Oleanolic acid improves hepatic insulin resistance via antioxidant, hypolipidemic and anti-inflammatory effects

Abstract

Insulin resistance is the hallmark of type 2 diabetes mellitus (T2DM), which is closely related to disorder of lipid metabolism. The study was designed to evaluate the effects of oleanolic acid (OA) on hepatic insulin resistance and underlying mechanisms in Lep(db)(/)(db) obese diabetic mice. db/db Mice were administered with OA (20mg/kg/day, i.p.) for two weeks. OA reduced body weight, liver weight, and fat weight, and protected liver morphology and function. OA decreased fasting blood glucose, improved glucose and insulin tolerance, enhanced insulin signaling and inhibited gluconeogenesis. In livers, mitochondrial biogenesis, ultrastructure and function were influenced, accompanied by increased cellular and mitochondrial ROS production. OA inhibited all these changes, in which process Nrf2-GCLc mediated stabilization of mitochondrial glutathione pool may be involved. Moreover, OA decreased serum triglyceride, total cholesterol, LDL, HDL, and free fatty acids, increased serum HDL, and reduced hepatic lipid accumulation. Furthermore, inflammatory condition in db/db mice was improved by OA, as evidenced by decreased level of IL-1 β, IL-6, and TNFα in circulation and in liver. The evidence suggests that OA improves hepatic insulin resistance through inhibition of mitochondrial ROS, hypolipidemic and anti-inflammatory effects. The effectiveness of OA leads to interesting therapeutic perspectives.

Keywords: ALT; AMP-activated protein kinase; AMPK; AST; AUC; Akt; DCF; DHE; Dyslipidemia; FBG; FFAs; G6P; GCL; GCLc; GSH; GSSG; Glucose-6-phosphatase; HDL; HDL-cholesterol; Hepatic insulin resistance; IL-1β; IL-6; IPGTT; IPITT; Inflammation; LDL; LDL-cholesterol; MMP; Nrf2; OA; Oleanolic acid; PEPCK; PGC-1α; ROS; Reactive oxygen species; Rho123; Rhodamine 123; T2DM; TBARS; TC; TEM; TG; TNFα; TZDs; area under the curve; aspartate aminotransferase; dichlorodihydrofluorescein diacetate; dihydroethidium; fasting blood glucose; free fatty acids; glutathione; glutathione (oxidized form); glutathione cysteine ligase catalytic subunit; interleukin-1β; interleukin-6; intraperitoneal glucose tolerance test; intraperitoneal insulin tolerance test; mitochondrial membrane potential; nuclear factor erythroid 2 p45-related factor 2; oleanolic acid; peroxisome proliferator-activated receptor-γ coactivator; phosphoenolpyruvate carboxykinase; protein kinase B; reactive oxygen species; serum alanine aminotransferase; thiazolidinediones; thiobarbituric acid reactive substances; total cholesterol; transmission electron microscopy; triglyceride; tumor necrosis factor α; type 2 diabetes mellitus; γ-Glutamylcysteine ligase.