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

Research output: Contribution to journalArticle

96 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)46-59
Number of pages14
JournalAutophagy
Volume11
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

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AMP-Activated Protein Kinases
Metformin
Autophagy
Caloric Restriction
Oleic Acid
Glucose
Liver
Hep G2 Cells
Intraperitoneal Injections
Small Interfering RNA
Hepatocytes
Homeostasis
Body Weight
Diet
Lipids

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Song, Young Mi ; Lee, Yong Ho ; Kim, Ji Won ; Ham, Dong Sik ; Kang, Eun Seok ; Cha, Bong Soo ; Lee, Hyun Chul ; Lee, Byung Wan. / Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. In: Autophagy. 2015 ; Vol. 11, No. 1. pp. 46-59.
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Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. / Song, Young Mi; Lee, Yong Ho; Kim, Ji Won; Ham, Dong Sik; Kang, Eun Seok; Cha, Bong Soo; Lee, Hyun Chul; Lee, Byung Wan.

In: Autophagy, Vol. 11, No. 1, 01.01.2015, p. 46-59.

Research output: Contribution to journalArticle

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