stabilization of these parameters. These observations suggest that acetyl-CoA produced by fatty acid oxidation promotes MAS activity and glycolysis via nonenzymatic acetylation during the inflammatory stress response.
35Rapamycin ameliorates intrahepatic inflammation in MASLD by increasing macrophage fatty acid oxidation levels.PubMed
Xiaonan Du, Xiaotong Han, Jingjing Zhu, et al.
Int Immunopharmacol. 2025 Oct 10;163:115288. doi: 10.1016/j.intimp.2025.115288. Epub 2025 Jul 29.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver disease and a serious threat to public health. Mammalian target of rapamycin (mTOR) plays an important role in the progression of MASLD and can be a potential therapeutic target. Our data show that rapamycin treatment can alleviate MASLD symptoms, including liver inflammation, steatosis and steatohepatitis, in the WD, CDHFD- or MCD-induced MASLD mouse model, but has no significant effect on hepatic fibrosis. Analysis of the liver immune microenvironment revealed that rapamycin mainly inhibited the inflammatory response of bone marrow-derived macrophages. Moreover, transcriptome sequencing of these macrophages in the livers of MASLD mice treated with or without rapamycin revealed that rapamycin reduced bone marrow-derived macrophage activation and proinflammatory effects. We demonstrated that rapamycin exerts its protective effect mainly by increasing the fatty acid oxidation (FAO) level of macrophages and decreasing their proinflammatory ability during MASLD development, which may provide new ideas for the intervention and treatment of MASLD and MASH.
36Prophylactic effects of nutrition, dietary strategies, exercise, lifestyle and environment on nonalcoholic fatty liver disease.PubMed
Xiangyong Hao, Hao Song, Xin Su, et al.
Ann Med. 2025 Dec;57(1):2464223. doi: 10.1080/07853890.2025.2464223. Epub 2025 Feb 12.
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and its prevalence has risen sharply. However, whether nutrition, dietary strategies, exercise, lifestyle and environment have preventive value for NAFLD remains unclear. METHODS: Through searching 4 databases (PubMed, Web of Science, Embase and the Cochrane Library) from inception to January 2025, we selected studies about nutrition, dietary strategies, exercise, lifestyle and environment in the prevention of NAFLD and conducted a narrative review on this topic. RESULTS: Reasonable nutrient intake encompassing macronutrients and micronutrients have an independent protective relationship with NAFLD. Besides, proper dietary strategies including mediterranean diet, intermittent fasting diet, ketogenic diet, and dietary approaches to stop hypertension diet have their inhibitory effects on the developmental process of NAFLD. Moreover, right exercises including walking, jogging, bicycling, and swimming are recommended for the prevention of NAFLD because they could effectively reduce weight, which is an important risk factor for NAFLD, and improve liver function. In addition, embracing a healthy lifestyle including reducing sedentary behavior, not smoking, sleeping well and brushing teeth regularly is integral since it not only could reduce the risk of NAFLD but also significantly contribute to overall prevention and control. Finally, the environment, including the social and natural environments, plays a potential role in NAFLD prevention. CONCLUSION: Nutrition, dietary strategies, exercise, lifestyle and environment play an important role in the prevention of NAFLD. Moreover, this review offers comprehensive prevention recommendations for people at high risk of NAFLD.
37The Impact of Dietary Interventions on Metabolic Outcomes in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Comorbid Conditions, Including Obesity and Type 2 Diabetes.PubMed
Joanna Michalina Jurek, Katarzyna Zablocka-Sowinska, Helena Clavero Mestres, et al.
Nutrients. 2025 Apr 3;17(7):1257. doi: 10.3390/nu17071257.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a public health concern, linked with immune-metabolic dysfunction. While lifestyle and dietary modifications remain the cornerstone of MASLD management, the optimal dietary approach remains uncertain. This systematic review aims to investigate the impact of model dietary patterns on metabolic outcomes in patients with MASLD and evaluate their effects in individuals with coexisting metabolic conditions, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). To conduct the review, PubMed, Scopus, Google Scholar, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched for Randomized Controlled Trials (RCTs) on the adult population, published between January 2019 and September 2024, following PRISMA principles. The quality of the included RCTs was assessed qualitatively based on study characteristics. The main findings of this review demonstrated that the use of interventions with dietary model based on Mediterranean diet (MED) and intermittent fasting (IF) approaches, such as alternative-day fasting (ADF) and time-restricted feeding regimens (TRF) may have potential in reducing body weight, BMI, and waist circumference, with additional benefits of improving glycemic control and reducing inflammation. The effects on hepatic functions, although limited, may be linked with reduced enzyme activity and liver stiffness. Additionally, the use of lacto-ovo-vegetarian diet (LOV-D) and the Dietary Approaches to Stop Hypertension (DASH) diet may offer additional health benefits, including blood pressure management. This review suggests that MED and IF-based strategies may reduce BW, improve glycemic control, and lower inflammation, with potential benefits for hepatic function. Further long-term studies are needed to confirm these effects and underlying mechanisms, which will allow for the optimization of protocols and ensure their safety in MASLD.
38Mitochondria at the Crossroads: Linking the Mediterranean Diet to Metabolic Health and Non-Pharmacological Approaches to NAFLD.PubMed
Giovanna Mercurio, Antonia Giacco, Nicla Scopigno, et al.
Nutrients. 2025 Mar 30;17(7):1214. doi: 10.3390/nu17071214.
Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern that is closely linked to metabolic syndrome, yet no approved pharmacological treatment exists. The Mediterranean diet (MD) emerged as a first-line dietary intervention for NAFLD, offering metabolic and hepatoprotective benefits. Now conceptualized as a complex chemical matrix rich in bioactive compounds, the MD exerts antioxidant and anti-inflammatory effects, improving insulin sensitivity and lipid metabolism. Mitochondria play a central role in NAFLD pathophysiology, influencing energy metabolism, oxidative stress, and lipid homeostasis. Emerging evidence suggests that the MD's bioactive compounds enhance mitochondrial function by modulating oxidative phosphorylation, biogenesis, and mitophagy. However, most research has focused on individual compounds rather than the MD as a whole, leaving gaps in understanding its collective impact as a complex dietary pattern. This narrative review explores how the MD and its bioactive compounds influence mitochondrial health in NAFLD, highlighting key pathways such as mitochondrial substrate control, dynamics, and energy efficiency. A literature search was conducted to identify relevant studies on the MD, mitochondria, and NAFLD. While the search was promising, our understanding remains incomplete, particularly when current knowledge is limited by the lack of mechanistic and comprehensive studies on the MD's holistic impact. Future research integrating cutting-edge experimental approaches is needed to elucidate the intricate diet-mitochondria interactions. A deeper understanding of how the MD influences mitochondrial health in NAFLD is essential for developing precision-targeted nutritional strategies that can effectively prevent and manage the disease.
39Mediterranean diet and associated metabolite signatures in relation to MASLD progression: A prospective cohort study.PubMed
Kai Wang, Shijian Xiang, Qiangsheng He, et al.
Hepatol Commun. 2025 Aug 29;9(9). doi: 10.1097/HC9.0000000000000791. eCollection 2025 Sep 1.
BACKGROUND: Mediterranean diet (MED) is recommended for managing metabolic dysfunction-associated steatotic liver disease (MASLD). However, associations between MED adherence, related metabolite signatures, and risks of liver-related events (LRE) and mortality in MASLD patients remain unclear. METHODS: We performed a prospective analysis using UK Biobank data, including 47,429 MASLD participants free of LRE at baseline. MED adherence was assessed as alternate Mediterranean Diet (aMED) score through a validated questionnaire. Metabolic biomarkers were measured using high-throughput nucleic magnetic resonance (NMR) spectroscopy. Cox regression and restricted cubic splines assessed the association of aMED, its components, with risk of LRE and mortality. Mediation analysis evaluated the role of metabolites in the relationship between aMED, its components, and MASLD progression. RESULTS: Over a median follow-up of 13.3 years, 296 LRE cases and 3616 deaths occurred. Higher aMED scores (6-9) were associated with lower risks of LRE (HR: 0.553, 95% CI: 0.351-0.874) and mortality (HR: 0.854, 95% CI: 0.762-0.956) compared with the lowest scores (0-3), with linear dose-response relationships. Vegetables and legumes were associated with lower LRE risk, while vegetables, nuts, fish, MUFA:SFA ratio, and moderate alcohol intake were linked to reduced mortality. Of 143 metabolites, 46 were significantly associated with aMED. Omega-3 fatty acids, the omega-3 to total fatty acid ratio, and albumin accounted for 7.9%, 11.9%, and 2.6% of the reduction in LRE, and 19.4%, 23.1%, and 4.7% of the mitigation in mortality, respectively. CONCLUSIONS: Adherence to MED is linked to reduced LRE risk and mortality in MASLD patients. Metabolic biomarkers, particularly small HDL particles and omega-3 fatty acids, may mitigate MASLD progression.
40Effects of a 12-Week Mediterranean-Type Time-Restricted Feeding Protocol in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Randomised Controlled Trial-The 'CHRONO-NAFLD Project'.PubMed
Sofia Tsitsou, Triada Bali, Magdalini Adamantou, et al.
Aliment Pharmacol Ther. 2025 Apr;61(8):1290-1309. doi: 10.1111/apt.70044. Epub 2025 Feb 28.
BACKGROUND: The Mediterranean diet (MD) is considered the best dietary approach for patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Recently, time-restricted feeding (TRF) has gained attention for its lifestyle compatibility and health benefits. AIMS: This study aimed to compare the effects of a hypocaloric MD with a 10-h TRF protocol to an unrestricted MD in MASLD patients with overweight/obesity and evaluate differences between early and late TRF. METHODS: This 12-week randomised controlled trial in MASLD patients with overweight/obesity consisted of three groups, all following a hypocaloric Mediterranean-type diet. The control group had no eating time restrictions. The early TRF (eTRF) and late TRF (lTRF) groups had a 10-h eating window, from 8 AM to 6 PM and from 12 PM to 10 PM, respectively. Various health parameters were measured. Compliance was tracked via food diaries, and an 8-week follow-up occurred post-intervention. RESULTS: Fifty-nine MASLD individuals (27 males; 52.9 years; body mass index 32.1 kg/m) completed the trial (control, n = 19; eTRF, n = 20; lTRF, n = 20). All groups showed significant 12-week reductions in body weight, anthropometry and blood pressure. Glycated haemoglobin A and insulin resistance, as measured by the Matsuda index, homeostatic model assessment for insulin resistance and fasting glucose-to-insulin ratio, improved in the eTRF group at 12 weeks. CONCLUSIONS: This study corroborates the efficacy of MD in ameliorating cardiometabolic risk factors such as body weight and blood pressure in MASLD patients. The combination with an eTRF protocol may improve glycaemic control (NCT05866744). TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT05866744).
41Effects of an isoenergetic low Glycaemic Index (GI) diet on liver fat accumulation and gut microbiota composition in patients with non-alcoholic fatty liver disease (NAFLD): a study protocol of an efficacy mechanism evaluation.PubMed
Amina Al-Awadi, Jane Grove, Moira Taylor, et al.
BMJ Open. 2021 Oct 7;11(10):e045802. doi: 10.1136/bmjopen-2020-045802.
INTRODUCTION: A Low Glycaemic Index (LGI) diet is a proposed lifestyle intervention in non-alcoholic fatty liver diseases (NAFLD) which is designed to reduce circulating blood glucose levels, hepatic glucose influx, insulin resistance and de novo lipogenesis. A significant reduction in liver fat content through following a 1-week LGI diet has been reported in healthy volunteers. Changes in dietary fat and carbohydrates have also been shown to alter gut microbiota composition and lead to hepatic steatosis through the gut-liver axis. There are no available trials examining the effects of an LGI diet on liver fat accumulation in patients with NAFLD; nor has the impact of consuming an LGI diet on gut microbiota composition been studied in this population. The aim of this trial is to investigate the effects of LGI diet consumption on liver fat content and its effects on gut microbiota composition in participants with NAFLD compared with a High Glycaemic Index (HGI) control diet. METHODS AND ANALYSIS: A 2×2 cross-over randomised mechanistic dietary trial will allocate 16 participants with NAFLD to a 2-week either HGI or LGI diet followed by a 4-week wash-out period and then the LGI or HGI diet, alternative to that followed in the first 2 weeks. Baseline and postintervention (four visits) outcome measures will be collected to assess liver fat content (using MRI/S and controlled attenuation parameter-FibroScan), gut microbiota composition (using 16S RNA analysis) and blood biomarkers including glycaemic, insulinaemic, liver, lipid and haematological profiles, gut hormones levels and short-chain fatty acids. ETHICS AND DISSEMINATION: Study protocol has been approved by the ethics committees of The University of Nottingham and East Midlands Nottingham-2 Research Ethics Committee (REC reference 19/EM/0291). Data from this trial will be used as part of a Philosophy Doctorate thesis. Publications will be in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04415632.
42Dietary fiber intake, genetic predisposition of gut microbiota, and the risk of metabolic dysfunction-associated steatotic liver disease.PubMed
Jinguo Jiang, Yang Liu, Honghao Yang, et al.
Food Res Int. 2025 Jun;211:116497. doi: 10.1016/j.foodres.2025.116497. Epub 2025 Apr 17.
This study aimed to explore the association between dietary fiber intake and the risk of metabolic dysfunction-associated steatotic liver disease (MASLD), as well as liver fat content, while considering genetic predispositions of MASLD, gut microbial abundance, and butyrate levels. This study analyzed data from 190,276 participants in the UK Biobank. Dietary fiber intake was assessed using 24-h dietary recall. MASLD cases were diagnosed through hospital admission records and death registries, and liver fat content was measured via magnetic resonance imaging. The genetic predispositions of MASLD, gut microbial abundance, and butyrate levels were evaluated using single nucleotide polymorphisms. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95 % confidence intervals (CIs). Over a median follow-up of 10.49 years, 1423 MASLD cases were recorded. Elevated dietary fiber intake was associated with a reduced risk of MASLD (HR: 0.72; 95 % CI: 0.58, 0.90) and a lower level of liver fat content (β: -0.97; 95 % CI: -1.21, -0.73) (all P for trend <0.05). Restricted cubic spline analyses further confirmed the linear inverse associations between fiber intake and the risk of MASLD. Notably, the negative associations between dietary fiber intake and both MASLD and liver fat content were consistent across different genetic predispositions of gut microbial abundance and butyrate levels. Moreover, the inverse association between dietary fiber intake and liver fat was strengthened by high genetic susceptibility of MASLD and elevated body mass index (both P for interaction <0.05). Overall, increased dietary fiber consumption was associated with a lower MASLD risk and decreased liver fat content regardless of genetic predispositions of gut microbial abundance and butyrate levels.
43Seed oil of Rosa roxburghii Tratt against non-alcoholic fatty liver disease in vivo and in vitro through PPARα/PGC-1α-mediated mitochondrial oxidative metabolism.PubMed
Hai-Yan Ni, Liang Yu, Xue-Lian Zhao, et al.
Phytomedicine. 2022 Apr;98:153919. doi: 10.1016/j.phymed.2021.153919. Epub 2022 Jan 1.
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis and hepatocyte injury, is an obesity-induced metabolic dysregulation with few available therapeutic options. Enhancement of the mitochondrial function was considered as an effective treatment for NALFD. Unsaturated fatty acids (UFAs) have been shown to have beneficial effects on metabolic syndrome disease such as hyperlipidemia, coronary artery disease and cardiovascular diseases. The seed oil of Rosa roxburghii Tratt (ORRT) was of high quality in terms of its high amount of unsaturated fatty acids. However, the effects of ORRT on NALFD have not been reported so far. PURPOSE: The study aimed to evaluate the protective effects and molecular mechanism of ORRT for the treatment of NAFLD in vivo and in vitro. METHODS: The beneficial effects, especially improving the mitochondrial function, and the potential mechanism of ORRT on NAFLD were studied both in vivo and in vitro. Lipid levels were determined by triglyceride (TG), total cholesterol (TC), and Oil Red O staining. Oxidative stress and inflammation were assessed by detecting antioxidant enzyme activity, MDA content, and ELISA assay. Blood TG, TC, HDL-c and LDL-c levels were measured in HFD mice. Western blot analyses were used to determine the levels of the protein involved in fatty acid oxidation, oxidative metabolism, and mitochondria biogenesis and function. The mitochondrial membrane potential level was measured by JC-1 staining to teste the effect of ORRT on mitochondrial function in vitro. GW6471 (inhibitor of PPARα) was used to confirm the relationship between PPARα and PGC-1α. RESULTS: ORRT significantly restrained NAFLD progression by attenuating lipid accumulation, oxidative stress and inflammatory response. Furthermore, ORRT upregulated thermogenesis-related gene expressions, such as uncoupling protein 1 (UCP1) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that the expression of key genes involved in fatty acid oxidation (e.g., CPT-1α, ACADL, PPARα) and in mitochondrial biogenesis and function (e.g., TFAM, NRF1, PGC-1α, and COX IV) was significantly increased. Together with the observed MMP improvement, these findings suggested that ORRT activated the mitochondrial oxidative pathway. Additionally, GW6471 inhibited the ORRT on promoting the expression of PGC-1α, CPT-1α, and ACADL. In conclusion, ORRT possessed the potential to prevent lipid accumulation via the PPARα/PGC-1α signaling pathway, which could be developed as a natural health-promoting oil against NAFLD.
44Aerobic vs. resistance exercise in non-alcoholic fatty liver disease: A systematic review.PubMed
Ryuki Hashida, Takumi Kawaguchi, Masafumi Bekki, et al.
J Hepatol. 2017 Jan;66(1):142-152. doi: 10.1016/j.jhep.2016.08.023. Epub 2016 Sep 14.
BACKGROUND & AIMS: Exercise is a first-line therapy for patients with non-alcoholic fatty liver disease (NAFLD). We sought to: 1) summarize effective aerobic and resistance exercise protocols for NAFLD; and 2) compare the effects and energy consumption of aerobic and resistance exercises. METHODS: A literature search was performed using PubMed, Web of Science, and Scopas to January 28, 2016. From a total of 95 articles, 23 studies including 24 aerobic and 7 resistance exercise protocols were selected for the summary of exercise protocols. Twelve articles including 13 aerobic and 4 resistance exercise protocols were selected for the comparative analysis. RESULTS: For aerobic exercise, the median effective protocol was 4.8 metabolic equivalents (METs) for 40min/session, 3times/week for 12weeks. For resistance exercise, the median effective protocol was 3.5 METs for 45min/session, 3times/week for 12weeks. Aerobic and resistance exercise improved hepatic steatosis. No significant difference was seen in the duration, frequency, or period of exercise between the two exercise groups; however, %VOmax and energy consumption were significantly lower in the resistance than in the aerobic group (50% [45-98] vs. 28% [28-28], p=0.0034; 11,064 [6394-21,087] vs. 6470 [4104-12,310] kcal/total period, p=0.0475). CONCLUSIONS: Resistance exercise improves NAFLD with less energy consumption. Thus, resistance exercise may be more feasible than aerobic exercise for NAFLD patients with poor cardiorespiratory fitness or for those who cannot tolerate or participate in aerobic exercise. These data may indicate a possible link between resistance exercise and lipid metabolism in the liver. LAY SUMMARY: Both aerobic and resistance exercise reduce hepatic steatosis in non-alcoholic fatty liver disease (NAFLD) with similar frequency, duration, and period of exercise (40-45min/session 3times/week for 12weeks); however, the two forms of exercise have different characteristics. Intensity and energy consumption were significantly lower for resistance than for aerobic exercise. Resistance exercise may be more feasible than aerobic exercise for NAFLD patients with poor cardiorespiratory fitness or for those who cannot tolerate or participate in aerobic exercise.
45Muscle strength and non-alcoholic fatty liver disease/metabolic-associated fatty liver disease.PubMed
Xuan-Yu Hao, Kai Zhang, Xing-Yong Huang, et al.
World J Gastroenterol. 2024 Feb 21;30(7):636-643. doi: 10.3748/wjg.v30.i7.636.
This editorial comments on an article published in a recent issue of entitled "Association of low muscle strength with metabolic dysfunction-associated fatty liver disease: A nationwide study". We focused on the association between muscle strength and the incidence of non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD), as well as the mechanisms underlying the correlation and related clinical applications. NAFLD, which is now redefined as MAFLD, is one of the most common chronic liver diseases globally with an increasing prevalence and is characterized by malnutrition, which may contribute to decreased muscle strength. Reduction of muscle strength reportedly has a pathogenesis similar to that of NAFLD/ MAFLD, including insulin resistance, inflammation, sedentary behavior, as well as insufficient vitamin D. Multiple studies have focused on the relationship between sarcopenia or muscle strength and NAFLD. However, studies investigating the relationship between muscle strength and MAFLD are limited. Owing to the shortage of specific medications for NAFLD/MAFLD treatment, early detection is essential. Furthermore, the relationship between muscle strength and NAFLD/MAFLD suggests that improvements in muscle strength may have an impact on disease prevention and may provide novel insights into treatments including dietary therapy, as well as tailored physical activity.
46Metabolic dysfunction-associated steatotic liver disease: A story of muscle and mass.PubMed
Vasily Isakov
World J Gastroenterol. 2025 May 28;31(20):105346. doi: 10.3748/wjg.v31.i20.105346.
Skeletal muscle alterations (SMA) are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting disease progression and outcomes. Sarcopenia is common in patients with MASLD, with a prevalence ranging from 20% to 40% depending on the population and diagnostic criteria used. In advanced stages, such as metabolic dysfunction-associated steatohepatitis and fibrosis, its prevalence is even higher. Sarcopenia exacerbates insulin resistance, systemic inflammation, and oxidative stress, all of which worsen MASLD. It is an independent risk factor for fibrosis progression and poor outcomes including mortality. Myosteatosis refers to the abnormal accumulation of fat within muscle tissue, leading to decreased muscle quality. Myosteatosis is prevalent (> 30%) in patients with MASLD, especially those with obesity or type 2 diabetes, although this can vary with the imaging techniques used. It reduces muscle strength and metabolic efficiency, further contributing to insulin resistance and is usually associated with advanced liver disease, cardiovascular complications, and lower levels of physical activity. Altered muscle metabolism, which includes mitochondrial dysfunction and impaired amino acid metabolism, has been reported in metabolic syndromes, including MASLD, although its actual prevalence is unknown. Altered muscle metabolism limits glucose uptake and oxidation, worsening hyperglycemia and lipotoxicity. Reduced muscle perfusion and oxygenation due to endothelial dysfunction and systemic metabolic alterations are common in MASLD associated with comorbidities, such as obesity, hypertension, and atherosclerosis. It decreases the muscle capacity for aerobic metabolism, leading to fatigue and reduced physical activity in patients with MASLD, aggravating metabolic dysfunction. Various SMA in MASLD worsen insulin resistance and hepatic fat accumulation, may accelerate progression to fibrosis and cirrhosis, and increase the risk of cardiovascular disease and mortality. Management strategies for SMA include resistance training, aerobic exercise, and nutritional support (, high-protein diets, vitamin D, and omega-3 fatty acids), which are essential for mitigating skeletal muscle loss and improving outcomes. However, pharmacological agents that target the muscle and liver (such as glucagon-like peptide-1 receptor agonists) show promise but have not yet been approved for the treatment of MASLD.
47"Weekend Warrior" Exercise Pattern Protects Against MASLD and Mortality Comparable to Regular Exercise: National Cohort Study.PubMed
Shira Zelber-Sagi, James M Paik, Dana Ivancovsky-Wajcmen, et al.
Liver Int. 2025 Aug;45(8):e70226. doi: 10.1111/liv.70226.
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) guidelines recommend > 150 min per week of moderate-to-vigorous physical activity (MVPA). It is unclear if concentrating MVPA into 1-2 days per week ["weekend warrior" (WW) pattern] offers similar benefits to spreading activity throughout the week. We aimed to assess the association of WW activity pattern with MASLD prevalence, mortality, and atherosclerotic cardiovascular disease (ASCVD) risk among individuals with MASLD. METHODS: Data from the National Health and Nutrition Examination Survey 2003-2006 were linked to mortality records through 2019. Using accelerometer measurements, participants were categorised as WW (> 150 min of MVPA with ≥ 50% of total MVPA accomplished over 1-2 days), active (> 150 min of MVPA, not meeting WW criteria) and inactive (≤ 150 min of MVPA per week). MASLD was defined as a United States Fatty Liver Index (US FLI) ≥ 30 with at least one cardiometabolic risk factor, excluding other liver diseases. RESULTS: Among 2490 participants (mean age: 48.5 years; 47.4% male), both WW and active groups had lower odds of MASLD compared to the inactive group [WW; OR: 0.36 (95% CI 0.24-0.53); active; OR: 0.47 (0.36-0.62)], adjusting for sociodemographic variables. Among 859 MASLD, over 14.3 of years median follow-up, multivariable Cox regression showed lower all-cause mortality in the WW [HR: 0.35 (0.13-0.94)] and active [HR: 0.48 (0.24-0.98)] groups. Both WW [OR: 0.27 (0.09-0.75)] and active [OR: 0.39 (0.20-0.78)] groups had lower odds of high ASCVD risk. CONCLUSIONS: WW physical activity patterns protect from MASLD and all-cause mortality comparable to regular exercise.
48Association of Daily Steps with Incident Nonalcoholic Fatty Liver Disease: Evidence from the UK Biobank Cohort.PubMed
Evelynne S Fulda, Laura Portas, Charlie Harper, et al.
Med Sci Sports Exerc. 2025 Sep 1;57(9):1905-1913. doi: 10.1249/MSS.0000000000003738. Epub 2025 Apr 24.
PURPOSE: Low physical activity has been shown to be associated with a higher risk of nonalcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study. METHODS: The wrist-worn accelerometer substudy of the UK Biobank ( N = ~100,000) was used to characterize median daily step count over a 7-d period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. RESULTS: Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 min of walking) was associated with a 12% (95% confidence interval, 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1000-step increase was associated with a 6% (95% confidence interval, 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association. CONCLUSIONS: Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.
49Impact of healthy lifestyles on the risk of metabolic dysfunction-associated steatotic liver disease among adults with comorbid hypertension and diabetes: Novel insight from a largely middle-aged and elderly cohort in South China.PubMed
Jun-Yan Xi, Yi-Jing Wang, Xiao-Heng Li, et al.
Diabetes Obes Metab. 2025 May;27(5):2800-2809. doi: 10.1111/dom.16289. Epub 2025 Mar 7.
AIMS: The association between lifestyle and metabolic dysfunction-associated steatotic liver disease (MASLD) has been well documented. However, evidence is still limited from vulnerable populations, especially middle-aged and elderly adults with comorbid hypertension and diabetes, who are at higher risk of developing MASLD than the general population. We aimed to examine the potential causal links of a healthy lifestyle with the risk of MASLD in this vulnerable population. MATERIALS AND METHODS: A total of 41,964 middle-aged and elderly participants with comorbid hypertension and diabetes were included in a longitudinal cohort from 2010 to 2023. Weighted scores for lifestyle were evaluated by exercise frequency, alcohol consumption, smoking status and salt intake. Marginal structural models were used to estimate the single lifestyle-MASLD associations, which were further risk stratified by quartile ranges of weighted scores. RESULTS: A mean follow-up period of 5.2 years (217 972 person-years) revealed that 21 697 participants developed MASLD. The hazard ratio (HR) of daily exercise, never consuming alcohol, never smoking and low salt intake for the risk of MASLD was 0.617 (95% confidence interval: 0.365 ~ 1.042), 0.237 (0.093 ~ 0.603), 0.153 (0.097 ~ 0.240) and 0.945 (0.919 ~ 0.971), respectively. Compared with weighted scores that were below the 25th percentile, the HR was 0.952 (0.902 ~ 1.005), 0.747 (0.694 ~ 0.803) and 0.097 (0.065 ~ 0.144) for the 25th, 50th and 75th percentiles, respectively. CONCLUSIONS: In this vulnerable population, daily exercise, abstinence from alcohol and smoking and a low-salt diet may reduce the risk of MASLD, and the most stringent combination of healthy lifestyles could reduce the risk of MASLD by over 90%.
50Association between non-alcoholic fatty liver disease and obstructive sleep apnea.PubMed
Ilaria Umbro, Valerio Fabiani, Mario Fabiani, et al.
World J Gastroenterol. 2020 May 28;26(20):2669-2681. doi: 10.3748/wjg.v26.i20.2669.
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is an emerging liver disease and currently the most common cause of incidental abnormal liver tests. The pathogenesis of NAFLD is multifactorial and many mechanisms that cause fatty liver infiltration, inflammation, oxidative stress and progressive fibrosis have been proposed. Obstructive sleep apnea (OSA) may be linked with the pathogenesis and the severity of NAFLD. AIM: To study the association between NAFLD and OSA considering also the efficacy of continuous positive airway pressure (CPAP) treatment. METHODS: A PubMed search was conducted using the terms "non-alcoholic fatty liver disease AND (obstructive sleep apnea OR obstructive sleep disorders OR sleep apnea)". Research was limited to title/abstract of articles published in English in the last 5 years; animal and child studies, case reports, commentaries, letters, editorials and meeting abstracts were not considered. Data were extracted on a standardized data collection table which included: First author, publication year, country, study design, number of patients involved, diagnosis and severity of OSA, diagnosis of NAFLD, patient characteristics, results of the study. RESULTS: In total, 132 articles were initially retrieved on PubMed search and 77 in the last five years. After removal of irrelevant studies, 13 articles were included in the qualitative analysis. There was a total of 2753 participants across all the studies with a mean age between 42 and 58 years. The proportion of males ranged from 21% to 87.9% and the mean body mass index ranged from 24.0 to 49.9 kg/m. The results of this review showed an increased prevalence of NAFLD in patients with diagnosis of OSA, even in the absence of coexisting comorbidities such as obesity or metabolic syndrome. Furthermore, the severity of NAFLD is associated with the increase in OSA severity. Effective CPAP treatment, although not always decisive, may stabilize or slow NAFLD progression with benefits on metabolic and cardiovascular functions. CONCLUSION: In NAFLD patients, although asymptomatic, it is recommended to systematically perform polysomnography in order to early and better treat them before the development of potentially life threatening systemic dysfunctions.
51Sleep apnoea and metabolic dysfunction.PubMed
Maria R Bonsignore, Anne-Laure Borel, Elizabeth Machan, et al.
Eur Respir Rev. 2013 Sep 1;22(129):353-64. doi: 10.1183/09059180.00003413.
Obstructive sleep apnoea (OSA) is a highly prevalent condition often associated with central obesity. In the past few years, several studies have analysed the potential independent contribution of OSA to the pathogenesis of metabolic abnormalities, including type 2 diabetes, the metabolic syndrome and non-alcoholic fatty liver disease. New perspectives in OSA patient care have been opened by the promotion of lifestyle interventions, such as diet and exercise programmes that could improve both OSA and the metabolic profile. The rich clinical literature on this subject, together with the growing amount of data on pathophysiological mechanisms provided by animal studies using the chronic intermittent hypoxia model, urged the organising Committee of the Sleep and Breathing meeting to organise a session on sleep apnoea and metabolic dysfunction, in collaboration with the European Association for the Study of Diabetes. This review summarises the state-of-the-art lectures presented in the session, more specifically the relationship between OSA and diabetes, the role of OSA in the metabolic consequences of obesity, and the effects of lifestyle interventions on nocturnal respiratory disturbances and the metabolic profile in OSA patients.
52Occupational stress trajectories and metabolic dysfunction-associated steatotic liver disease among female nurses: a prospective Cohort Study.PubMed
Hanxiao Luo, Linlin Xing, Tongtong Fu, et al.
BMC Public Health. 2024 Nov 16;24(1):3188. doi: 10.1186/s12889-024-20742-z.
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prominent cause of chronic liver disease, and occupational stress may serve as a potential risk factor. This study aims to assess the association between occupational stress trajectories and incident MASLD among Chinese female nurses. METHODS: We conducted a prospective longitudinal study using data from the Nurse' Health Cohort Study, involving 1,113 female nurses, free of MASLD at baseline (2018). Occupational stress was measured using the Chinese Nurse Job Stress Scale at four time points. Group-based trajectory modeling was used to identify distinct stress trajectories. Through doctors' diagnoses, we assessed incident MASLD over a subsequent 6-year period from 2019 to 2024. Cox proportional hazards regression models evaluated the association of stress trajectories and MASLD risk, adjusting for demographics, work-related factors, and medical conditions. RESULTS: During follow-up, 256 nurses reported incident physician-diagnosed MASLD. Three occupational stress trajectories were identified: moderate decreasing (36.4%), moderate stable (55.9%), and moderate increasing (7.7%). Participants in the moderate increasing stress trajectory had a significantly higher risk of developing MASLD (adjusted HR: 3.14, 95% CI: 2.19-4.49, p < .001) compared to those in the moderate stable trajectory. This association between stress trajectory and MASLD risk was not modified by age or BMI (p>0.50). CONCLUSIONS AND RELEVANCE: The study concludes that increasing stress levels over time are associated with a higher incidence of MASLD. These findings underscore the importance of stress management interventions in reducing the risk of MASLD progression. Further research is needed to explore the underlying mechanisms and to develop targeted strategies for stress reduction in clinical settings.
53The effects of HAPA theory-based case management in patients with metabolic dysfunction-associated steatotic liver disease.PubMed
Jia Mei, Yuncai Xie, Pingping Huang, et al.
Ann Hepatol. 2025 Jul-Dec;30(2):101790. doi: 10.1016/j.aohep.2025.101790. Epub 2025 Feb 14.
INTRODUCTION AND OBJECTIVES: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease affecting people's health, with its incidence increasing year by year. This study aims to determine the effects of Health Action Process Approach (HAPA)-based health management on patients diagnosed with MASLD. PATIENTS AND METHODS: 204 MASLD patients were selected from the hospital's physical examination center from January 1, 2023, through April 1, 2023. Patients are randomly assigned to two groups (n = 102 each) using an envelope-based. Individuals in the experimental group received case management based on the HAPA theory, while standard health management was employed for control group patients. All subjects were monitored over a 6-month period, comparing body mass index (BMI), waist-to-hip ratio (WHR), levels of liver function (AST, ALT), blood lipid levels (total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and health behaviours (as assessed with the HPLP-II health promotion lifestyle scale) before and after the intervention. RESULTS: Post-intervention, the experimental group showed significant improvement in fatty liver (P < 0.01) and reductions in biochemical indices, BMI, and WHR levels (P < 0.05), and a corresponding improvement in HDL-C levels (P < 0.001), compared to the control group. Additionally, patients in the experimental group exhibited significantly better health behaviour scores related to stress management, exercise, diet, and health responsibility compared to controls (P < 0.01). CONCLUSIONS: HAPA theory-based case management can improve blood lipid profiles, liver function, and health-related behaviours in MASLD patients, highlighting its potential as an effective management strategy for this condition.
54Resmetirom: First Approval.PubMed
Susan J Keam
Drugs. 2024 Jun;84(6):729-735. doi: 10.1007/s40265-024-02045-0. Epub 2024 May 21.
Resmetirom (Rezdiffra™) is an oral thyroid hormone receptor-β (THR-β) agonist being developed by Madrigal Pharmaceuticals, Inc., to target the key underlying causes of metabolic dysfunction associated steatohepatitis (MASH) [previously known as nonalcoholic steatohepatitis (NASH)]. In March 2024, resmetirom was approved for use (under accelerated approval) in conjunction with diet and exercise for the treatment of adults with noncirrhotic NASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis) in the USA. Resmetirom is also under regulatory review in the EU for the treatment of MASH/NASH. This article summarizes the milestones in the development of resmetirom leading to this first approval for the treatment of adults with MASH/NASH.
55Resmetirom: the first approved therapy for treating metabolic dysfunction associated steatohepatitis.PubMed
Sheena Bhushan, Aalam Sohal, Mazen Noureddin, et al.
Expert Opin Pharmacother. 2025 Apr;26(6):663-675. doi: 10.1080/14656566.2025.2478917. Epub 2025 Mar 19.
INTRODUCTION: Metabolic dysfunction associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH), has emerged as one of the leading indications for liver transplantation in the United States. The disease is associated with increased cardiovascular mortality in patients with early-stage liver fibrosis and a heightened risk of hepatic complications in those with advanced fibrosis. Despite its growing prevalence and significant healthcare burden, there were no approved drugs to treat this chronic disease. In March 2024, Resmetirom, a selective thyroid hormone receptor-beta agonist, became the first drug to receive FDA approval for the treatment of patients with MASH and fibrosis stages F2/F3. This accelerated approval was granted based on significantly higher rates of MASH resolution and fibrosis. AREAS COVERED: This review summarizes the current literature on the mechanism of action, preclinical data, pharmacokinetics, clinical efficacy, indications, and contraindications of resmetirom in the management of patients with MASH. EXPERT OPINION: The approval of resmetirom for patients with MASH and moderate to advanced hepatic fibrosis is a major advance in the management of MASH. The recent positive results of the ESSENCE trial of semaglutide, if associated with conditional approval, may offer clinicians two options to treat MASH in patients with moderate to advanced fibrosis.
56Resmetirom, the first FDA-approved drug for MASH: From drug discovery and action mechanisms to clinical trials.PubMed
Jiaman Liu, Fenghua Yang, Boya Gao, et al.
Arch Pharm Res. 2025 Dec;48(11-12):1299-1313. doi: 10.1007/s12272-025-01574-w. Epub 2025 Oct 30.
Metabolically-dysfunction-associated steatohepatitis (MASH) represents one spectrum of MASLD, affecting over 5.27% of adults globally. Until the approval of resmetirom, no pharmacological therapies were available for MASH. Resmetirom is prescribed for the management of non-cirrhotic MASH in adults with moderate to advanced hepatic fibrosis, specifically at Stages F2 to F3. This drug is uniquely transported via liver-targeted transporters and exerts its effects by closely replicating the physiological actions of T3 (FT3). It exhibits a 28-fold selectivity for the thyroid hormone receptor beta (THR-β), predominant in the liver, over THR-α in functional assays. The approval of resmetirom marks a significant milestone, addressing a critical unmet need in MASH treatment while initiating a new chapter in therapeutic strategies for this complex chronic liver disease.
57The first MASH drug therapy on the horizon: Current perspectives of resmetirom.PubMed
Salvatore Petta, Giovanni Targher, Stefano Romeo, et al.
Liver Int. 2024 Jul;44(7):1526-1536. doi: 10.1111/liv.15930. Epub 2024 Apr 5.
The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver-targeted thyroid hormone receptor-β selective drug, has shown promise in clinical trials for treating non-cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long-term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non-invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.
58An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH.PubMed
Frank Tacke, Tobias Puengel, Rohit Loomba, et al.
J Hepatol. 2023 Aug;79(2):552-566. doi: 10.1016/j.jhep.2023.03.038. Epub 2023 Apr 14.
Successful development of treatments for non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH), has been challenging. Because NASH and fibrosis lead to progression towards cirrhosis and clinical outcomes, approaches have either sought to attenuate metabolic dysregulation and cell injury, or directly target the inflammation and fibrosis that ensue. Targets for reducing the activation of inflammatory cascades include nuclear receptor agonists (e.g. resmetirom, lanifibranor, obeticholic acid), modulators of lipotoxicity (e.g. aramchol, acetyl-CoA carboxylase inhibitors) or modification of genetic variants (e.g. PNPLA3 gene silencing). Extrahepatic inflammatory signals from the circulation, adipose tissue or gut are targets of hormonal agonists (semaglutide, tirzepatide, FGF19/FGF21 analogues), microbiota or lifestyle interventions. Stress signals and hepatocyte death activate immune responses, engaging innate (macrophages, innate lymphocyte populations) and adaptive (auto-aggressive T cells) mechanisms. Therapies have also been developed to blunt immune cell activation, recruitment (chemokine receptor inhibitors), and responses (e.g. galectin-3 inhibitors, anti-platelet drugs). The disease-driving pathways of NASH converge to elicit fibrosis, which is reversible. The activation of hepatic stellate cells into matrix-producing myofibroblasts can be inhibited by antagonising soluble factors (e.g. integrins, cytokines), cellular crosstalk (e.g. with macrophages), and agonising nuclear receptor signalling. In advanced fibrosis, cell therapy with restorative macrophages or reprogrammed (CAR) T cells may accelerate repair through hepatic stellate cell deactivation or killing, or by enhancing matrix degradation. Heterogeneity of disease - either due to genetics or divergent disease drivers - is an obstacle to defining effective drugs for all patients with NASH that will be overcome incrementally.
59Efficacy and safety of resmetirom in MASLD and MASH: network meta-analysis of randomized clinical trials.PubMed
Hazem Ayesh, Azizullah Beran, Sajida Suhail, et al.
J Basic Clin Physiol Pharmacol. 2025 Jan 9;36(1):3-11. doi: 10.1515/jbcpp-2024-0140. eCollection 2025 Jan 1.
INTRODUCTION: Metabolic-Associated Steatohepatitis-Related Liver Disease (MASLD) and, its progressive form, Metabolic-Associated Steatohepatitis (MASH) pose significant global health challenges. Current therapeutic strategies targeting metabolic abnormalities have shown promise but lack specificity for the liver. Thyroid hormones, particularly thyroid hormone receptor beta (THR-β) agonists like resmetirom, offer a targeted approach to liver-related pathways. CONTENT: A network meta-analysis (NMA) comparing different doses of resmetirom to placebo for MASLD and MASH was conducted. PubMed, Scopus, Cochrane, and Web of Science were searched for relevant randomized controlled trials (RCTs). Efficacy outcomes included histological, radiological, and biochemical parameters, while safety outcomes comprised adverse events and treatment discontinuation. SUMMARY: Resmetirom demonstrated dose-dependent efficacy in histological and radiological assessments, with the 100 mg dose showing superior MASH resolution and hepatic fat reduction. Biochemical markers indicated improved liver function with resmetirom treatment. However, adverse events, particularly diarrhea and nausea, were more prevalent in the resmetirom group, leading to higher treatment discontinuation rates. OUTLOOK: Resmetirom shows promise as a therapeutic option for MASLD and MASH management, with significant improvements in liver health parameters. However, safety concerns warrant careful monitoring in clinical practice. Further research is needed to optimize its long-term safety and efficacy.
60Safety and efficacy of resmetirom in metabolic dysfunction-associated steatohepatitis (MASH): a systematic review and meta-analysis.PubMed
Laraib Abbasi, Qunoot Irfan, Syed Muhammad Mehdi Zaidi, et al.
Eur J Gastroenterol Hepatol. 2025 Apr 1;37(4):395-402. doi: 10.1097/MEG.0000000000002901. Epub 2024 Dec 3.
Metabolic dysfunction-associated steatohepatitis (MASH) affects nearly 38% of the population, potentially progressing to cirrhosis and cancer. Lifestyle changes remain the cornerstone of management, but adherence is challenging, prompting the exploration of therapeutic options. Resmetirom, targeting thyroid hormone receptors, regulates liver enzymes and fat metabolism, showing potential as a treatment for MASH. This systematic review and meta-analysis evaluates the safety of resmetirom in MASH patients. Three randomized controlled trials with adult participants were analyzed, sourced from PubMed and the Cochrane Library until April 2024. Participants received either resmetirom or placebo, and data on adverse effects and efficacy outcomes were extracted. Statistical analyses, including risk ratios (RRs) and confidence intervals (CI), were performed using Review Manager (version 5.4.1) with a random-effects model. The pooled RR for serious adverse events was 0.85 (95% CI: 0.63-1.14; P = 0.28), indicating no significant difference. However, diarrhea (RR = 1.82, 95% CI: 1.41-2.35; P < 0.001) and nausea (RR = 1.73, 95% CI: 1.31-2.28; P < 0.001) showed higher incidence. No significant differences were found for fatigue (RR = 1.19, 95% CI: 0.77-1.84; P = 0.43) or urinary tract infections (RR = 1.07, 95% CI: 0.76-1.52; P = 0.69). Liver fat content, lipid profiles, and liver enzymes also showed significant improvement in the resmetirom group. Low heterogeneity across most outcomes indicated consistent findings among the studies. While resmetirom demonstrates efficacy in improving lipid and liver profiles, its increased risk of diarrhea and nausea should be considered in therapeutic decisions.
61Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease?PubMed
Maximilian Huttasch, Michael Roden, Sabine Kahl
Metabolism. 2024 Aug;157:155937. doi: 10.1016/j.metabol.2024.155937. Epub 2024 May 21.
Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRβ-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.
62Efficacy and safety of resmetirom among patients with non-alcoholic steatohepatitis: a systematic review and meta-analysis.PubMed
Saad Mazhar, Aima Azhar, Ariba Khan, et al.
Ann Med Surg (Lond). 2024 Jul 15;86(9):5447-5454. doi: 10.1097/MS9.0000000000002314. eCollection 2024 Sep.
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a severe medical illness that has few available therapeutic options. Resmetirom, a liver-targeting agonist of the thyroid hormone receptor (THR), has recently been licenced by the FDA. We assess the effectiveness and safety of resmetirom in patients with NASH. METHODS: PubMed, SCOPUS and Cochrane Central were searched till March 2024 to find potential articles. Outcomes assessed included MRI-proton density fat fraction (MRI-PDFF), Fat Reduction, and NASH Resolution Without Fibrosis, changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), low-density lipoprotein (LDL), and triglyceride (TG) levels, along with diarrhoea, nausea, urinary tract infection (UTI), and headache. Subgroup analysis was performed between outcomes before and after 6 months. Outcomes were analyzed with a random-effects model and results presented as mean difference (MD) for continuous outcomes and odds ratios (OR) for safety analysis, along with their 95% confidence intervals. A risk of bias assessment was performed using Cochrane Risk of Bias tool. RESULTS: Four randomized controlled trials (RCTs) were included in our analysis. Resmetirom shown a substantial improvement in MRI-PDFF with a MD of -19.23 (<0.00001). Additionally, it resulted in a 30% reduction in fat (OR: 3.54, =0.004) and resolution of NASH without fibrosis (OR: 2.41, =0.04). There was no notable enhancement observed in AST levels, with a mean difference of -0.87 and a value of 0.73. The usage of resmetirom resulted in significant improvement in ALT levels (MD: -4.36, value: 0.32), GGT levels (MD: -17.87, value: <0.00001), TG levels (MD: -23.48, value: <0.00001), LDL levels (mean difference: -12.80, value: <0.00001), and rT3 levels (MD: -2.08, value: <0.00001). The use of Resmetirom was associated with a higher likelihood of experiencing diarrhoea (OR: 2.07, <0.0001) and nausea (OR: 1.81, =0.0003). However, there was no significant difference observed in the occurrence of UTI (OR: 1.04, =0.85) or headaches (OR: 0.79, =0.48). CONCLUSION: Resmetirom demonstrates efficacy in enhancing MRI-PDFF score, diminishing adipose tissue, resolving NASH without fibrosis, reducing GGT, TG, LDL, reverse triiodothyronine (rT3) levels in NASH patients. Nevertheless, there is also an observed heightened susceptibility to experiencing diarrhoea and nausea. Additional trials are necessary to further examine the efficacy and safety of this medication.
63Safety and efficacy of resmetirom in the treatment of patients with non-alcoholic steatohepatitis and liver fibrosis: a systematic review and meta-analysis.PubMed
Adarsh Raja, Raja Subhash Sagar, Sadia Saeed, et al.
Ann Med Surg (Lond). 2024 May 22;86(7):4130-4138. doi: 10.1097/MS9.0000000000002195. eCollection 2024 Jul.
INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD), spanning from non-alcoholic steatohepatitis (NASH) to liver fibrosis, poses a global health challenge amid rising obesity and metabolic syndrome rates. Effective pharmacological treatments for NASH and liver fibrosis are limited. OBJECTIVE: This study systematically reviews and meta-analyzes the safety and efficacy of resmetirom, a selective thyroid hormone receptor-β agonist, in NASH and liver fibrosis treatment. By analyzing data from clinical trials, we aim to offer evidence-based recommendations for resmetirom's use in managing these conditions and identify avenues for future research. METHODS: Electronic databases (PubMed, Scopus, Science Direct, Google Scholar, ClinicalTrials.gov, and Cochrane CENTRAL) were systematically searched, supplemented by manual screening of relevant sources. Only English-language randomized controlled trials were included. Data extraction, risk of bias assessment, pooled analyses, and meta-regression were performed. RESULTS: Three randomized controlled trials involving 2231 participants were analyzed. Resmetirom demonstrated significant reductions in hepatic fat fraction [standardized mean difference (SMD) -4.61, 95% CI -6.77 to -2.44, < 0.0001], NASH resolution without worsening fibrosis [risk ratio (RR) 2.51, 95% CI 1.74-3.64, = 0.00001), and liver fibrosis improvement (RR 2.31, 95% CI 1.20-4.44, = 0.01). Secondary outcomes showed significant improvements in lipid profiles, liver enzymes, and NASH biomarkers with resmetirom treatment. Meta-regression revealed associations between covariates and primary outcomes. CONCLUSION: Resmetirom exhibits promising efficacy in reducing hepatic fat, improving NASH resolution, and ameliorating liver fibrosis with a favorable safety profile. Further research is warranted to validate findings and optimize therapeutic strategies for NASH and liver fibrosis management.
64A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.PubMed
Stephen A Harrison, Pierre Bedossa, Cynthia D Guy, et al.
N Engl J Med. 2024 Feb 8;390(6):497-509. doi: 10.1056/NEJMoa2309000.
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).
65NAFLD and NAFLD Related HCC: Emerging Treatments and Clinical Trials.PubMed
Tripti Khare, Karina Liu, Lindiwe Oslee Chilambe, et al.
Int J Mol Sci. 2025 Jan 1;26(1):306. doi: 10.3390/ijms26010306.
Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most prevalent liver disease worldwide. It is associated with an increased risk of developing hepatocellular carcinoma (HCC) in the background of cirrhosis or without cirrhosis. The prevalence of NAFLD-related HCC is increasing all over the globe, and HCC surveillance in NAFLD cases is not that common. In the present review, we attempt to summarize promising treatments and clinical trials focused on NAFLD, nonalcoholic steatohepatitis (NASH), and HCC in the past five to seven years. We categorized the trials based on the type of intervention. Most of the trials are still running, with only a few completed and with conclusive results. In clinical trial NCT03942822, 25 mg/day of milled chia seeds improved NAFLD condition. Completed trial NCT03524365 concluded that Rouxen-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) results in histological resolution of NASH without worsening of fibrosis, while NCT04677101 validated sensitivity/accuracy of blood biomarkers in predicting NASH and fibrosis stage. Moreover, trials with empagliflozin (NCT05694923), curcuvail (NCT06256926), and obeticholic acid (NCT03439254) were completed but did not provide conclusive results. However, trial NCT03900429 reported effective improvement in fibrosis by at least one stage, without worsening of NAFLD activity score (NAS), as well as improvement in lipid profile of the NASH patients by 80 or 100 mg MGL-3196 (resmetirom). Funded by Madrigal Pharmaceuticals, Rezdiffra (resmetirom), used in the clinical trial NCT03900429, is the first FDA-approved drug for the treatment of NAFLD/NASH.
66Linking Cardiovascular Disease and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): The Role of Cardiometabolic Drugs in MASLD Treatment.PubMed
Marios Zisis, Maria Eleni Chondrogianni, Theodoros Androutsakos, et al.
Biomolecules. 2025 Feb 23;15(3):324. doi: 10.3390/biom15030324.
The link between cardiovascular disease (CVD) and metabolic dysfunction-associated steatotic liver disease (MASLD) is well-established at both the epidemiological and pathophysiological levels. Among the common pathophysiological mechanisms involved in the development and progression of both diseases, oxidative stress and inflammation, insulin resistance, lipid metabolism deterioration, hepatokines, and gut dysbiosis along with genetic factors have been recognized to play a pivotal role. Pharmacologic interventions with drugs targeting common modifiable cardiometabolic risk factors, such as T2DM, dyslipidemia, and hypertension, are a reasonable strategy to prevent CVD development and progression of MASLD. Recently, a novel drug for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom, has shown positive effects regarding CVD risk, opening new opportunities for the therapeutic approach of MASLD and CVD. This review provides current knowledge on the epidemiologic association of MASLD to CVD morbidity and mortality and enlightens the possible underlying pathophysiologic mechanisms linking MASLD with CVD. The role of cardiometabolic drugs such as anti-hypertensive drugs, hypolipidemic agents, glucose-lowering medications, acetylsalicylic acid, and the thyroid hormone receptor-beta agonist in the progression of MASLD is also discussed. Metformin failed to prove beneficial effects in MASLD progression. Studies on the administration of thiazolinediones in MASLD suggest effectiveness in improving steatosis, steatohepatitis, and fibrosis, while newer categories of glucose-lowering agents such as GLP-1Ra and SGLT-2i are currently being tested for their efficacy across the whole spectrum of MASLD. Statins alone or in combination with ezetimibe have yielded promising results. The conduction of long-duration, large, high-quality, randomized-controlled trials aiming to assess by biopsy the efficacy of cardiometabolic drugs to reverse MASLD progression is of great importance.
67Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.PubMed
Arun J Sanyal, Philip N Newsome, Iris Kliers, et al.
N Engl J Med. 2025 Jun 5;392(21):2089-2099. doi: 10.1056/NEJMoa2413258. Epub 2025 Apr 30.
BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). METHODS: In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. The results of a planned interim analysis conducted at week 72 involving the first 800 patients are reported here (part 1). The primary end points for part 1 were the resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. RESULTS: Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Results for the three secondary outcomes that were included in the plan to adjust for multiple testing were as follows: combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo (estimated difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001). Mean changes in bodily pain scores did not differ significantly between the two groups. Gastrointestinal adverse events were more common in the semaglutide group. CONCLUSIONS: In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT04822181.).
68Mechanism of Semaglutide in MASLD Treatment: Where Is the Master Key?PubMed
Devaraj Ezhilarasan
J Gastroenterol Hepatol. 2025 Sep;40(9):2163-2175. doi: 10.1111/jgh.17037. Epub 2025 Jun 19.
BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is used for weight reduction and metabolic improvement. Semaglutide effectively improves MASH but not confers histological fibrosis resolution. The key question remains whether semaglutide exerts direct, independent effects in ameliorating MASH or if its benefits are merely secondary to improvements in weight, insulin resistance, and glycemic control. The exact mechanisms of action through which semaglutide or other GLP-1 RAs offer liver protection are not entirely clear. METHODS: A comprehensive search in PubMed and EMBASE was conducted using the keywords "Semaglutide and NAFLD/MASLD", "glucagon-like peptide-1 receptor agonist and MASLD/NALFD", and "Semaglutide and type II diabetes/obesity and hypertension". Relevant papers published before February, 2025, were included. RESULTS: Semaglutide modulates several lipid-associated molecular pathways through unknown mechanisms. Preclinical and clinical studies suggest that semaglutide acts by (i) reducing appetite and increasing satiety, thereby decreasing dietary intake and subsequent free fatty acid export to the liver; (ii) reducing insulin resistance and improving insulin sensitivity and adipose dysfunction; (iii) reducing de novo lipogenesis by downregulating ChREBP and SREBP-1c signaling, as well as the expression of lipid-synthesizing genes; (iv) reducing the weight of white and brown adipose tissue; and (v) reducing inflammation by decreasing pro-inflammatory markers in GLP-1-expressing macrophages and favorably altering the gut microbiota. CONCLUSION: While this review explores the potential mechanisms of semaglutide action, the lack of GLP-1 receptor expression in the livers of mice and humans suggests that these mechanisms are associated with indirect modulation. Consequently, further mechanistic studies are needed to elucidate these pathways. TRIAL REGISTRATION: NOT APPLICABLE.
69The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet.PubMed
Emmanuel Somm, Sophie A Montandon, Ursula Loizides-Mangold, et al.
Transl Res. 2021 Jan;227:75-88. doi: 10.1016/j.trsl.2020.07.008. Epub 2020 Jul 22.
Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disorder related to type 2 diabetes (T2D). The disease can evolve toward nonalcoholic steatohepatitis (NASH), a state of hepatic inflammation and fibrosis. There is presently no drug that effectively improves and/or prevents NAFLD/NASH/fibrosis. GLP-1 receptor agonists (GLP-1Ra) are effective in treating T2D. As with the endogenous gut incretins, GLP-1Ra potentiate glucose-induced insulin secretion. In addition, GLP-1Ra limit food intake and weight gain, additional beneficial properties in the context of obesity/insulin-resistance. Nevertheless, these pleiotropic effects of GLP-1Ra complicate the elucidation of their direct action on the liver. In the present study, we used the classical methionine-choline deficient (MCD) dietary model to investigate the potential direct hepatic actions of the GLP-1Ra liraglutide. A 4-week infusion of liraglutide (570 µg/kg/day) did not impact body weight, fat accretion or glycemic control in MCD-diet fed mice, confirming the suitability of this model for avoiding confounding factors. Liraglutide treatment did not prevent lipid deposition in the liver of MCD-fed mice but limited the accumulation of C16 and C24-ceramide/sphingomyelin species. In addition, liraglutide treatment alleviated hepatic inflammation (in particular accumulation of M1 pro-inflammatory macrophages) and initiation of fibrosis. Liraglutide also influenced the composition of gut microbiota induced by the MCD-diet. This included recovery of a normal Bacteroides proportion and, among the Erysipelotrichaceae family, a shift between Allobaculum and Turicibacter genera. In conclusion, liraglutide prevents accumulation of C16 and C24-ceramides/sphingomyelins species, inflammation and initiation of fibrosis in MCD-diet-fed mice liver, suggesting beneficial hepatic actions independent of weight loss and global hepatic steatosis.
70Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity.PubMed
Philip Newsome, Sven Francque, Stephen Harrison, et al.
Aliment Pharmacol Ther. 2019 Jul;50(2):193-203. doi: 10.1111/apt.15316. Epub 2019 Jun 10.
BACKGROUND: Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment. AIM: To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD. METHODS: Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight. RESULTS: Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change. CONCLUSIONS: Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.
71Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis.PubMed
Sanjay Bandyopadhyay, Saibal Das, Shambo Samrat Samajdar, et al.
Diabetes Metab Syndr. 2023 Oct;17(10):102849. doi: 10.1016/j.dsx.2023.102849. Epub 2023 Sep 13.
AIM: This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of 24 weeks of semaglutide treatment in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). METHODS: PubMed, Embase, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov databases were searched for relevant studies. The primary outcome was the change in the serum alanine transaminase level. The secondary outcomes were changes in liver stiffness, liver function test parameters, metabolic parameters, and safety. Pooled mean differences and relative risks were calculated using random-effects models. RESULTS: Six hundred studies were screened and eight were included (n = 2413). Semaglutide treatment showed a reduction in serum alanine transaminase [mean difference: 14.07 U/L (95% CI: 19.39 to -8.75); p < 0.001] and aspartate transaminase [mean difference: 6.89 U/L (95% CI: 9.14 to -4.63); p < 0.001] levels. There was a significant improvement in liver fat content [mean difference: 4.97% (95% CI: 6.65 to -3.29); p < 0.001] and liver stiffness [mean difference: 0.96 kPa (95% CI: 1.87 to -0.04); p = 0.04]. There were significant improvements in the glycated hemoglobin level and the lipid profile. However, the risk of serious adverse events [relative risk: 1.54 (95% CI: 1.02 to 2.34); p = 0.04] was high following semaglutide treatment as compared to placebo; the most common ones were gastrointestinal (nausea and vomiting, dyspepsia, decreased appetite, constipation, and diarrhea) and gallbladder-related diseases. CONCLUSION: Treatment with 24 weeks of semaglutide could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters in patients with NAFLD/NASH. However, the gastrointestinal adverse effects could be a major concern.
72Mechanism of O-GlcNAcylation regulating liver lipid synthesis in mice through FASN.PubMed
Xiaoshuang Li, Ziyang Zhang, Meng Zhang, et al.
FASEB J. 2025 Feb 28;39(4):e70359. doi: 10.1096/fj.202402451RR.
Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases. O-Linked attachment of beta-N-acetylglucosamine (O-GlcNAc) are ubiquitous post-translational modifications of proteins as "nutrient sensors" and "stress receptors" in the body that are involved in maintaining normal cellular physiological functions. Increased levels of O-GlcNAcylation have been found in the liver samples of patients with NAFLD and nonalcoholic steatohepatitis. However, the role of O-GlcNAcylation in the development and pathogenesis of NAFLD remains unclear. Here, we sought to determine the specific role of O-GlcNAcylation in NAFLD. In this study, the results demonstrated that inhibition of O-GlcNAc transferase (OGT) led to decreased expression of liver lipid synthesis genes and proteins in vitro. In addition, we showed that fatty acid synthase (FASN) expression was positively correlated with O-GlcNAcylation levels. Immunoprecipitation and pulldown assays confirmed the interaction between FASN and OGT at the serine 1483 of FASN, to inhibit K48-linked ubiquitination and degradation of FASN, thereby promoting hepatic lipid accumulation and the development of NAFLD. Administration of the OGT inhibitor OSMI-1 to ob/ob mice led to decreased liver lipid accumulation, further confirming our in vitro experimental results. Finally, we used liver-specific Ogt gene knockout mice fed a high-fat diet to elucidate the specific mechanism of O-GlcNAcylation on NAFLD and found that knockdown of the Ogt gene led to decreased liver lipid accumulation. In conclusion, our findings show that inhibiting the O-GlcNAcylation of FASN at the S1483 site promotes the K48-linked ubiquitination and degradation of FASN and leads to inhibition of lipid accumulation in the liver. Treatment with the OGT inhibitor OSMI-1 leads to decreased lipid accumulation in the liver, suggesting that targeting O-GlcNAcylation sites could be a potential therapeutic strategy for alleviating NAFLD.
73The Nutrient-Dependent O-GlcNAc Modification Controls the Expression of Liver Fatty Acid Synthase.PubMed
Steffi F Baldini, Cindy Wavelet, Isabelle Hainault, et al.
J Mol Biol. 2016 Aug 14;428(16):3295-3304. doi: 10.1016/j.jmb.2016.04.035. Epub 2016 May 13.
Liver Fatty Acid Synthase (FAS) is pivotal for de novo lipogenesis. Loss of control of this metabolic pathway contributes to the development of liver pathologies ranging from steatosis to nonalcoholic steatohepatitis (NASH) which can lead to cirrhosis and, less frequently, to hepatocellular carcinoma. Therefore, deciphering the molecular mechanisms governing the expression and function of key enzymes such as FAS is crucial. Herein, we link the availability of this lipogenic enzyme to the nutrient-dependent post-translational modification O-GlcNAc that is thought to be deregulated in metabolic diseases (diabetes, obesity, and metabolic syndrome). We demonstrate that expression and activity of liver FAS correlate with O-GlcNAcylation contents in ob/ob mice and in mice fed with a high-carbohydrate diet both in a transcription-dependent and -independent manner. More importantly, inhibiting the removal of O-GlcNAc residues in mice intraperitoneally injected with the selective and potent O-GlcNAcase (OGA) inhibitor Thiamet-G increases FAS expression. FAS and O-GlcNAc transferase (OGT) physically interact, and FAS is O-GlcNAc modified. Treatment of a liver cell line with drugs or nutrients that elevate the O-GlcNAcylation interferes with FAS expression. Inhibition of OGA increases the interaction between FAS and the deubiquitinase Ubiquitin-specific protease-2a (USP2A) in vivo and ex vivo, providing mechanistic insights into the control of FAS expression through O-GlcNAcylation. Together, these results reveal a new type of regulation of FAS, linked to O-GlcNAcylation status, and advance our knowledge on deregulation of lipogenesis in diverse forms of liver diseases.
74Fatty Acid Synthase-Suppressor Screening Identifies Sorting Nexin 8 as a Therapeutic Target for NAFLD.PubMed
Yufeng Hu, Wenzhi He, Yongping Huang, et al.
Hepatology. 2021 Nov;74(5):2508-2525. doi: 10.1002/hep.32045. Epub 2021 Sep 21.
BACKGROUND AND AIMS: NAFLD is the most prevalent chronic liver disease without any Food and Drug Administration-approved pharmacological intervention in clinic. Fatty acid synthase (FASN) is one of the most attractive targets for NAFLD treatment because of its robust rate-limiting capacity to control hepatic de novo lipogenesis. However, the regulatory mechanisms of FASN in NAFLD and potential therapeutic strategies targeting FASN remain largely unknown. METHODS AND RESULTS: Through a systematic interactomics analysis of FASN-complex proteins, we screened and identified sorting nexin 8 (SNX8) as a binding partner of FASN. SNX8 directly bound to FASN and promoted FASN ubiquitination and subsequent proteasomal degradation. We further demonstrated that SNX8 mediated FASN protein degradation by recruiting the E3 ligase tripartite motif containing 28 (TRIM28) and enhancing the TRIM28-FASN interaction. Notably, Snx8 interference in hepatocytes significantly deteriorated lipid accumulation in vitro, whereas SNX8 overexpression markedly blocked hepatocyte lipid deposition. Furthermore, the aggravating effect of Snx8 deletion on NAFLD was validated in vivo as hepatic steatosis and lipogenic pathways in the liver were significantly exacerbated in Snx8-knockout mice compared to wild-type controls. Consistently, hepatocyte-specific overexpression of Snx8 in vivo markedly suppressed high-fat, high-cholesterol diet (HFHC)-induced hepatic steatosis. Notably, the protective effect of SNX8 against NAFLD was largely dependent on FASN suppression. CONCLUSIONS: These data indicate that SNX8 is a key suppressor of NAFLD that promotes FASN proteasomal degradation. Targeting the SNX8-FASN axis is a promising strategy for NAFLD prevention and treatment.
75FMO2 ameliorates nonalcoholic fatty liver disease by suppressing ER-to-Golgi transport of SREBP1.PubMed
Changle Ke, Changchen Xiao, Jiamin Li, et al.
Hepatology. 2025 Jan 1;81(1):181-197. doi: 10.1097/HEP.0000000000000643. Epub 2023 Oct 24.
BACKGROUND AND AIMS: NAFLD comprises a spectrum of liver disorders with the initial abnormal accumulation of lipids in hepatocytes called NAFL, progressing to the more serious NASH in a subset of individuals. Our previous study revealed that global flavin-containing monooxygenase 2 (FMO2) knockout causes higher liver weight in rats. However, the role of FMO2 in NAFLD remains unclear. Herein, we aimed to determine the function and mechanism of FMO2 in liver steatosis and steatohepatitis. APPROACH AND RESULTS: The expression of FMO2 was significantly downregulated in patients with NAFL/NASH and mouse models. Both global and hepatocyte-specific knockout of FMO2 resulted in increased lipogenesis and severe hepatic steatosis, inflammation, and fibrosis, whereas FMO2 overexpression in mice improved NAFL/NASH. RNA sequencing showed that hepatic FMO2 deficiency is associated with impaired lipogenesis in response to metabolic challenges. Mechanistically, FMO2 directly interacts with SREBP1 at amino acids 217-296 competitively with SREBP cleavage-activating protein (SCAP) and inhibits SREBP1 translocation from the endoplasmic reticulum (ER) to the Golgi apparatus and its subsequent activation, thus suppressing de novo lipogenesis (DNL) and improving NAFL/NASH. CONCLUSIONS: In hepatocytes, FMO2 is a novel molecule that protects against the progression of NAFL/NASH independent of enzyme activity. FMO2 impairs lipogenesis in high-fat diet-induced or choline-deficient, methionine-deficient, amino acid-defined high-fat diet-induced steatosis, inflammation, and fibrosis by directly binding to SREBP1 and preventing its organelle translocation and subsequent activation. FMO2 thus is a promising molecule for targeting the activation of SREBP1 and for the treatment of NAFL/NASH.
76Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice.PubMed
Emmanuel Dauda Dixon, Thierry Claudel, Alexander Daniel Nardo, et al.
J Hepatol. 2025 Apr;82(4):658-675. doi: 10.1016/j.jhep.2024.09.037. Epub 2024 Sep 30.
BACKGROUND & AIMS: Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice. METHODS: Streptozotocin-injected male mice were fed a high-fat diet to induce MASH. Mice receiving the ATGL inhibitor atglistatin (ATGLi) were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated the benefits of ATGLi on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model. RESULTS: ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic triacylglycerol species containing polyunsaturated fatty acids, like linoleic acid, as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signalling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors. CONCLUSIONS: Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BA composition, interfering with dietary lipid absorption, and improving metabolic disturbances. Validation with NG-497 opens a new therapeutic perspective for MASLD. IMPACT AND IMPLICATIONS: Despite the recent approval of drugs novel mechanistic insights and pathophysiology-oriented therapeutic options for MASLD (metabolic dysfunction-associated steatotic liver disease) are still urgently needed. Herein, we show that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis, using atglistatin (ATGLi), improves MASH (metabolic dysfunction-associated steatohepatitis), fibrosis, and key features of metabolic dysfunction in mouse models of MASH and liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings reveal a possible new avenue for MASLD treatment.
77Structure-activity relationship studies for the development of inhibitors of murine adipose triglyceride lipase (ATGL).PubMed
Nicole Mayer, Martina Schweiger, Elisabeth Fuchs, et al.
Bioorg Med Chem. 2020 Aug 15;28(16):115610. doi: 10.1016/j.bmc.2020.115610. Epub 2020 Jul 4.
High serum fatty acid (FA) levels are causally linked to the development of insulin resistance, which eventually progresses to type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) generalized in the term metabolic syndrome. Adipose triglyceride lipase (ATGL) is the initial enzyme in the hydrolysis of intracellular triacylglycerol (TG) stores, liberating fatty acids that are released from adipocytes into the circulation. Hence, ATGL-specific inhibitors have the potential to lower circulating FA concentrations, and counteract the development of insulin resistance and NAFLD. In this article, we report about structure-activity relationship (SAR) studies of small molecule inhibitors of murine ATGL which led to the development of Atglistatin. Atglistatin is a specific inhibitor of murine ATGL, which has proven useful for the validation of ATGL as a potential drug target.
78USP29 alleviates the progression of MASLD by stabilizing ACSL5 through K48 deubiquitination.PubMed
Sha Hu, Zhouxiang Wang, Kun Zhu, et al.
Clin Mol Hepatol. 2025 Jan;31(1):147-165. doi: 10.3350/cmh.2024.0478. Epub 2024 Oct 2.
BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by hepatic steatosis. Ubiquitin-specific protease 29 (USP29) plays pivotal roles in hepatic ischemiareperfusion injury and hepatocellular carcinoma, but its role in MASLD remains unexplored. Therefore, the aim of this study was to reveal the effects and underlying mechanisms of USP29 in MASLD progression. METHODS: USP29 expression was assessed in liver samples from MASLD patients and mice. The role and molecular mechanism of USP29 in MASLD were assessed in high-fat diet-fed and high-fat/high-cholesterol diet-fed mice and palmitic acid and oleic acid treated hepatocytes. RESULTS: USP29 protein levels were significantly reduced in mice and humans with MASLD. Hepatic steatosis, inflammation and fibrosis were significantly exacerbated by USP29 deletion and relieved by USP29 overexpression. Mechanistically, USP29 significantly activated the expression of genes related to fatty acid β-oxidation (FAO) under metabolic stimulation, directly interacted with long-chain acyl-CoA synthase 5 (ACSL5) and repressed ACSL5 degradation by increasing ACSL5 K48-linked deubiquitination. Moreover, the effect of USP29 on hepatocyte lipid accumulation and MASLD was dependent on ACSL5. CONCLUSION: USP29 functions as a novel negative regulator of MASLD by stabilizing ACSL5 to promote FAO. The activation of the USP29-ACSL5 axis may represent a potential therapeutic strategy for MASLD.
79Integrated screening identifies GPR31 as a key driver and druggable target for metabolic dysfunction-associated steatohepatitis.PubMed
Xiao-Jing Zhang, Jiajun Fu, Xu Cheng, et al.
J Clin Invest. 2025 Sep 2;135(17). doi: 10.1172/JCI173193.
Metabolic dysfunction-associated steatohepatitis (MASH) is a globally prevalent but intractable disease lacking effective pharmacotherapies. Here, we performed an integrated multilayered screening for pathogenic genes and druggable targets for MASH. We identified the subclass of metabolite-sensing G protein-coupled receptors, specifically GPR31, a critical contributor to MASH occurrence, which, to our knowledge, was previously uncharacterized. Mechanistically, Gαi3 is the essential downstream effector for the pro-MASH efficiency of GPR31 via glycosylation-dependent interaction with GPR31 and extra activation of PKCδ-MAPK signaling. Hepatocyte-specific GPR31 deficiency robustly blocked hepatic lipotoxicity and fibrosis in a mouse model of diet-induced MASH, whereas expression of the GPR31 transgene aggravated MASH development. Of translational importance, we developed a small-molecule inhibitor, named G4451, that specifically inhibits the GPR31-Gαi3 interaction by targeting the GPR31 conformational transition. Encouragingly, oral administration of G4451 effectively blocked MASH progression in preclinical models in both rodents and nonhuman primates. Collectively, the present study provides proof of concept that interference with GPR31 constitutes an attractive therapeutic strategy for MASH.
80Metformin and berberine synergistically improve NAFLD via the AMPK-SREBP1-FASN signaling pathway.PubMed
Na Li, Quan-Wei Chen, Xiao-Long Gong, et al.
Sci Rep. 2025 Aug 11;15(1):29400. doi: 10.1038/s41598-025-15495-7.
Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic condition linked to dyslipidemia, insulin resistance, and persistent inflammation. Due to its complex pathogenesis, no approved pharmacological treatments currently exist. The research sought to explore the combined impact of metformin (Met) and berberine (BBR) on NAFLD, focusing on the AMPK-SREBP1-FASN pathway implicated in liver lipid regulation. The study design incorporated in both living organisms and laboratory conditions to examine how these interventions influenced NAFLD-associated metabolic abnormalities. The HFD-fed mice provided insight into systemic effects, while the OA/PA-stimulated HepG2 cells offered a controlled environment to investigate cellular mechanisms. By employing this dual approach, the researchers could thoroughly characterize the efficacy of Met, BBR, and their combination in mitigating metabolic disturbances. An Adenosine 5'-monophosphate (AMP)-activated protein kinase(AMPK) inhibitor was used in cellular experiments to verify the AMPK-dependent mechanism. Our findings highlight that compared to monotherapies, combination treatment significantly enhanced AMPK activation and inhibited sterol regulatory element-binding protein 1 (SREBP1) expression and that of its downstream target fatty acid synthase (FASN). In HepG2 cells, these effects were partially reversed by the AMPK inhibitor, confirming AMPK dependence. In vivo, the combined therapy effectively inhibited body weight gain, reduced visceral fat accumulation, improved insulin sensitivity, and attenuated hepatic steatosis and inflammation. The combination of metformin and berberine exerts synergistic effects in ameliorating NAFLD by activating AMPK, downregulating SREBP1 and FASN, and improving lipid metabolism. These findings provide evidence supporting a potentially effective multi-modal treatment approach for NAFLD.
81Comparative efficacy of THR-β agonists, FGF-21 analogues, GLP-1R agonists, GLP-1-based polyagonists, and Pan-PPAR agonists for MASLD: A systematic review and network meta-analysis.PubMed
Ru-Tao Lin, Qin-Mei Sun, Xin Xin, et al.
Metabolism. 2024 Dec;161:156043. doi: 10.1016/j.metabol.2024.156043. Epub 2024 Sep 30.
AIMS: To compare the efficacy of thyroid hormone receptor beta (THR-β) agonists, fibroblast growth factor 21 (FGF-21) analogues, glucagon-like peptide-1 receptor agonists (GLP-1RAs), GLP-1-based polyagonists, and pan-peroxisome proliferator-activated receptor (Pan-PPAR) agonists in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: A database search for relevant randomized double-blind controlled trials published until July 11, 2024, was conducted. Primary outcomes were the relative change in hepatic fat fraction (HFF) and liver stiffness assessed non-invasively by magnetic resonance imaging proton density fat fraction and elastography. Secondary outcomes included histology, liver injury index, lipid profile, glucose metabolism, blood pressure, and body weight. RESULTS: Twenty-seven trials (5357 patients with MASLD) were identified. For HFF reduction, GLP-1-based polyagonists were most potentially effective (mean difference [MD] -51.47; 95 % confidence interval [CI]: -68.25 to -34.68; surface under the cumulative ranking curve [SUCRA] 84.9) vs. placebo, followed by FGF-21 analogues (MD -47.08; 95 % CI: -58.83 to -35.34; SUCRA 75.5), GLP-1R agonists (MD -37.36; 95 % CI: -69.52 to -5.21; SUCRA 52.3) and THR-β agonists (MD -33.20; 95 % CI: -43.90 to -22.51; SUCRA 36.9). For liver stiffness, FGF-21 analogues were most potentially effective (MD -9.65; 95 % CI: -19.28 to -0.01; SUCRA 82.2) vs. placebo, followed by THR-β agonists (MD -5.79; 95 % CI: -9.50 to -2.09; SUCRA 58.2), and GLP-1RAs (MD -5.58; 95 % CI: -15.02 to 3.86; SUCRA 54.7). For fibrosis improvement in histology, GLP-1-based polyagonists were most potentially effective, followed by FGF-21 analogues, THR-β agonists, Pan-PPAR agonists, and GLP-1R agonists; For MASH resolution in histology, GLP-1-based polyagonists were most potentially effective, followed by THR-β agonists, GLP-1R agonists, FGF-21 analogues, and Pan-PPAR agonists. THR-β agonists are well-balanced in liver steatosis and fibrosis, and excel at improving lipid profiles; FGF-21 analogues are effective at improving steatosis and particularly exhibit strong antifibrotic abilities. GLP-1R agonists showed significant benefits in improving liver steatosis, glucose metabolism, and body weight. GLP-1-based polyagonists have demonstrated the most potential efficacy overall in terms of comprehensive curative effect. Pan-PPAR agonists showed distinct advantages in improving liver function and glucose metabolism. CONCLUSION: These results illustrate the relative superiority of the five classes of therapy in the treatment of MASLD and may serve as guidance for the development of combination therapies.
82MASH clinical trials and drugs pipeline: An impending tsunami.PubMed
Mazen Noureddin
Hepatology. 2025 Nov 1;82(5):1325-1340. doi: 10.1097/HEP.0000000000000860. Epub 2024 Mar 19.
Metabolic dysfunction-associated steatotic liver disease, formerly known as NAFLD, has ascended to prominence as the predominant chronic liver disease in Western countries and now stands as a leading cause of liver transplantations. In the more advanced stage, metabolic dysfunction-associated steatohepatitis (MASH) may lead to fibrosis, a gateway to cirrhosis, liver cancer, and liver failure. Despite extensive research and exploration of various drug mechanisms, the anticipation for the inaugural approved drug to materialize by 2024 is palpable, marking a significant milestone. Numerous pathways have been investigated for MASH treatment, exploring thyroid hormone receptors, glucagon-like peptides 1, peroxisome proliferator-activated receptors, and agents influencing hepatic steatosis synthesis, inflammatory pathways, genetic components, fibrosis mechanisms, and an array of other avenues. Over time, key regulatory directions have crystallized, now manifesting in 2 primary endpoints under investigation: resolution of steatohepatitis without worsening fibrosis and/or improvement of fibrosis stage without worsening of steatohepatitis, especially used in phase 3 clinical trials, while alternative noninvasive endpoints are explored in phase 2 trials. The prospect of proving efficacy in clinical trials opens doors to combination therapies, evaluating the ideal combination of drugs to yield comprehensive benefits, extending beyond the liver to other organs. Certain combination drug trials are already underway. In this review, we discuss the forefront of MASH drug research as of 2023/2024, illuminating mechanisms, outcomes, and future trajectories. Furthermore, we tackle the challenges confronting MASH trials and propose potential strategies for surmounting them.
83New advances in drug development for metabolic dysfunction-associated diseases and alcohol-associated liver disease.PubMed
Jinming Zhang, Yixin Li, Liu Yang, et al.
Cell Biosci. 2024 Jul 6;14(1):90. doi: 10.1186/s13578-024-01267-9.
Metabolic disorders are currently threatening public health worldwide. Discovering new targets and developing promising drugs will reduce the global metabolic-related disease burden. Metabolic disorders primarily consist of lipid and glucose metabolic disorders. Specifically, metabolic dysfunction-associated steatosis liver disease (MASLD) and alcohol-associated liver disease (ALD) are two representative lipid metabolism disorders, while diabetes mellitus is a typical glucose metabolism disorder. In this review, we aimed to summarize the new drug candidates with promising efficacy identified in clinical trials for these diseases. These drug candidates may provide alternatives for patients with metabolic disorders and advance the progress of drug discovery for the large disease burden.
84Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges.PubMed
Jean-François Dufour, Cyrielle Caussy, Rohit Loomba
Gut. 2020 Oct;69(10):1877-1884. doi: 10.1136/gutjnl-2019-319104. Epub 2020 May 7.
Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.
85Current Progress and Challenges in the Development of Pharmacotherapy for Metabolic Dysfunction-Associated Steatohepatitis.PubMed
Yang Zhi, Yinuo Dong, Xiaoyun Li, et al.
Diabetes Metab Res Rev. 2024 Oct;40(7):e3846. doi: 10.1002/dmrr.3846.
Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), poses a significant threat to global health. Despite extensive research efforts over the past decade, only one drug has received market approval under accelerated pathways. In this review, we summarise the pathogenesis of MASH and present a comprehensive overview of recent advances in phase 2-3 clinical trials targeting MASH. These trials have highlighted considerable challenges, including low response rates to drugs, limitations of current surrogate histological endpoints, and inadequacies in the design of MASH clinical trials, all of which hinder the progress of MASH pharmacotherapy. We also explored the potential of non-invasive tests to enhance clinical trial design. Furthermore, given the strong association between MASLD and cardiometabolic disorders, we advocate for an integrated approach to disease management to improve overall patient outcomes. Continued investigation into the mechanisms and pharmacology of combination therapies may offer valuable insights for developing innovative MASH treatments.
86Current and new pharmacotherapy options for non-alcoholic steatohepatitis.PubMed
Yoshio Sumida, Masato Yoneda, Yuji Ogawa, et al.
Expert Opin Pharmacother. 2020 Jun;21(8):953-967. doi: 10.1080/14656566.2020.1744564. Epub 2020 Apr 1.
INTRODUCTION: There is an unmet medical need for an effective anti-fibrotic treatment for NASH with advanced fibrosis. AREAS COVERED: The authors review the current and novel agents for the treatment of NASH with fibrosis. They also consider the potential future strategies of combination therapies. EXPERT OPINION: Farnesoid X receptor (FXR) agonist (obeticholic acid [OCA]) significantly ameliorated hepatic fibrosis in NASH stage 2/3 fibrosis in an interim analysis of phase 3 trial. Because OCA has several drawbacks such as itching and elevated low-density lipoprotein-cholesterol (LDL-C), non-bile acid FXR agonists are now under development. Selonsertib (apoptosis signaling kinase 1 inhibitor), emricasan (an irreversible pan-caspase inhibitor), and simtsuzumab (a monoclonal antibody against lysyl oxidase-like 2) were discontinued because of no efficacy over placebo. Peroxisome proliferator-activator receptor α/δ agonists, C-C motif chemokine receptor-2/5 antagonists, and thyroid β receptor agonist are ongoing in phase 3 trials. A variety of agents including fibroblast growth factor (FGF)-21 and FGF-19 agonists, as well as acetyl-CoA carboxylase inhibitors, are also expected. Among antidiabetic agents, semaglutide, a novel GLP-1 RA, is ongoing for NASH stage 1-3 fibrosis in a phase 2 trial. Furthermore, the combination of GLP-RA/glucagon receptor agonist and GLP-RA/gastrointestinal peptide agonist are promising future options.
87Bariatric Surgery ComplicationsPubMed
Sathyaprasad Burjonrappa, Karan Grover
Morbid obesity is associated with several significant comorbidities, including obstructive sleep apnea, hypertension, type 2 diabetes mellitus, and metabolic syndrome—with resolution rates of 80% or more after effective intervention. Over 200 comorbidities are linked to obesity, including several types of cancer. With nearly 40% of adults and one-third of children in the United States classified as obese or overweight, ongoing research continues into pharmacotherapy options and the endocrine factors influencing weight regulation. Newer medications, such as glucagon-like peptide-1 (GLP-1) agonists and combination GLP-1/gastric inhibitory peptide/glucose-dependent insulinotropic peptide (GIP) (GLP-1/GIP) agonists, have shown promise in achieving greater than 20% total body weight loss in patients with morbid obesity. However, concerns about cost, adverse events, and long-term safety remain. Despite these advances, weight loss surgery remains the gold standard for resolving comorbidities in those who are morbidly obese, offering 30% to 40% total body weight loss. Older antiobesity medications (AOMs), such as phentermine, topiramate, buprenorphine, and naltrexone, contribute to 5% to 10% weight reduction, with newer AOMs filling the gap for those in between. Laparoscopic sleeve gastrectomy, a restrictive weight loss procedure, is the most commonly performed bariatric surgery in the United States, accounting for over two-thirds of all bariatric surgeries, with over 160,000 procedures conducted in 2022. The Roux-en-Y gastric bypass is the second most common, with gastric banding and duodenal switch procedures being much rarer. Bariatric surgery can effectively reverse comorbidities such as diabetes, obstructive sleep apnea, metabolic syndrome, and pseudotumor cerebrii. Though generally safe when performed by experienced surgeons, complications can arise immediately postoperatively and even years later. These complications can range from subtle, gradually progressing symptoms to more acute conditions requiring urgent intervention. Common complications include deep vein thrombosis, bleeding, hiatal hernia, nutritional deficiencies, anastomotic leaks or strictures, gastric and marginal ulcers, and dumping syndrome. Bariatric individuals must have timely access to follow-up care to address any potential complications as they arise.
88Liver fat deposition and mitochondrial dysfunction in morbid obesity: An approach combining metabolomics with liver imaging and histology.PubMed
Nahum Calvo, Raúl Beltrán-Debón, Esther Rodríguez-Gallego, et al.
World J Gastroenterol. 2015 Jun 28;21(24):7529-44. doi: 10.3748/wjg.v21.i24.7529.
AIM: To explore the usefulness of magnetic resonance imaging (MRI) and spectroscopy (MRS) for assessment of non-alcoholic fat liver disease (NAFLD) as compared with liver histological and metabolomics findings. METHODS: Patients undergoing bariatric surgery following procedures involved in laparoscopic sleeve gastrectomy were recruited as a model of obesity-induced NAFLD in an observational, prospective, single-site, cross-sectional study with a pre-set duration of 1 year. Relevant data were obtained prospectively and surrogates for inflammation, oxidative stress and lipid and glucose metabolism were obtained through standard laboratory measurements. To provide reliable data from MRI and MRS, novel procedures were designed to limit sampling variability and other sources of error using a 1.5T Signa HDx scanner and protocols acquired from the 3D or 2D Fat SAT FIESTA prescription manager. We used our previously described (1)H NMR-based metabolomics assays. Data were obtained immediately before surgery and after a 12-mo period including histology of the liver and measurement of metabolites. Values from (1)H NMR spectra obtained after surgery were omitted due to technical limitations. RESULTS: MRI data showed excellent correlation with the concentration of liver triglycerides, other hepatic lipid components and the histological assessment, which excluded the presence of non-alcoholic steatohepatitis (NASH). MRI was sufficient to follow up NAFLD in obese patients undergoing bariatric surgery and data suggest usefulness in other clinical situations. The information provided by MRS replicated that obtained by MRI using the -CH3 peak (0.9 ppm), the -CH2- peak (1.3 ppm, mostly triglyceride) and the -CH=CH- peak (2.2 ppm). No patient depicted NASH. After surgery all patients significantly decreased their body weight and steatosis was virtually absent even in patients with previous severe disease. Improvement was also observed in the serum concentrations of selected variables. The most relevant findings using metabolomics indicate increased levels of triglyceride and monounsaturated fatty acids in severe steatosis but those results were accompanied by a significant depletion of diglycerides, polyunsaturated fatty acids, glucose-6-phosphate and the ATP/AMP ratio. Combined data indicated the coordinated action on mitochondrial fat oxidation and glucose transport activity and may support the consideration of NAFLD as a likely mitochondrial disease. This concept may help to explain the dissociation between excess lipid storage in adipose tissue and NAFLD and may direct the search for plasma biomarkers and novel therapeutic strategies. A limitation of our study is that data were obtained in a relatively low number of patients. CONCLUSION: MRI is sufficient to stage NAFLD in obese patients and to assess the improvement after bariatric surgery. Other data were superfluous for this purpose.
89Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.PubMed
Guillaume Lassailly, Robert Caiazzo, Line-Carolle Ntandja-Wandji, et al.
Gastroenterology. 2020 Oct;159(4):1290-1301.e5. doi: 10.1053/j.gastro.2020.06.006. Epub 2020 Jun 15.
BACKGROUND AND AIMS: Studies are needed to determine the long-term effects of bariatric surgery for patients with nonalcoholic steatohepatitis (NASH). We evaluated sequential liver samples, collected the time of bariatric surgery and 1 and 5 years later, to assess the long-term effects of bariatric surgery in patients with NASH. METHODS: We performed a prospective study of 180 severely obese patients with biopsy-proven NASH, defined by the NASH clinical research network histologic scores. The patients underwent bariatric surgery at a single center in France and were followed for 5 years. We obtained liver samples from 125 of 169 patients (76%) having reached 1 year and 64 of 94 patients (68%) having reached 5 years after surgery. The primary endpoint was the resolution of NASH without worsening of fibrosis at 5 years. Secondary end points were improvement in fibrosis (reduction of ≥1 stage) at 5 years and regression of fibrosis and NASH at 1 and 5 years. RESULTS: At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients (n = 64; 95% confidence interval, 73.1%-92.2%). Fibrosis decreased, compared with baseline, in samples from 70.2% of patients (95% CI, 56.6%-81.6%). Fibrosis disappeared from samples from 56% of all patients (95% CI, 42.4%-69.3%) and from samples from 45.5% of patients with baseline bridging fibrosis. Persistence of NASH was associated with no decrease in fibrosis and less weight loss (reduction in body mass index of 6.3 ± 4.1 kg/m in patients with persistent NASH vs reduction of 13.4 ± 7.4 kg/m; P = .017 with resolution of NASH). Resolution of NASH was observed at 1 year after bariatric surgery in biopsies from 84% of patients, with no significant recurrence between 1 and 5 years (P = .17). Fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years (P < .001). CONCLUSIONS: In a long-term follow-up of patients with NASH who underwent bariatric surgery, we observed resolution of NASH in liver samples from 84% of patients 5 years later. The reduction of fibrosis is progressive, beginning during the first year and continuing through 5 years.
90Long-term liver outcomes after metabolic surgery in compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis.PubMed
Ali Aminian, Abdullah Aljabri, Sarah Wang, et al.
Nat Med. 2025 Mar;31(3):988-995. doi: 10.1038/s41591-024-03480-y. Epub 2025 Jan 27.
No therapy has been shown to reduce the risk of major adverse liver outcomes (MALO) in patients with cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH). The Surgical Procedures Eliminate Compensated Cirrhosis In Advancing Long-term (SPECCIAL) observational study compared the effects of metabolic surgery and nonsurgical treatment in patients with obesity and compensated histologically proven MASH-related cirrhosis. Using a doubly robust estimation methodology to balance key baseline characteristics between groups, the time-to-incident MALO was compared between 62 patients (68% female) who underwent metabolic surgery and 106 nonsurgical controls (71% female), with a mean follow-up of 10.0 ± 4.5 years. The 15 year cumulative incidence of MALO was 20.9% (95% confidence interval (CI), 2.5-35.9%) in the surgical group compared with 46.4% (95% CI, 25.6-61.3%) in the nonsurgical group, with an adjusted hazard ratio of 0.28 (95% CI, 0.12-0.64), P = 0.003. The 15 year cumulative incidence of decompensated cirrhosis was 15.6% (95% CI, 0-31.3%) in the surgical group compared with 30.7% (95% CI, 12.9-44.8%) in the nonsurgical group, with an adjusted hazard ratio of 0.20 (95% CI, 0.06-0.68), P = 0.01. Among patients with compensated MASH-related cirrhosis and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MALO. In the absence of approved medical therapies for compensated MASH-related cirrhosis, metabolic surgery may represent a safe and effective therapeutic option to influence the trajectory of cirrhosis.
91Bariatric surgery in liver cirrhosis.PubMed
A S Mehdorn, Y Moulla, M Mehdorn, et al.
Front Surg. 2022 Dec 15;9:986297. doi: 10.3389/fsurg.2022.986297. eCollection 2022.
INTRODUCTION: Obesity is frequently associated with its hepatic manifestation, the nonalcoholic fatty liver disease (NAFLD). The most effective treatment for morbid obesity is bariatric surgery (BS) also improving NAFLD and liver function. In patients where NAFLD has already progressed to liver cirrhosis, BS can be considered a high-risk procedure. Hence, consideration of the procedure and the most appropriate timing is crucial. MATERIAL AND METHODS: Obese patients suffering from NAFLD who underwent BS from two German University Medical Centers were retrospectively analyzed. RESULTS: Twenty-seven patients underwent BS. Most common procedures were laparoscopic Roux-en-Y-gastric (RYGB) and laparoscopic sleeve gastrectomy (SG). All patients suffered from liver cirrhosis Child A. A preoperative transjugular portosystemic shunt (TIPS) was established in three patients and failed in another patient. Postoperative complications consisted of wound healing disorders (= 2), anastomotic bleeding (= 1), and leak from the staple line (= 1). This patient suffered from intraoperatively detected macroscopic liver cirrhosis. Excess weight loss was 73% and 85% after 1 and 2 years, respectively. Two patients suffered from postoperative aggravation of their liver function, resulting in a higher Child-Pugh score, while three could be removed from the waiting list for a liver transplantation. CONCLUSION: BS leads to weight loss, both after SG and RYGB, and potential improvement of liver function in liver cirrhosis. These patients need to be considered with care when evaluated for BS. Preoperative TIPS implantation may reduce the perioperative risk in selected patients.
92Bariatric Surgery in NAFLD.PubMed
Mahak Chauhan, Kuldeep Singh, Paul J Thuluvath
Dig Dis Sci. 2022 Feb;67(2):408-422. doi: 10.1007/s10620-021-07317-3. Epub 2022 Jan 4.
Currently, there are no approved medications to treat patients with nonalcoholic steatohepatitis (NASH) with fibrosis or cirrhosis. Although the management goal in these patients is weight reduction by 7-10% with lifestyle modifications, only less than 10% of patients achieve this target at 1-year, and fewer maintain the weight loss at 5 years. Bariatric surgery is an option that may be considered in those who fail to lose weight by lifestyle changes. Bariatric surgery has been shown to improve liver histology including fibrosis secondary to NASH, in addition to other benefits including an improvement or resolution of type 2 diabetes mellitus, dyslipidemia, and hypertension, and a reduction of cardiovascular morbidity or mortality. There are no guidelines of bariatric surgery indications for the management of NASH. The purpose of this review is to critically appraise the current knowledge of the role of bariatric surgery and the potential mechanisms for its perceived benefits in the management of patients with NASH-related liver disease.
93Non-Alcoholic Fatty Liver Disease (NAFLD) and Bariatric/Metabolic Surgery as Its Treatment Option: A Review.PubMed
Paulina Głuszyńska, Dorota Lemancewicz, Janusz Bogdan Dzięcioł, et al.
J Clin Med. 2021 Dec 7;10(24):5721. doi: 10.3390/jcm10245721.
The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) has considerably increased over the last years. NAFLD is currently the most common cause of chronic liver disease in the developing world. The diagnosis of NAFLD/NASH is often incidental, as the early-stage of disease is frequently free of symptoms. Most patients recognized with NAFLD have severe obesity and other obesity-related disease such as type 2 diabetes mellitus (T2DM), insulin-resistance, dyslipidemia and hypertension. The only proven method for NAFLD improvement and resolution is weight loss. Bariatric surgery leads to significant and long-term weight loss as well as improvement of coexisting diseases. There is a lot of evidence suggesting that metabolic/bariatric surgery is an effective method of NAFLD treatment that leads to reduction in steatosis, hepatic inflammation and fibrosis. However, there is still a need to perform long-term studies in order to determine the role of bariatric surgery as a treatment option for NAFLD and NASH. This review discusses current evidence about epidemiology, pathogenesis and treatment options for NAFLD including bariatric/metabolic surgery and its effect on improvement and resolution of NAFLD.
94Nonalcoholic fatty liver disease and bariatric surgery: a comprehensive review.PubMed
Everton Cazzo, José Carlos Pareja, Elinton Adami Chaim
Sao Paulo Med J. 2017 May-Jun;135(3):277-295. doi: 10.1590/1516-3180.2016.0306311216. Epub 2017 May 29.
CONTEXT AND OBJECTIVE:: Nonalcoholic fatty liver disease (NAFLD) has been increasingly diagnosed worldwide and is now recognized as a source of public health concern. It comprises a wide spectrum of histological features that range from simple steatosis to severe forms of fibrosis, steatohepatitis and even cirrhosis. The impact of bariatric surgery on the course of NAFLD in individuals with obesity has been extensively studied. DESIGN AND SETTING:: Narrative review; public university hospital. METHODS:: A comprehensive review was conducted based on an online search on the electronic databases MEDLINE and LILACS using the MeSH terms "fatty liver" and "bariatric surgery". RESULTS:: The exact mechanisms that lead to improvement in NAFLD following bariatric surgery are not completely understood. Since Roux-en-Y gastric bypass (RYGB) is the bariatric surgical procedure most performed worldwide, it is also the one from which the effects on NAFLD have been most studied, although there is also consistent evidence regarding the effects from gastric banding, sleeve gastrectomy and biliopancreatic diversions. CONCLUSION:: According to the currently available evidence, bariatric surgery leads to significant improvement in NAFLD. Further research, especially by means of randomized controlled trials enrolling larger cohorts of individuals, is needed to determine the optimal procedure for this group of subjects.
95TREM2 macrophages mediate the beneficial effects of bariatric surgery against MASH.PubMed
Gavin Fredrickson, Kira Florczak, Fanta Barrow, et al.
Hepatology. 2025 Jun 1;81(6):1776-1791. doi: 10.1097/HEP.0000000000001098. Epub 2024 Sep 18.
BACKGROUND AND AIMS: For patients with obesity and metabolic syndrome, bariatric procedures such as vertical sleeve gastrectomy (VSG) have a clear benefit in ameliorating metabolic dysfunction-associated steatohepatitis (MASH). While the effects of bariatric surgeries have been mainly attributed to nutrient restriction and malabsorption, whether immuno-modulatory mechanisms are involved remains unclear. APPROACH AND RESULT: Using murine models, we report that VSG ameliorates MASH progression in a weight loss-independent manner. Single-cell RNA sequencing revealed that hepatic lipid-associated macrophages (LAMs) expressing the triggering receptor expressed on myeloid cells 2 (TREM2) repress inflammation and increase their lysosomal activity in response to VSG. Remarkably, TREM2 deficiency in mice ablates the reparative effects of VSG, suggesting that TREM2 is required for MASH resolution. Mechanistically, TREM2 prevents the inflammatory activation of macrophages and is required for their efferocytic function. CONCLUSIONS: Overall, our findings indicate that bariatric surgery improves MASH through a reparative process driven by TREM2+ macrophages, providing insights into the mechanisms of disease reversal that may result in new therapies and improved surgical interventions.
96Resolution of Comorbidities and Impact on Longevity Following Bariatric and Metabolic Surgery.PubMed
Tammy Fouse, Stacy Brethauer
Surg Clin North Am. 2016 Aug;96(4):717-32. doi: 10.1016/j.suc.2016.03.007.
Bariatric surgery is the most effective and durable treatment of severe obesity. In addition to weight loss, these operations result in significant improvement or resolution of many obesity-related comorbid diseases. There are now numerous studies demonstrating that bariatric surgery decreases all-cause mortality long-term compared with cohorts of patients who did not undergo surgery. Decreases in cancer, diabetes, and cardiovascular-related mortality are major contributors to this overall effect on life expectancy after bariatric surgery.
97Bariatric Surgery and Remission of Metabolic Syndrome: A Meta-analysis of Randomised Controlled Trials and Prospective Studies.PubMed
Yomna E Dean, Mohamed I Mohamed, Abdulrahman Shokri, et al.
Obes Surg. 2025 Apr;35(4):1337-1349. doi: 10.1007/s11695-025-07750-7. Epub 2025 Feb 25.
BACKGROUND: Studies have discussed the efficacy of bariatric surgery (BS) in remission of individual components of metabolic syndrome (MS). We aimed to analyse the prevalence of MS following BS. METHODS: On October 5, 2023, we conducted a literature search on PubMed, Scopus, Web of Science, and Cochrane. RevManv5.4 was used for the analysis. RESULTS: MS patients who underwent BS had lower odds of MS within the first year post-BS (OR 0.14, 95%CI 0.12-0.17); patients who had a preoperative BMI < 50 showed a higher reduction in MS post-BS compared with patients who suffered from super obesity (OR 0.12 versus OR 0.17). Older patients (age > 42) had lower odds of MS post-BS compared with younger patients (OR 0.05 versus OR 0.17). There was not a difference in MS prevalence between 1 and 2 years postoperatively (OR 1.07, 95%CI 0.72-1.58). Asians reported the highest reduction in MS post-BS (OR 0.08). MS patients who received medical treatment had three times the odds of having MS compared with patients who underwent BS. Patients who had BS reported a decline in their anti-hypertensives and oral anti-diabetic drugs (OR 0.26, 95%CI 0.15-0.46, OR 0.11, 95%CI 0.07-0.16, respectively). There was not a significant difference in MS prevalence between patients who underwent RYGB and those who had SG (OR 2.16, 95%CI 0.74-6.26). CONCLUSIONS: BS is superior to medical treatment in the remission of MS. Age, preoperative BMI, and country of origin affect the rates of MS remission. BS results in a sustainable resolution of MS across 1, 2, and 5 years post-surgery. A tailored approach is warranted to achieve the best outcomes.
98The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD).PubMed
Zahra Safari, Philippe Gérard
Cell Mol Life Sci. 2019 Apr;76(8):1541-1558. doi: 10.1007/s00018-019-03011-w. Epub 2019 Jan 25.
NAFLD is currently the main cause of chronic liver disease in developed countries, and the number of NAFLD patients is growing worldwide. NAFLD often has similar symptoms to other metabolic disorders, including type 2 diabetes and obesity. Recently, the role of the gut microbiota in the pathophysiology of many diseases has been revealed. Regarding NAFLD, experiments using gut microbiota transplants to germ-free animal models showed that fatty liver disease development is determined by gut bacteria. Moreover, the perturbation of the composition of the gut microbiota has been observed in patients suffering from NAFLD. Numerous mechanisms relating the gut microbiome to NAFLD have been proposed, including the dysbiosis-induced dysregulation of gut endothelial barrier function that allows for the translocation of bacterial components and leads to hepatic inflammation. In addition, the various metabolites produced by the gut microbiota may impact the liver and thus modulate NAFLD susceptibility. Therefore, the manipulation of the gut microbiome by probiotics, prebiotics or synbiotics was shown to improve liver phenotype in NAFLD patients as well as in rodent models. Hence, further knowledge about the interactions among dysbiosis, environmental factors, and diet and their impacts on the gut-liver axis can improve the treatment of this life-threatening liver disease and its related disorders.
99[Gut Microbiota and Obesity].PubMed
Seung Young Kim
Korean J Helicobacter Up Gastrointest Res. 2023 Dec;23(4):240-246. doi: 10.7704/kjhugr.2023.0057. Epub 2023 Dec 8.
Obesity is a global health concern associated with a wide range of diseases, including diabetes, metabolic syndrome, fatty liver, and cardiovascular conditions. Recent studies highlight the significant role of gut microbiota in obesity. Research indicates notable changes in the composition and diversity of gut microbiota in individuals diagnosed with obesity. The gut microbiota participate in energy metabolism, lipid synthesis, and regulation of inflammation and therefore play a key role in the pathogenesis of obesity. Therapeutic approaches based on the use of probiotics, prebiotics, Akkermansia muciniphila, and fecal microbiota transplantation have shown promise in animal studies as useful strategies against obesity and metabolic syndrome. However, further research is warranted to conclusively establish the specific strains, dosages, and mechanisms underlying the effectiveness of these novel strategies against obesity in humans.
100Updated mechanisms of MASLD pathogenesis.PubMed
Yuxuan Li, Peipei Yang, Jialu Ye, et al.
Lipids Health Dis. 2024 Apr 22;23(1):117. doi: 10.1186/s12944-024-02108-x.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.
101Role of Probiotics in Non-alcoholic Fatty Liver Disease: Does Gut Microbiota Matter?PubMed
Chencheng Xie, Dina Halegoua-DeMarzio
Nutrients. 2019 Nov 19;11(11):2837. doi: 10.3390/nu11112837.
Non-alcoholic fatty liver disease (NAFLD) is the hepatic consequence of metabolic syndrome, which often also includes obesity, diabetes, and dyslipidemia. The connection between gut microbiota (GM) and NAFLD has attracted significant attention in recent years. Data has shown that GM affects hepatic lipid metabolism and influences the balance between pro/anti-inflammatory effectors in the liver. Although studies reveal the association between GM dysbiosis and NAFLD, decoding the mechanisms of gut dysbiosis resulting in NAFLD remains challenging. The potential pathophysiology that links GM dysbiosis to NAFLD can be summarized as: (1) disrupting the balance between energy harvest and expenditure, (2) promoting hepatic inflammation (impairing intestinal integrity, facilitating endotoxemia, and initiating inflammatory cascades with cytokines releasing), and (3) altered biochemistry metabolism and GM-related metabolites (i.e., bile acid, short-chain fatty acids, aromatic amino acid derivatives, branched-chain amino acids, choline, ethanol). Due to the hypothesis that probiotics/synbiotics could normalize GM and reverse dysbiosis, there have been efforts to investigate the therapeutic effect of probiotics/synbiotics in patients with NAFLD. Recent randomized clinical trials suggest that probiotics/synbiotics could improve transaminases, hepatic steatosis, and reduce hepatic inflammation. Despite these promising results, future studies are necessary to understand the full role GM plays in NAFLD development and progression. Additionally, further data is needed to unravel probiotics/synbiotics efficacy, safety, and sustainability as a novel pharmacologic approaches to NAFLD.
102Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review.PubMed
Federica Di Vincenzo, Angelo Del Gaudio, Valentina Petito, et al.
Intern Emerg Med. 2024 Mar;19(2):275-293. doi: 10.1007/s11739-023-03374-w. Epub 2023 Jul 28.
The intestine is the largest interface between the internal body and the external environment. The intestinal barrier is a dynamic system influenced by the composition of the intestinal microbiome and the activity of intercellular connections, regulated by hormones, dietary components, inflammatory mediators, and the enteric nervous system (ENS). Over the years, it has become increasingly evident that maintaining a stable intestinal barrier is crucial to prevent various potentially harmful substances and pathogens from entering the internal environment. Disruption of the barrier is referred to as 'leaky gut' or leaky gut wall syndrome and seems to be characterized by the release of bacterial metabolites and endotoxins, such as lipopolysaccharide (LPS), into the circulation. This condition, mainly caused by bacterial infections, oxidative stress, high-fat diet, exposure to alcohol or chronic allergens, and dysbiosis, appear to be highly connected with the development and/or progression of several metabolic and autoimmune systemic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), neurodegeneration, cardiovascular disease, inflammatory bowel disease, and type 1 diabetes mellitus (T1D). In this review, starting from a description of the mechanisms that enable barrier homeostasis and analyzing the relationship between this complex ecosystem and various pathological conditions, we explore the role of the gut barrier in driving systemic inflammation, also shedding light on current and future therapeutic interventions.
103Nonalcoholic Fatty Liver Disease and the Gut Microbiome.PubMed
Jerome Boursier, Anna Mae Diehl
Clin Liver Dis. 2016 May;20(2):263-75. doi: 10.1016/j.cld.2015.10.012. Epub 2015 Dec 24.
Recent progress has allowed a more comprehensive study of the gut microbiota. Gut microbiota helps in health maintenance and gut dysbiosis associates with chronic metabolic diseases. Modulation of short-chain fatty acids and choline bioavailability, lipoprotein lipase induction, alteration of bile acid profile, endogenous alcohol production, or liver inflammation secondary to endotoxemia result from gut dysbiosis. Modulation of the gut microbiota by pre/probiotics gives promising results in animal, but needs to be evaluated in human before use in clinical practice. Gut microbiota adds complexity to the pathophysiology of nonalcoholic fatty liver disease but represents an opportunity to discover new therapeutic targets.
104Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications.PubMed
Jiezhong Chen, Luis Vitetta
Int J Mol Sci. 2020 Jul 23;21(15):5214. doi: 10.3390/ijms21155214.
Gut microbiota dysregulation plays a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through its metabolites. Therefore, the restoration of the gut microbiota and supplementation with commensal bacterial metabolites can be of therapeutic benefit against the disease. In this review, we summarize the roles of various bacterial metabolites in the pathogenesis of NAFLD and their therapeutic implications. The gut microbiota dysregulation is a feature of NAFLD, and the signatures of gut microbiota are associated with the severity of the disease through altered bacterial metabolites. Disturbance of bile acid metabolism leads to underactivation of bile acid receptors FXR and TGR5, causal for decreased energy expenditure, increased lipogenesis, increased bile acid synthesis and increased macrophage activity. Decreased production of butyrate results in increased intestinal inflammation, increased gut permeability, endotoxemia and systemic inflammation. Dysregulation of amino acids and choline also contributes to lipid accumulation and to a chronic inflammatory status. In some NAFLD patients, overproduction of ethanol produced by bacteria is responsible for hepatic inflammation. Many approaches including probiotics, prebiotics, synbiotics, faecal microbiome transplantation and a fasting-mimicking diet have been applied to restore the gut microbiota for the improvement of NAFLD.
105Gut microbial metabolites in obesity, NAFLD and T2DM.PubMed
Emanuel E Canfora, Ruth C R Meex, Koen Venema, et al.
Nat Rev Endocrinol. 2019 May;15(5):261-273. doi: 10.1038/s41574-019-0156-z.
Evidence is accumulating that the gut microbiome is involved in the aetiology of obesity and obesity-related complications such as nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes mellitus (T2DM). The gut microbiota is able to ferment indigestible carbohydrates (for example, dietary fibre), thereby yielding important metabolites such as short-chain fatty acids and succinate. Numerous animal studies and a handful of human studies suggest a beneficial role of these metabolites in the prevention and treatment of obesity and its comorbidities. Interestingly, the more distal colonic microbiota primarily ferments peptides and proteins, as availability of fermentable fibre, the major energy source for the microbiota, is limited here. This proteolytic fermentation yields mainly harmful products such as ammonia, phenols and branched-chain fatty acids, which might be detrimental for host gut and metabolic health. Therefore, a switch from proteolytic to saccharolytic fermentation could be of major interest for the prevention and/or treatment of metabolic diseases. This Review focuses on the role of products derived from microbial carbohydrate and protein fermentation in relation to obesity and obesity-associated insulin resistance, T2DM and NAFLD, and discusses the mechanisms involved.
106Gut microbiome and nonalcoholic fatty liver diseases.PubMed
Lixin Zhu, Robert D Baker, Susan S Baker
Pediatr Res. 2015 Jan;77(1-2):245-51. doi: 10.1038/pr.2014.157. Epub 2014 Oct 13.
We review recent findings and hypotheses on the roles of gut microbiome in the pathogenesis of nonalcoholic fatty liver diseases (NAFLD). Microbial metabolites and cell components contribute to the development of hepatic steatosis and inflammation, key components of nonalcoholic steatohepatitis (NASH), the severe form of NAFLD. Altered gut microbiome can independently cause obesity, the most important risk factor for NAFLD. This capability is attributed to short-chain fatty acids (SCFAs), major gut microbial fermentation products. SCFAs account for a large portion of caloric intake of the host, and they enhance intestinal absorption by activating GLP-2 signaling. However, elevated SCFAs may be an adaptive measure to suppress colitis, which could be a higher priority than imbalanced calorie intake. The microbiome of NASH patients features an elevated capacity for alcohol production. The pathomechanisms for alcoholic steatohepatitis may apply to NASH. NAFLD/NASH is associated with elevated Gram-negative microbiome and endotoxemia. However, many NASH patients exhibited normal serum endotoxin indicating that endotoxemia is not required for the pathogenesis of NASH. These observations suggest that microbial intervention may benefit NAFLD/NASH patients. However, very limited effects were observed using traditional probiotic species. Novel probiotic therapy based on NAFLD/NASH specific microbial composition represents a promising future direction.
107Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway.PubMed
Qixing Nie, Xi Luo, Kai Wang, et al.
Cell. 2024 May 23;187(11):2717-2734.e33. doi: 10.1016/j.cell.2024.03.034. Epub 2024 Apr 22.
The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo. By activity-based protein purification and identification, we identified an enzyme annotated as β-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila. Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.
108Microbiome and metabolomics reveal the effect of gut microbiota on liver regeneration of fatty liver disease.PubMed
Yiqing Hu, Xiaoyi Hu, Li Jiang, et al.
EBioMedicine. 2025 Jan;111:105482. doi: 10.1016/j.ebiom.2024.105482. Epub 2024 Dec 6.
BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with impaired regenerative capacity and poor postoperative prognosis following hepatectomy. Previous research has highlighted the importance of the gut-liver axis in the physiological and pathological processes of the liver. However, the contribution of gut bacteria to the regeneration of livers with MAFLD and its metabolic regulatory mechanisms remain elusive. METHODS: Partial hepatectomy (PHx) was performed on C57Bl/6J mice fed with high-fat diet (HFD) for 12 weeks. Pathological examination, immunohistochemistry, and qRT-PCR analysis were performed to assess the severity of steatosis and proliferative potential. The gut microbiome was examined by 16S rRNA gene sequencing and shotgun metagenomics, whereas liver metabolomics was analysed via untargeted and targeted metabolomics using liquid chromatography-tandem mass spectrometry (LC-MS). FINDINGS: HFD-induced hepatic steatosis in mice led to impaired liver regeneration following PHx. The gut microbiota and liver metabolites were altered along with the liver regeneration process. Longitudinal time-series analysis revealed dynamic alterations in these data, whereas correlation analysis screened out bacterial candidates that potentially influence liver regeneration in MAFLD by modulating metabolic pathways. Among these bacteria, the dominant bacterium Akkermansia was selected for subsequent investigation. MAFLD mice gavaged with Akkermansia muciniphila (A. muciniphila) exhibited reduced liver lipid accumulation and accelerated liver regeneration, possibly through the regulation of the tricarboxylic acid (TCA) cycle. INTERPRETATION: These data demonstrated the interplay between the gut microbiome, liver metabolomics, and liver regeneration in mice with MAFLD. A. muciniphila has the potential to serve as a clinical intervention agent to accelerate postoperative recovery in MAFLD. FUNDING: This work was supported by the Research Project of Jinan Microecological Biomedicine Shandong Laboratory [JNL-2022008B]; the Zhejiang Provincial Natural Science Foundation of China [LZ21H180001]; the Fundamental Research Funds for the Central Universities [No. 2022ZFJH003].
109Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis.PubMed
Yong Rao, Zhiqi Kuang, Chan Li, et al.
Gut Microbes. 2021 Jan-Dec;13(1):1-19. doi: 10.1080/19490976.2021.1927633.
The gut bacterium has been increasingly recognized for its therapeutic potential in treating metabolic disorders, including obesity, diabetes, and metabolicdysfunction-associated fatty liver disease (MAFLD). However, its underlying mechanism involved in its well-known metabolic actions needs further evaluation. The present study explored the therapeutic effect and mechanism of in intervening MAFLD by using a high-fat and high-cholesterol (HFC) diet induced obese mice model. Mice treated with efficiently reversed MAFLD in the liver, such as hepatic steatosis, inflammatory, and liver injury. These therapeutic effects persisted after long-term drug withdrawal and were slightly weakened in the antibiotics-treated obese mice. treatment efficiently increased mitochondrial oxidation and bile acid metabolism in the gut-liver axis, ameliorated oxidative stress-induced cell apoptosis in gut, leading to the reshaping of the gut microbiota composition. These metabolic improvements occurred with increased L-aspartate levels in the liver that transported from the gut. The administration of L-aspartate or in mice displayed the similar beneficial metabolic effects mentioned above and efficiently ameliorated MAFLD. Together, these data indicate that the anti-MAFLD activity of correlated with lipid oxidation and improved gut-liver interactions through regulating the metabolism of L-aspartate. could be a potential agent for clinical intervention in MAFLD.
110inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated γδT17 cell and macrophage polarization.PubMed
Yuqiu Han, Qi Ling, Li Wu, et al.
Gut Microbes. 2023 Jan-Dec;15(1):2221485. doi: 10.1080/19490976.2023.2221485.
Current evidence indicates that the next-generation probiotic () has therapeutic potential for nonalcoholic fatty liver disease (NAFLD), especially its inflammatory stage known as nonalcoholic steatohepatitis (NASH). However, the mechanisms of in NASH prevention remain unknown. Here, supplementation prevented hepatic inflammation in high-fat diet-induced NASH mice, characterized by reduced hepatic proinflammatory macrophages (M1) and γδT and γδT17 cells. Consistently, hepatic M1 and γδT cells were enriched in biopsy-proven NASH patients and high-fat/high-carbohydrate diet-induced NASH mice. Antibiotics reduced hepatic M1, γδT and γδT17 cells in NASH mice. Furthermore, inhibited intestinal barrier disruption and accordingly downregulated hepatic Toll-like receptor 2 (TLR2) expression in NASH mice. The activation of TLR2 by lipoteichoic acid enriched hepatic γδT17 cells (not M1) in normal diet-fed mice and neutralized the γδT cell-lowering and liver inflammation-protecting effects of in NASH mice. Additionally, activated γδT cells could promote macrophage polarization via IL-17. Our study first supported that prevented NASH by modulating TLR2-activated γδT17 cells and further macrophage polarization, facilitating clinical therapeutic applications.
111The carotenoid torularhodin alleviates NAFLD by promoting Akkermanisa muniniphila-mediated adenosylcobalamin metabolism.PubMed
Chang Liu, Xiaojiao Zheng, Jian Ji, et al.
Nat Commun. 2025 Apr 8;16(1):3338. doi: 10.1038/s41467-025-58500-3.
Torularhodin, a unique carotenoid, confers beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the precise mechanism underlying its therapeutic effects remains unknown. Here, we report that torularhodin alleviates NAFLD in male mice by modulating the gut microbiota. Additionally, transplanting fecal microbiota from torularhodin-treated mice to germ-free mice also improves NAFLD. Mechanistically, torularhodin specifically enriches the abundance of Akkermansia muciniphila, which alleviates NAFLD by promoting the synthesis of adenosylcobalamin. Utilizing a human gastrointestinal system and a colonic organoid model, we further demonstrate that adenosylcobalamin confers protective effects against NAFLD through reducing ceramides, a well-known liver damaging compound, and this effect is mediated by inhibition of the hypoxia-inducible factor 2α pathway. Notably, we construct electrospun microsphere-encapsulated torularhodin, which facilitates the slow release of torularhodin in the colon. Together, our findings indicate the therapeutic potential of microbial utilization of carotenoids, such as torularhodin, for treating NAFLD.
112Gut Commensal Barnesiella Intestinihominis Ameliorates Hyperglycemia and Liver Metabolic Disorders.PubMed
Ye Zhang, Dong Xu, Xuyi Cai, et al.
Adv Sci (Weinh). 2025 Feb;12(8):e2411181. doi: 10.1002/advs.202411181. Epub 2024 Dec 31.
Recent studies have highlighted the role of the gut microbiota in type 2 diabetes (T2D). Improving gut microbiota dysbiosis can be a potential strategy for the prevention and management of T2D. Here, this work finds that the abundance of Barnesiella intestinihominis is significantly decreased in the fecal of T2D patients from 2-independent centers. Oral treatment of live B. intestinihominis (LBI) considerably ameliorates hyperglycemia and liver metabolic disorders in HFD/STZ-induced T2D models and db/db mice. LBI-derived acetate has similar protective effects against T2D. Mechanistically, acetate enhances fibroblast growth factor 21 (FGF21) through inhibition of histone deacetylase 9 (HDAC9) to increase H3K27 acetylation at the FGF21 promoter. The screening puerarin from Gegen Qinlian decoction in a gut microbiota-dependent manner improved hyperglycemia and liver metabolic disorders by promoting the growth of B. intestinihominis. This study suggests that gut commensal B. intestinihominis and puerarin, respectively have the potential as a probiotic and prebiotic in the treatment of T2D.
113Gut microbiota in patients with metabolic, dysfunction-associated steatotic liver disease.PubMed
Lissette Duarte, Fabien Magne, Martin Gotteland
Curr Opin Clin Nutr Metab Care. 2025 Jul 1;28(4):307-315. doi: 10.1097/MCO.0000000000001128. Epub 2025 Apr 23.
PURPOSE OF REVIEW: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition that can progress to fibrosis, steatohepatitis, and hepatocellular carcinoma. This review examines recent advances concerning the role of gut microbiota in MASLD and microbiota-focused interventions to positively impact disease outcome. RECENT FINDINGS: Dysbiotic microbiota and a compromised gut barrier facilitate the translocation of microbial-associated molecular patterns and harmful metabolites into the portal circulation and liver, where they exacerbate inflammatory and fibrogenic processes. Conversely, other bacterial metabolites have protective effects in the liver. Therefore, microbiota homeostasis is essential for maintaining liver health. SUMMARY: Levels of harmful bacterial metabolites including ethanol, NH 3 , trimethylamine-L-oxide, 2-oleylglycerol, and litocholic acid are often increased in patients with MASLD. Conversely, short-chain fatty acids, indole derivatives, histidine, and the acids taurodeoxycholic, 3-succinylcholic, and hyodeoxycholic are decreased. The main aim of current interventions/treatments is to reduce harmful metabolites and increase beneficial ones. These interventions include drugs (pemafibrate, metformin, obeticholic acid), natural compounds (silymarin, lupeol, dietary fiber, peptides), exogenous bacteria (probiotics, gut symbionts), special diets (Mediterranean diet, time-restricted feeding), as well as microbiota transplantation, and phage therapy. Most improve gut permeability, liver inflammation, and fibrosis through microbiota regulation, and are promising alternatives for MASLFD management. However, most results come from animal studies, while clinical trials in MASLD patients are lacking. Further research is therefore needed in this area.
114Fu brick tea supplementation ameliorates non-alcoholic fatty liver disease and associated endotoxemia via maintaining intestinal homeostasis and remodeling hepatic immune microenvironment.PubMed
Gaolong Zuo, Menghua Li, Xiaoli Guo, et al.
Food Res Int. 2025 May;209:116207. doi: 10.1016/j.foodres.2025.116207. Epub 2025 Mar 14.
Non-alcoholic fatty liver disease (NAFLD) is a prevalent disorder of excessive fat accumulation and inflammation in the liver that currently lacks effective therapeutic interventions. Fu brick tea (FBT) has been shown to ameliorate liver damage and modulate gut microbiota dysbiosis in NAFLD, but the potential mechanisms have not been comprehensively elucidated, especailly whether its hepatoprotective effects are determined to depend on the homeostasis of gut microbiota, intestinal barrier function and hepatic immune microenvironment. In this study, our results further demonstrated that FBT not only alleviated NAFLD symptoms and related endotoxemia in high-fat diet (HFD)-fed rats, but also attenuated intestinal barrier dysfunction and associated inflammation, also confirmed in Caco-2 cell experiment. Meanwhile, FBT intervention significantly relieved HFD-induced gut microbiota dysbiosis, characterized by increased diversity and composition, particularly facilitating beneficial microbes, including short chain fatty acids (SCFAs) and bile acids producers, such as Blautia and Fusicatenibacter, and inhibiting Gram-negative bacteria, such as Prevotella_9 and Phascolarctobacterium. Also, the gut microbiota-dependent hepatoprotective effects of FBT were verified by fecal microbiota transplantation (FMT) experiment. Thus, the beneficial moulation of gut microbiota altered by FBT in levels of SCFAs, bile acids and lipopolysaccharides, intestinal barrier function and TLR4/NF-κB pathway contributed to alleviate liver steatosis and inflammation. Additionally, the hepatoprotective effects of FBT was further demonstrated by suppressing Kupffer cell activation and regulating lipid metabolism using an ex vivo model of liver organoid. Therefore, FBT supplementation can maintain intenstinal homeostasis and remodel hepatic immune microenvironment to prevent NAFLD and associated endotoxemia.
115Possible correlation between high circulatory levels of trimethylamine-N-oxide and 2177G>C polymorphisms of hepatic flavin containing monooxygenase 3 in Kurdish Population with non-alcoholic fatty liver disease.PubMed
Mohammad Moradzad, Mohammad Abdi, Farshad Sheikh Esmaeili, et al.
Mol Biol Rep. 2022 Jul;49(7):5927-5937. doi: 10.1007/s11033-022-07375-4. Epub 2022 Mar 29.
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disorder with complicated pathophysiology. Trimethylamine-N-oxide (TMAO) has been thought to be correlated with the pathogenesis of NAFLD. The single nucleotide polymorphisms (SNPs) of hepatic flavin-containing monooxygenase 3 (FMO3) regulate the concentration of TMAO. This case-control study investigated the plasma levels of TMAO as well as its possible correlation with the frequency of specific genotype of FMO3 (-2650C>G, -2543T>A, -2177G>C, -2589C>T, -2106G>A polymorphisms) in Kurdish patients with NAFLD. METHODS AND RESULTS: In 85 confirmed NAFLD patients and 30 healthy individuals, triglycerides (TG), total cholesterol (Chol), low-density lipoprotein (LDL), high-density lipoprotein (HDL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities were measured. TMAO was also measured using the LC-MS/MS method. High-resolution melting analysis was applied to determine FMO3 genotypes. Plasma TMAO levels were significantly higher in patients (p = 0.030). A CC genotype with a frequency of 12.9% for SNP -2177G>C was found in Kurdish NAFLD patients. The distribution of the GC genotype was also significantly different (p = 0.017). CONCLUSIONS: The current results provide documentation for high circulatory levels of TMAO and its possible correlation with the presence of the specific genotype -2177G>C FMO3 in Kurdish NAFLD patients.
116Genetics and epigenetics of NAFLD and NASH: Clinical impact.PubMed
Mohammed Eslam, Luca Valenti, Stefano Romeo
J Hepatol. 2018 Feb;68(2):268-279. doi: 10.1016/j.jhep.2017.09.003. Epub 2017 Nov 6.
Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.
117Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies.PubMed
Norbert Stefan, Hans-Ulrich Häring, Kenneth Cusi
Lancet Diabetes Endocrinol. 2019 Apr;7(4):313-324. doi: 10.1016/S2213-8587(18)30154-2. Epub 2018 Aug 30.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD.
118Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy.PubMed
Yating Zhang, Mingxu Xie, Jun Wen, et al.
Gut. 2025 Mar 6;74(4):639-651. doi: 10.1136/gutjnl-2024-333154.
BACKGROUND: Transmembrane 6 superfamily member 2 (TM6SF2) has a protective role against metabolic dysfunction-associated steatotic liver disease (MASLD). OBJECTIVE: We aim to investigate the mechanistic role and therapeutic potential of hepatic TM6SF2 in MASLD-related hepatocellular carcinoma (HCC). DESIGN: Hepatocyte-specific knockout ( ) mice were fed with high-fat/high-cholesterol (HFHC) diet or diethylnitrosamine plus HFHC diet to induce MASLD-HCC. TM6SF2 function was also evaluated in orthotopic MASLD-HCC mice. Human MASLD-HCC specimens were included to evaluate clinical significance. RESULTS: TM6SF2 was downregulated in tumours compared with adjacent normal tissues from MASLD-HCC patients. Hepatocyte-specific knockout exacerbated tumour formation in mice with diet-induced or diet-induced and carcinogen-induced MASLD-HCC. The tumour-promoting effect of knockout was verified in orthotopic MASLD-HCC mice, while mice bearing -overexpressing tumours had opposite phenotypes. We observed the reduction of interferon-gamma (IFN-γ)CD8 T cells in the tumours of mice and orthotopic knockout mice, while the tumour-suppressive effect of was abolished after depleting CD8 T cells. The correlation between TM6SF2 and CD8 T cells was confirmed in human MASLD-HCC tissues, inferring that TM6SF2 could promote antitumour immunity. Mechanistically, TM6SF2 directly bound to IKKβ and inhibited NF-κB signalling pathway to reduce interleukin (IL)-6 secretion, thereby activating cytotoxic CD8 T cells. IL-6 neutralisation abolished the tumour-promoting and immunosuppressive effects of knockout in mice. Moreover, introducing by adenovirus improved immunotherapy response against MASLD-HCC in mice. CONCLUSION: Hepatic TM6SF2 protects against MASLD-HCC and activates cytotoxic CD8 T cells via NF-κB-IL-6 axis. TM6SF2 is a promising strategy for sensitising MASLD-HCC to immunotherapy.
119Genome-wide association meta-analysis identifies 17 loci associated with nonalcoholic fatty liver disease.PubMed
Yanhua Chen, Xiaomeng Du, Annapurna Kuppa, et al.
Nat Genet. 2023 Oct;55(10):1640-1650. doi: 10.1038/s41588-023-01497-6. Epub 2023 Sep 14.
Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.
120Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort.PubMed
Quentin M Anstee, Rebecca Darlay, Simon Cockell, et al.
J Hepatol. 2020 Sep;73(3):505-515. doi: 10.1016/j.jhep.2020.04.003. Epub 2020 Apr 13.
BACKGROUND & AIMS: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. METHODS: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. RESULTS: Case-control analysis identified signals showing p values ≤5 × 10 at 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1 × 10 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p = 8.2 × 10). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. CONCLUSIONS: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. LAY SUMMARY: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments.
121Fatty liver and serum cholinesterase are independently correlated with HbA1c levels: cross-sectional analysis of 5384 people.PubMed
Shuichi Katoh, Markku Peltonen, Takashi Wada, et al.
J Int Med Res. 2014 Apr;42(2):542-53. doi: 10.1177/0300060513517485. Epub 2014 Mar 4.
OBJECTIVES: To examine the association between glycosylated haemoglobin (HbA1c) and fatty liver markers. METHODS: This cross-sectional analysis stratified subjects into quintiles based on HbA1c. Fatty liver using ultrasonography scores (FLUS) were assigned as follows: 2 points, moderate or severe fatty liver; 1 point, mild fatty liver; and 0 points, normal liver. Subjects with viral hepatitis, alcohol intake >175 g/week or receiving hypoglycaemic treatment were excluded. RESULTS: The study included 5384 subjects. Serum cholinesterase (ChE) and FLUS showed a significant graded increase with increasing HbA1c. In linear regression analysis stratified by body mass index (BMI) and age, ChE and FLUS were significantly associated with lower (1 + 2) and higher (3 + 4 + 5) HbA1c quintiles, respectively, independent of BMI and age. CONCLUSIONS: The findings show that both ChE and FLUS are significantly correlated with HbA1c, independent of BMI and age.
122Association between cumulative uric acid exposure and metabolic dysfunction-associated fatty liver disease.PubMed
Yunpeng Li, Hong Ji, Fei Tian, et al.
BMC Gastroenterol. 2025 Jul 1;25(1):497. doi: 10.1186/s12876-025-04038-z.
OBJECTIVE: To explore the impact of cumulative uric acid (cum UA) exposure on the incidence of metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: This prospective cohort study analyzed 21,333 active and retired employees who completed three consecutive health examinations (2006, 2008, 2010), with a mean follow-up time of 6.24 years (SD = 2.59) revealing 8,280 (38.81%) incident MAFLD cases. Participants were stratified into quartiles (Q1-Q4) based on cum UA levels measured across the triennial assessments. Kaplan-Meier survival curves quantified cumulative MAFLD incidence rates across quartiles, followed by multivariable-adjusted Cox proportional hazards regression models to evaluate dose-response relationships between cum UA exposure and MAFLD risk. RESULTS: Following comprehensive adjustment for confounding variables, multivariable analysis revealed progressively elevated hazard ratios for MAFLD development across cum UA quartiles. Compared to the reference quartile 1 (Q1), adjusted HRs (95% CI) were 1.055 (0.989-1.125) for Q2, 1.202 (1.126-1.284) for Q3, and 1.237 (1.154-1.326) for Q4. Restricted cubic spline (RCS) analysis confirmed a significant non-linear dose-response relationship between cumulative UA exposure and MAFLD risk (non-linearity association P < 0.05). The Kaplan-Meier Survival Curves showed significantly diverging cumulative incidence rates across quartiles (Log-rank χ²=87.98; P < 0.001). Incidence densities followed an ascending pattern: 55.07 (Q1), 58.46 (Q2), 66.34 (Q3), and 67.12 cases/1,000 person-years (Q4). Corresponding cumulative incidence rates were 52.20%, 52.49%, 58.29%, and 60.50% respectively. Stratified analysis was performed for gender, abdominal obesity, and smoking. Gender stratification: Q4 HR = 1.315 (1.216-1.422) in males vs. 1.079 (0.953-1.223) in females. Abdominal obesity status: Q4 HR = 1.208 (1.082-1.349) in obese vs. 1.348 (1.237-1.468) in non-obese. Smoking status: Q4 HR = 1.385 (1.238-1.549) in smoking vs. 1.186 (1.087-1.295) in non-smoking. Sensitivity analyses excluding participants with baseline chronic kidney disease (CKD) or follow-up time < 2 years demonstrated comparable risk gradients, confirming the robustness of our primary findings. CONCLUSION: This study found that cum UA is an independent risk factor for MAFLD. In this longitudinal cohort analysis, both the cumulative incidence and the risk of developing MAFLD increased as the cum UA level rose. Among all the participants, especially subjects who regularly engage in physical exercise, males, individuals with abdominal obesity, and smokers have a higher risk of developing MAFLD. TRIAL REGISTRATION: trial registration number ChiCTRTNC11001489, registration date 20,110,824, registration institution Chinese Clinical Trial Registry, registration site: http://www.chictr.org.cn/index.aspx .
123High uric acid exacerbates nonalcoholic steatohepatitis through NLRP3 inflammasome and gasdermin D-mediated pyroptosis.PubMed
Zixin Xu, Chenxi Tang, Xin Song, et al.
J Biol Chem. 2025 Jun;301(6):110249. doi: 10.1016/j.jbc.2025.110249. Epub 2025 May 19.
Hyperuricemia is independently associated with an increased risk of nonalcoholic steatohepatitis (NASH), but the underlying mechanisms responsible for this association remain unclear. We first analyzed the association between intrahepatic UA levels and gasdermin D (GSDMD)-mediated pyroptosis in vivo and in vitro. We subsequently generated hepatic-specific glucose transporter 9 (GLUT9)-knockout mice and GSDMD knockout (GSDMD) mice to explore the role of intrahepatic UA in GSDMD-induced pyroptosis in NASH. We found that high intrahepatic UA levels were positively related to GSDMD-mediated pyroptosis in NASH mice. The inhibition of hepatic UA production by allopurinol alleviated hepatic inflammation and GSDMD-mediated pyroptosis in NASH mice. Hepatic-specific knockout of Glut9 significantly decreased intrahepatic UA levels, attenuated NOD-like receptor family pyrin domain containing 3 (NLRP3)-Caspase-1-GSDMD-mediated pyroptosis in hepatocytes, and ameliorated hepatic inflammation and fibrosis in different mouse models of NASH. Further experiments revealed that inhibiting the NLRP3/Caspase-1/GSDMD pathway obviously blocked UA-induced pyroptosis and inflammation in hepatocytes. Additionally, GSDMD deficiency markedly reversed hepatic inflammation and fibrosis in NASH mice. In conclusion, our results showed that high UA could induce NLRP3-Caspase1-GSDMD-mediated pyroptosis, thereby aggravating NASH in mice.
124Combined effect of fasting blood glucose and serum uric acid on nonalcoholic fatty liver disease.PubMed
Yifan Hao, Xuerui Li, Yiting Zhang, et al.
Lipids Health Dis. 2025 May 8;24(1):168. doi: 10.1186/s12944-025-02538-1.
BACKGROUND: This study sought to investigate the independent and synergistic impacts of fasting blood glucose (FBG) and serum uric acid (SUA) levels on non-alcoholic fatty liver disease (NAFLD) in participants with and without type 2 diabetes mellitus (T2DM). METHOD: A total of 12,430 participants (mean age: 54.34 ± 15.23, 34.34% female) were enrolled through the Health Screening Center of Tianjin Medical University General Hospital. FBG was classified as < 6 mmol/L, 6-7 mmol/L, and ≥ 7 mmol/L. SUA was classified into two categories: normal SUA and hyperuricemia (SUA level ≥ 420 µmol/L for men, ≥ 360 µmol/L for women). T2DM was ascertained through self-reported data. The diagnosis of NAFLD is established via abdominal ultrasound imaging. Logistic regression models and interaction effect models are used for data analysis. RESULT: Of the 12,430 participants, 4846 (38.99%) were diagnosed with NAFLD. In comparison to individuals with FBG < 6 mmol/L and no self-reported T2DM, those with FBG ≥ 7 mmol/L and no self-reported T2DM exhibited the highest prevalence of NAFLD (odds ratio [OR] 2.91, 95% CI 2.16-3.93) following multi-adjusted analysis. In the joint effect analysis of FBG and SUA, FBG ≥ 7 mmol/L and hyperuricemia were linked to a greater prevalence of NAFLD compared to FBG < 6 mmol/L and normal SUA, both in individuals with self-reported T2DM (OR 2.92, 95% CI 1.68-5.05) and those without self-reported T2DM (OR 7.87, 95% CI 3.57-17.34). An additive interaction existed between FBG and SUA regarding NAFLD in individuals without self-reported T2DM (AP 0.488, 95% CI: 0.068-0.909, P = 0.02). CONCLUSION: Elevated FBG levels are associated with NAFLD irrespective of self-reported T2DM status. The concomitant elevation of FBG and SUA levels exhibits a significant correlation with NAFLD, particularly in individuals lacking self-reported T2DM.
125Synergistic impact of serum uric acid and ferritin on MAFLD risk: A comprehensive cohort analysis.PubMed
Miyeong Bae, Kwang Min Kim, Mi Hyeon Jin, et al.
Sci Rep. 2025 May 29;15(1):18936. doi: 10.1038/s41598-025-02914-y.
The characterization of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) underscores metabolic anomalies as critical in fatty liver disease progression. Serum uric acid is increasingly recognized as a determinant for fatty liver diseases due to its association with metabolic disorders. Ferritin, in parallel, serves as an inflammatory marker closely tied to metabolic syndrome and insulin resistance. Our study explores the combined influence of serum uric acid and ferritin on MAFLD prevalence. We conducted a retrospective cohort analysis at Samsung Changwon Hospital's Health Screening Center (2011-2018), encompassing 7,818 individuals post-exclusion criteria. Participants were stratified into gender-specific quartiles based on serum uric acid and ferritin levels. Utilizing multivariable Cox proportional hazard models alongside Kaplan-Meier analysis, we assessed the incidence of MAFLD and its relationship with these serum biomarkers, also performing subgroup assessments by gender, age, and BMI. Over 41,819 person-years with an average observation period of 5.35 ± 2.06 years, 1,073 incident cases of MAFLD were recorded. The risk of MAFLD was notably higher within the upper quartiles of serum uric acid (HR: 2.17, 95% CI: 1.70-2.78). Each increment in natural logarithmic serum uric acid level correlated with an increased risk (HR: 3.65, 95% CI: 2.32-5.74). Serum ferritin also indicated an enhanced risk, albeit less pronounced. The simultaneous presence of elevated levels of both uric acid and ferritin correlated with the highest MAFLD risk (HR: 3.89, 95% CI: 2.41-6.28). Our findings affirm that high serum uric acid levels significantly escalate the risk of MAFLD, with serum ferritin levels contributing to a lesser yet substantial degree. The concurrent elevation of both biomarkers magnifies MAFLD risk, reinforcing the need for their combined assessment in MAFLD risk evaluation.
126MASLD Risk Score (MRS) and Random Forest model (RF Model): Novel tools for screening and severity assessment of MASLD.PubMed
Sanjaay Balakrishnan, Padmashree Ranganathan, Kaushiki S Prabhudesai, et al.
Comput Biol Med. 2025 Jun;192(Pt B):110314. doi: 10.1016/j.compbiomed.2025.110314. Epub 2025 May 5.
BACKGROUND AND AIMS: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) spans from simple steatosis to progressive forms like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, making early diagnosis and grading crucial. This study aimed to develop and validate predictive models for diagnosing and assessing MASLD severity using routinely available biomarkers from both public and clinical datasets. APPROACH & RESULTS: We developed a novel MASLD Risk Score (MRS) using data from the CDC NHANES (2000-2020) and validated it in a clinically profiled Indian cohort. Unlike existing indices, the predictors were derived through data-driven feature selection from large dataset, ensuring statistical robustness. It integrates novel (Uric Acid, HOMA-IR) and established (liver enzymes, triglycerides, waist circumference, BMI) biomarkers to improve metabolic profiling and predictive accuracy. The MRS also uniquely enables grading of MASLD severity, addressing a key limitation of previous models. The MRS achieved AUROCs of 0.91 (public) and 0.85 (clinical) with accuracies of 94 % and 82 %, respectively. A Random Forest (RF) model built on the same features provided AUROCs of 0.87 (public) and 0.94 (clinical), with accuracies of 83 % and 82 %. MRS parameters were optimized using a diverse population, improving generalizability across demographics. Both models showed strong correlation with ultrasonography results and outperformed existing indices. CONCLUSIONS: The MRS offers a novel, interpretable, and cost-effective solution for MASLD screening. Its development from a large, demographically diverse population and incorporation of varied biomarkers supports generalizability. While results are promising, external validation in multi-center clinical settings is needed to confirm broad utility.
127Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial.PubMed
Yu-Hao Lin, Zhi-Jun Zhang, Jin-Qing Zhong, et al.
PLoS One. 2024 May 3;19(5):e0302155. doi: 10.1371/journal.pone.0302155. eCollection 2024.
BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. METHODS: This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. DISCUSSION: This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. TRIAL REGISTRATION: This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).
128Resmetirom and Metabolic Dysfunction-Associated Steatohepatitis: Perspectives on Multidisciplinary Management from Global Healthcare Professionals.PubMed
Kahei Au, Ming-Hua Zheng, Wei-Jei Lee, et al.
Curr Obes Rep. 2024 Dec;13(4):818-830. doi: 10.1007/s13679-024-00582-z. Epub 2024 Aug 7.
PURPOSE OF REVIEW: The approval of resmetirom brings great hope to patients with metabolic dysfunction-associated steatohepatitis (MASH). The purpose of this review is to explore its impact on the global health environment. The implementation of multidisciplinary management MASH is proposed. RECENT FINDINGS: Resmetirom has benefits in the treatment of MASH, and its safety and effectiveness have been studied. The adverse events (AEs) need to be noticed. To improve patient outcomes, a multimodal approach with medication such as resmetirom, combined with metabolic and bariatric surgery (MBS) and lifestyle interventions can be conducted. MASH, a liver disease linked with obesity, is a challenging global healthcare burden compounded by the absence of any approved pharmacotherapy. The recent conditional approval by the Food and Drug Administration (FDA) in the United States of resmetirom, an oral, liver-directed, thyroid hormone receptor beta-selective agonist, marks a significant milestone, offering a treatment option for adults with non-cirrhotic MASH and who have moderate to advanced liver fibrosis. This narrative review discusses the efficacy and safety of resmetirom and its role in the therapeutic landscape of MASH treatment. Despite the promising hepatoprotective effect of resmetirom on histological liver endpoints, its use need further research, particularly regarding ethnic differences, effectiveness and cost-effectiveness, production scalability, social acceptance and accessibility. In addition, integrating resmetirom with other multidisciplinary therapeutic approaches, including lifestyle changes and MBS, might further improve clinical liver-related and cardiometabolic outcomes of individuals with MASH. This review highlights the importance of a comprehensive treatment strategy, supporting continued innovation and collaborative research to refine treatment guidelines and consensus for managing MASH, thereby improving clinical patient outcomes in the growing global epidemic of MASH. Studies done to date have been relatively short and ongoing, the course of the disease is highly variable, the conditions of various patients vary, and given this complex clinical phenotype, it may take many years of clinical trials to show long-term benefits.