Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing 100034, China.
Department of Gastrointestinal Surgery, Henan Provincial People's Hospital, Zhengzhou 450003, Henan Province, China.
World J Gastroenterol. 2022 Jul 7;28(25):2937-2954. doi: 10.3748/wjg.v28.i25.2937.
The lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to insufficient research on its pathogenesis. The pathogenesis of TM6SF2-efficient NAFLD remains unclear, resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.
To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.
Liver samples collected from both NAFLD mouse models and human participants (80 cases) were used to evaluate the expression of TM6SF2 by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction. RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2. Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD. MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.
Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models. TM6SF2 overexpression can reduce hepatic lipid accumulation, suggesting a protective role for TM6SF2 in a high-fat diet (HFD). Downregulation of TM6SF2, simulating the TM6SF2 E167K mutation condition, increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Owing to the potential effect of TM6SF2 deficiency on lipid metabolism, the application of an acetyl-CoA carboxylase inhibitor (MK-4074) could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.
TM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.
非酒精性脂肪性肝病（NAFLD）缺乏有效的药物治疗主要归因于其发病机制的研究不足。TM6SF2 高效性 NAFLD 的发病机制尚不清楚，导致 TM6SF2 缺乏型患者缺乏治疗策略。
研究 TM6SF2 在脂肪肝脂肪酸代谢中的作用，并提出可能的 TM6SF2 缺乏型 NAFLD 治疗策略。
采用 Western blot、免疫组化和实时定量聚合酶链反应检测 NAFLD 小鼠模型和人类患者（80 例）肝脏组织中 TM6SF2 的表达。从基因表达综合数据库中检索 RNA-seq 数据以验证 TM6SF2 的过表达。通过敲低和过表达 TM6SF2 来阐明 NAFLD 中肝内脂质积聚的机制基础。使用 MK-4074 作为治疗干预措施来评估其对 TM6SF2 缺乏型 NAFLD 的作用。
NAFLD 患者和 NAFLD 小鼠模型中肝 TM6SF2 水平升高。TM6SF2 过表达可减少肝内脂质积聚，提示 TM6SF2 在高脂饮食（HFD）中起保护作用。下调 TM6SF2，模拟 TM6SF2 E167K 突变状态，由于脂肪酸代谢紊乱导致细胞内脂质沉积增加，表现为脂肪酸摄取和合成增加，同时脂肪酸氧化受损。由于 TM6SF2 缺乏对脂质代谢的潜在影响，乙酰辅酶 A 羧化酶抑制剂（MK-4074）的应用可能逆转 TM6SF2 缺乏引起的 NAFLD 表型。
TM6SF2 在 HFD 条件下发挥保护作用；其缺乏通过失调的脂肪酸代谢增强肝内脂质积聚，MK-4074 治疗可减轻 TM6SF2 缺乏引起的 NAFLD 表型。
