Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Mol Metab. 2021 Aug;50:101238. doi: 10.1016/j.molmet.2021.101238. Epub 2021 Apr 20.
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.
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.
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.
非酒精性脂肪性肝病，或最近提出的“代谢相关脂肪性肝病”（MAFLD），其特征是肝细胞内甘油三酯和其他脂质的病理性积聚。这种常见疾病可从单纯性脂肪变性进展为脂肪性肝炎，最终发展为终末期肝病。MAFLD 与全身能量代谢紊乱密切相关，包括胰岛素抵抗和动脉粥样硬化性血脂异常。
肝脏是通过分泌极低密度脂蛋白（VLDL）和另一方面通过内化脂肪酸和脂蛋白来进行脂质代谢的中心器官。本文综述讨论了最近关于肝脏脂质合成、VLDL 产生和脂蛋白内化以及脂肪组织和肝脏之间脂质交换的研究，这些研究是在 MAFLD 的背景下进行的。
MAFLD 中的肝脂肪变性是由源自白色脂肪组织（WAT）的脂肪酸、从头合成（DNL）和内吞富含甘油三酯的脂蛋白残基引起的肝甘油三酯合成过度触发的。由于肝内脂质含量高，VLDL 分泌增强，这是 MAFLD 患者典型的复杂血脂异常的主要原因。降低 VLDL 分泌能力的干预措施可减轻血脂异常，但会加重 MAFLD，表明肝细胞中脂质储存与分泌之间的平衡是决定疾病结局的关键参数。概念验证研究表明，促进脂肪组织中的脂质储存和能量燃烧可减少肝脂质负荷，从而改善 MAFLD。此外，还可以针对 DNL 和 WAT 衍生脂肪酸的肝细胞内甘油三酯合成进行靶向治疗以治疗 MAFLD。然而，需要更多的研究来了解个体转运蛋白、酶及其同工型如何影响体内脂肪变性和血脂异常，以及 MAFLD 的这两个方面是否可以选择性治疗。富含胆固醇的脂蛋白的加工对脂肪变性似乎不太重要，但它可能会调节炎症，从而影响 MAFLD 的进展。
