3-Acetyl-oleanolic acid ameliorates non-alcoholic fatty liver disease in high fat diet-treated rats by activating AMPK-related pathways

摘要

3-Acetyl-oleanolic acid (3Ac-OA) is a derivative of oleanolic acid (OA),which has shown therapeutic beneficial effects on diabetes and metabolic syndrome.In this study we investigated whether 3Ac-OA exerted beneficial effect on non-alcoholic fatty liver disease (NAFLD) in rats and its potential underlying mechanisms.Treatment with 3Ac-OA (1-100 μmol/L) dose-dependently decreased the intracellular levels of total cholesterol (TC) and triglyceride (TG) in FFA-treated primary rat hepatocytes and human HepG2 cell lines in vitro.Furthermore,oil red staining studies showed that 3Ac-OA caused dose-dependent decrease in the number of lipid droplets in FFA-treated primary rat hepatocytes.SD rats were fed a high fat diet (HFD) for 6 weeks and subsequently treated with 3Ac-OA (60,30,15 mg·kg1·d1) for 4 weeks.3Ac-OA administration significantly decreased the body weight,liver weight and serum TC,TG,LDL-C levels in HFD rats.Furthermore,3Ac-OA administration ameliorated lipid accumulation and cell apoptosis in the liver of HFD rats.Using adipokine array analyses,we found that the levels of 11 adipokines (HGF,ICAM,IGF-1,IGFBP-3,IGFBP-5,IGFBP-6,lipocalin-2,MCP-1,M-CSF,Pref-1 and RAGE) were increased by more than twofold in the serum of 3Ac-OA-treated rats,whereas ICAM,IGF-1 and lipocalin-2 had levels increased by more than 20-fold.Moreover,3Ac-OA administration significantly increased the expression of glucose transporter type 2 (GLUT-2) and low-density lipoprotein receptor (LDLR),as well as the phosphorylation of AMP-activated protein kinase (AMPK),protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β) in the liver tissues of HFD rats.In conclusion,this study demonstrates that 3Ac-OA exerts a protective effect against hyperlipidemia in NAFLD rats through AMPK-related pathways.