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J. Biol. Chem., Vol. 283, Issue 29, 20015-20026, July 18, 2008

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F1000 Biology *Must Read* - FREE!

SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-activated Protein Kinase^*

Xiuyun Hou, Shanqin Xu, Karlene A. Maitland-Toolan, Kaori Sato, Bingbing Jiang, Yasuo Ido^¶, Fan Lan^¶, Kenneth Walsh, Michel Wierzbicki^||, Tony J. Verbeuren^||, Richard A. Cohen, and Mengwei Zang¹

From the Vascular Biology Unit and Molecular Cardiology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, and ^¶Section of Endocrinology, Boston University, Boston, Massachusetts 02118 and ^||Institut de Recherche Servier, Suresnes 92150, France

Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834 [GenBank] , increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser⁴²⁸, and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKKβ, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases.

Received for publication, March 19, 2008 , and in revised form, May 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P01 HL 68758, R01 DK76942, and R01 AG27080. This work was supported in part by a Strategic Alliance between the Vascular Biology Unit at Boston University Medical Center and Institut de Recherches Servier. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

¹ To whom correspondence should be addressed: Vascular Biology Unit, X704, Boston University School of Medicine, 650 Albany St., Boston, MA 02118. Tel.: 617-638-2799; Fax: 617-638-7113; E-mail: mwzang1{at}bu.edu.

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