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.