Sestrin2 유도를 통한 Resveratrol의 LXRα 매개성 지질 생합성 억제 효능

Abstract

Liver X receptor-α (LXRα), a member of the nuclear receptor superfamily of ligand-activated transcription factor, regulates de novo fatty acid synthesis that leads to stimulate hepatic steatosis. Although, resveratrol, a polyphenol in grapes, has beneficial effects on metabolic disease, but 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 identification of the molecular mechanism. Resveratrol treatment attenuated LXRα agonist (T0901317)-mediated hepatic fat accumulation in primary hepatocytes. Resveratrol inhibited the ability of LXRα to activate sterol regulatory element binding protein-1c (SREBP-1c) and thereby target genes expression (e.g., FAS, ACC, SCD-1) in hepatocytes. Moreover, resveratrol decreased LXRα-RXRα DNA binding activity and LXRE-luciferase (CYP7A1) transactivation. Resveratrol was known to activate Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) although precise mechanism of action remains controversial yet. We found that the ability of resveratrol to repress T0901317-induced SREBP-1c expression was not dependent on SIRT1 and AMPK activation. Treatment of chemical inhibitor or overexpression of dominant negative mutant plasmid fails to reverse resveratrol-mediated effects on LXRα-mediated SREBP-1c suppression. It is well established that hepatic steatosis is associated with antioxidant and redox signaling. Surprisingly, novel antioxidant protein sestrin2 expression is significantly down-regulated in the livers of high fat diet-fed mice compare to normal chow-fed diet. Morevover, resveratrol up-regulated sestrin2 expression, but not sestrin1 and sestrin3 expression. Sestrin2 overexpression repressed LXRα-activated SREBP-1c expression and LXRE-luciferase activity, suggesting that involvement of sestrin2 in the LXRα-mediated lipogenic gene expression. Our results showing that resveratrol has an effect of sestrin2 gene induction and contributing to the inhibition of LXRα -mediated hepatic lipogenesis.