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Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway

 Young Mi Song  ;  Yong-ho Lee  ;  Ji-Won Kim  ;  Dong-Sik Ham  ;  Eun-Seok Kang  ;  Bong Soo Cha  ;  Hyun Chul Lee  ;  Byung-Wan Lee 
 AUTOPHAGY, Vol.11(1) : 46-59, 2015 
Journal Title
Issue Date
AMP-Activated Protein Kinases/metabolism* ; Animals ; Autophagy/drug effects* ; Blood Glucose/metabolism ; Body Weight/drug effects ; Caloric Restriction ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Down-Regulation/drug effects ; Fatty Liver/blood ; Fatty Liver/metabolism* ; Fatty Liver/pathology* ; Fatty Liver/physiopathology ; Hep G2 Cells ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Lipid Metabolism/drug effects ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Metformin/pharmacology* ; Mice, Inbred C57BL ; Mice, Obese ; Models, Biological ; Oleic Acid/pharmacology ; Phagosomes/drug effects ; Phagosomes/metabolism ; Phagosomes/ultrastructure ; Signal Transduction/drug effects* ; Sirtuin 1/metabolism* ; Up-Regulation/drug effects
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
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.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Song, Young Mi(송영미)
Lee, Byung Wan(이병완) ORCID logo https://orcid.org/0000-0002-9899-4992
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Hyun Chul(이현철)
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
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