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·kg-1·d-1) for 4 weeks. 3Ac-OA administration significantly decreased the body weight, liver weight and serum TC, TG, LDL-C levels in HFD rats. Furthermore, 3AcOA 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.
Keywords: 3-acetyl-oleanolic acid; AMPK; adipokines; high fat diet; hyperlipidemia; non-alcoholic fatty liver disease; oleanolic acid.