title: Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway.
abstract: Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the mechanism by which metformin alleviates hepatosteatosis by examining the molecular interplay between SIRT1, PRKA, and autophagy. ob/ob mice were divided into 3 groups: one with ad libitum feeding of a standard chow diet, one with 300 mg/kg intraperitoneal metformin injections, and one with 3 g/d caloric restriction (CR) for a period of 4 wk. Primary hepatocytes or HepG2 cells were treated with oleic acid (OA) plus high glucose in the absence or presence of metformin. Both CR and metformin significantly improved body weight and glucose homeostasis, along with hepatic steatosis, in ob/ob mice. Furthermore, CR and metformin both upregulated SIRT1 expression and also stimulated autophagy induction and flux in vivo. Metformin also prevented OA with high glucose-induced suppression of both SIRT1 expression and SIRT1-dependent activation of autophagy machinery, thereby alleviating intracellular lipid accumulation in vitro. Interestingly, metformin treatment upregulated SIRT1 expression and activated PRKA even after siRNA-mediated knockdown of PRKAA1/2 and SIRT1, respectively. Taken together, these results suggest that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery.
authors.affiliation: a Brain Korea 21 PLUS Project for Medical Science ; Yonsei University College of Medicine ; Seoul , Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Song
authors.forename: Yong-ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Dong-Sik
authors.initials: DS
authors.lastname: Ham
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Kang
authors.forename: Bong Soo
authors.initials: BS
authors.lastname: Cha
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Lee
authors.forename: Byung-Wan
authors.initials: BW
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D031204:Caloric Restriction; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005234:Fatty Liver / Q000097:blood / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D019301:Oleic Acid / Q000494:pharmacology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D019301:Oleic Acid; D008687:Metformin; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1
keywords: 3MA, 3-methyladenine; CQ, chloroquine; CR, caloric restriction; GOT1/AST, glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT, glutamic-pyruvate transaminase (alanine aminotransferase); IPGTTs, intraperitoneal glucose tolerance tests; MTOR, mechanistic target of rapamycin; Met, metformin; NAFLD, nonalcoholic fatty liver disease; OA, oleic acid; ORO, Oil Red O; PRKA; PRKA, protein kinase, AMP-activated; SIRT1; SIRT1, sirtuin 1; T-CHO, total cholesterol; TG, triglyceride; autophagy; hepatoseatosis; metformin; siRNA, short interfering RNA