title: Resveratrol inhibits LXRα-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction.
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.
authors: College of Pharmacy, Chosun University, Gwangju 501-759, South Korea.
authors: So Hee
authors: SH
authors: Jin
authors: Ji Hye
authors: JH
authors: Yang
authors: Bo Yeon
authors: BY
authors: Shin
authors: Kyuhwa
authors: K
authors: Seo
authors: Sang Mi
authors: SM
authors: Shin
authors: Il Je
authors: IJ
authors: Cho
authors: Sung Hwan
authors: SH
authors: Ki
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics; D059305:Diet, High-Fat; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010544:Peroxidases; D011506:Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage; D000077185:Resveratrol; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000084622:Sestrins; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; D006360:Heat-Shock Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D010544:Peroxidases; D011506:Proteins; D034741:RNA, Small Interfering; D000077185:Resveratrol; D051780:Sterol Regulatory Element Binding Protein 1; D013267:Stilbenes; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C531059:Sesn1 protein, mouse; D000084622:Sestrins; C549101:Sesn3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C529380:Sesn2 protein, mouse
keywords: ACC; AMP-activated protein kinase; AMPK; Acetyl-CoA carboxylase; DN-AMPK; Dominant-negative AMP-activated protein kinase; FAS; FXR; Farnesoid X receptor; Fatty acid synthase; GSH; HFD; Hepatic lipogenesis; High-fat diet; LXRE; LXRα; Liver X receptor elements; Liver X receptor- α; Liver X receptor-α; NAFLD; NASH; NF-E2-related factor 2; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Nrf2; PXR; ROS; RXR; Reactive oxygen species; Resveratrol; Retinoid X receptor; SCD-1; SREBP-1c; Sesn; Sestrin; Sirt1; Sirtuin 1; Stearoyl-CoA desaturase-1; Sterol regulatory element binding protein-1c; T090; T0901317; glutathione; pregnane X receptor