Ezhilarasan Devaraj
Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India.
J Gastroenterol Hepatol. 2025 Sep;40(9):2163-2175. doi: 10.1111/jgh.17037. Epub 2025 Jun 19.
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.
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.
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.
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.
NOT APPLICABLE.
司美格鲁肽是一种胰高血糖素样肽-1受体激动剂（GLP-1 RA），用于减肥和改善代谢。司美格鲁肽可有效改善非酒精性脂肪性肝炎（NASH），但不能使组织学纤维化消退。关键问题仍然是，司美格鲁肽在改善NASH方面是发挥直接、独立的作用，还是其益处仅仅是体重、胰岛素抵抗和血糖控制改善的继发结果。司美格鲁肽或其他GLP-1 RA提供肝脏保护的确切作用机制尚不完全清楚。
使用关键词“司美格鲁肽与非酒精性脂肪性肝病/代谢相关脂肪性肝病（NAFLD/MASLD）”、“胰高血糖素样肽-1受体激动剂与MASLD/NAFLD”以及“司美格鲁肽与2型糖尿病/肥胖和高血压”在PubMed和EMBASE中进行全面检索。纳入2025年2月之前发表的相关论文。
司美格鲁肽通过未知机制调节多种与脂质相关的分子途径。临床前和临床研究表明，司美格鲁肽的作用方式包括：（i）降低食欲并增加饱腹感，从而减少饮食摄入以及随后游离脂肪酸向肝脏的输出；（ii）降低胰岛素抵抗，改善胰岛素敏感性和脂肪功能障碍；（iii）通过下调碳水化合物反应元件结合蛋白（ChREBP）和固醇调节元件结合蛋白-1c（SREBP-1c）信号通路以及脂质合成基因的表达来减少从头脂肪生成；（iv）减轻白色和棕色脂肪组织的重量；（v）通过降低表达GLP-1的巨噬细胞中的促炎标志物并有利地改变肠道微生物群来减轻炎症。
虽然本综述探讨了司美格鲁肽作用的潜在机制，但小鼠和人类肝脏中缺乏GLP-1受体表达表明这些机制与间接调节有关。因此，需要进一步的机制研究来阐明这些途径。
不适用。
