title: 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.
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Zhang
authors.forename: Nai
authors.initials: N
authors.lastname: Liao
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Wenli
authors.initials: W
authors.lastname: Li
authors.forename: Xujun
authors.initials: X
authors.lastname: Qin
authors.forename: Chunxu
authors.initials: C
authors.lastname: Hai
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005943:Gluconeogenesis; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D063269:Mitochondrial Turnover / Q000187:drug effects; D009828:Oleanolic Acid / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001786:Blood Glucose; D016207:Cytokines; D000960:Hypolipidemic Agents; D007328:Insulin; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid
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