RRC ID 27713
Author Jin SH, Yang JH, Shin BY, Seo K, Shin SM, Cho IJ, Ki SH.
Title Resveratrol inhibits LXRα-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction.
Journal Toxicol Appl Pharmacol
Abstract Liver X receptor-α (LXRα), 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 LXRα-dependent lipogenic gene expression. This study investigated the effect of resveratrol in LXRα-mediated lipogenesis and the underlying molecular mechanism. Resveratrol inhibited the ability of LXRα to activate sterol regulatory element binding protein-1c (SREBP-1c) and thereby inhibited target gene expression in hepatocytes. Moreover, resveratrol decreased LXRα-RXRα 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 LXRα-activated SREBP-1c expression and LXRE-luciferase activity. Finally, Sesn2 knockdown using siRNA abolished the effect of resveratrol in LXRα-induced FAS luciferase gene transactivation. We conclude that resveratrol affects Sesn2 gene induction and contributes to the inhibition of LXRα-mediated hepatic lipogenesis.
Volume 271(1)
Pages 95-105
Published 2013-8-15
DOI 10.1016/j.taap.2013.04.023
PII S0041-008X(13)00178-6
PMID 23651738
MeSH Animals Antioxidants / pharmacology* Cell Cycle Proteins / genetics Diet, High-Fat Gene Knockdown Techniques Heat-Shock Proteins / genetics Hep G2 Cells Humans Hydrocarbons, Fluorinated / pharmacology Lipogenesis / drug effects Liver X Receptors Male Mice Mice, Inbred C57BL Mice, Inbred ICR Nuclear Proteins Orphan Nuclear Receptors / antagonists & inhibitors* Orphan Nuclear Receptors / metabolism Peroxidases Proteins / genetics* RNA, Small Interfering / administration & dosage Resveratrol Sterol Regulatory Element Binding Protein 1 / genetics Stilbenes / pharmacology* Sulfonamides / pharmacology Up-Regulation / drug effects
IF 3.347
Times Cited 47
DNA material pGL4-phSESN2 (RDB07413)