上海交通大学学报（医学版）2025，Vol.45Issue(4)：415-425,11.DOI:10.3969/j.issn.1674-8115.2025.04.003
利拉鲁肽改善非酒精性脂肪性肝病小鼠肝纤维化的作用及其机制
Effects and mechanisms of liraglutide in ameliorating liver fibrosis in NAFLD mice
摘要
Abstract
Objective·To investigate the effects of liraglutide on liver fibrosis in mice with non-alcoholic fatty liver disease(NAFLD)and the underlying mechanisms.Methods·Twenty 8-week-old C57BL/6J mice were randomly divided into a normal chow diet group(Chow group)and a methionine-choline-deficient(MCD)diet group(MCD group),with 10 mice per group.The MCD diet was used to induce NAFLD.Each group was further divided into two subgroups,resulting in four subgroups:Chow+saline,Chow+liraglutide,MCD+saline,and MCD+liraglutide group.After daily intraperitoneal injection of liraglutide(400 μg/kg)or an equivalent volume of saline for 4 weeks,an intraperitoneal glucose tolerance test(IPGTT)was performed.Serum levels of aspartate transaminase(AST),alanine aminotransferase(ALT),total cholesterol(TC),triglyceride(TAG),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C)were measured.Liver tissues were collected post-euthanasia to assess TAG content.Histopathological changes,lipid deposition,and fibrosis were evaluated via hematoxylin-eosin(HE)staining,Oil Red O staining,and Masson staining.Real-time quantitative PCR(qPCR)and Western blotting were used to analyze the expression of α-smooth muscle actin(α-SMA),fibronectin(FN),collagen type Ⅰ α(COL1A),matrix metalloproteinase 9(MMP9),tissue inhibitor of metalloproteinase 1(TIMP1),transforming growth factor β(TGF-β),SMAD3,and phosphorylated SMAD3(pSMAD3).Results·The IPGTT revealed that liraglutide intervention reduced blood glucose levels at 15,30,and 60 min,with a decreased area under the curve(AUC)(both P<0.05).Biochemical analysis showed that liraglutide lowered AST and ALT levels(both P<0.001),increased TC and HDL-C levels(both P<0.05),but had no significant effect on TAG or LDL-C in MCD mice.HE staining and Oil Red O staining revealed reduced lipid droplets,ballooning degeneration,and inflammatory infiltration in hepatocytes after liraglutide treatment.Masson staining indicated decreased collagen fiber deposition in the liver.qPCR and Western blotting analysis demonstrated upregulated expression of α-SMA,FN,COL1A,TIMP1,TGF-β,and pSMAD3/SMAD3,alongside downregulated MMP9 in MCD mice.Liraglutide reversed these changes,lowering α-SMA,FN,COL1A,TIMP1,TGF-β,and pSMAD3/SMAD3 expression while increasing MMP9 expression.Conclusion·Liraglutide ameliorates liver injury,lipid deposition,and fibrosis in NAFLD mice,through modulation of the TGF-β/SMAD3 pathway and regulating fibrosis-associated protein expression.关键词
利拉鲁肽/转化生长因子β/Sma和Mad相关蛋白3/非酒精性脂肪性肝病/肝纤维化Key words
liraglutide/transforming growth factor-β(TGF-β)/Sma-and Mad-related protein 3(SMAD3)/non-alcoholic fatty liver disease/liver fibrosis分类
医药卫生引用本文复制引用
王仁杰,祝超瑜,方云云,肖元元,王倩倩,宋雯婧,魏丽..利拉鲁肽改善非酒精性脂肪性肝病小鼠肝纤维化的作用及其机制[J].上海交通大学学报（医学版）,2025,45(4):415-425,11.基金项目
上海市自然科学基金(20ZR1442500). Natural Science Foundation of Shanghai(20ZR1442500). （20ZR1442500）
