Resveratrol inhibits LXRalpha-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction.

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Jin SH, Yang JH, Shin BY, Seo K, Shin SM, Cho IJ, Ki SH

Resveratrol inhibits LXRalpha-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction.

Toxicol Appl Pharmacol. 2013 Aug 15;271(1):95-105. doi: 10.1016/j.taap.2013.04.023. Epub 2013 May 5.

PubMed ID
23651738 [ View in PubMed
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Abstract

Liver X receptor-alpha (LXRalpha), a member of the nuclear receptor superfamily of ligand-activated transcription factors, regulates de novo fatty acid synthesis that leads to stimulate hepatic steatosis. Although, resveratrol has beneficial effects on metabolic disease, it is not known whether resveratrol affects LXRalpha-dependent lipogenic gene expression. This study investigated the effect of resveratrol in LXRalpha-mediated lipogenesis and the underlying molecular mechanism. Resveratrol inhibited the ability of LXRalpha to activate sterol regulatory element binding protein-1c (SREBP-1c) and thereby inhibited target gene expression in hepatocytes. Moreover, resveratrol decreased LXRalpha-RXRalpha DNA binding activity and LXRE-luciferase transactivation. Resveratrol is known to activate Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK), although its precise mechanism of action remains controversial. We found that the ability of resveratrol to repress T0901317-induced SREBP-1c expression was not dependent on AMPK and Sirt1. It is well established that hepatic steatosis is associated with antioxidant and redox signaling. Our data showing that expression of Sestrin2 (Sesn2), which is a novel antioxidant gene, was significantly down-regulated in the livers of high-fat diet-fed mice. Moreover, resveratrol up-regulated Sesn2 expression, but not Sesn1 and Sesn3. Sesn2 overexpression repressed LXRalpha-activated SREBP-1c expression and LXRE-luciferase activity. Finally, Sesn2 knockdown using siRNA abolished the effect of resveratrol in LXRalpha-induced FAS luciferase gene transactivation. We conclude that resveratrol affects Sesn2 gene induction and contributes to the inhibition of LXRalpha-mediated hepatic lipogenesis.