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J Biol Chem. 2014 Jan 10;289(2):1079-91. doi: 10.1074/jbc.M113.491522. Epub 2013 Nov 21.

Ursodeoxycholic acid inhibits liver X receptor α-mediated hepatic lipogenesis via induction of the nuclear corepressor SMILE.

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  • 1From the National Creative Research Initiatives Center for Nuclear Receptor Signals and.

Abstract

Small heterodimer partner interacting leucine zipper protein (SMILE) has been identified as a nuclear corepressor of the nuclear receptor (NRs) family. Here, we examined the role of SMILE in the regulation of nuclear receptor liver X receptor (LXR)-mediated sterol regulatory element binding protein-1c (SREBP-1c) gene expression. We found that SMILE inhibited T0901317 (T7)-induced transcriptional activity of LXR, which functions as a major regulator of lipid metabolism by inducing SREBP-1c, fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) gene expression. Moreover, we demonstrated that SMILE physically interacts with LXR and represses T7-induced LXR transcriptional activity by competing with coactivator SRC-1. Adenoviral overexpression of SMILE (Ad-SMILE) attenuated fat accumulation and lipogenic gene induction in the liver of T7 administered or of high fat diet (HFD)-fed mice. Furthermore, we investigated the mechanism by which ursodeoxycholic acid (UDCA) inhibits LXR-induced lipogenic gene expression. Interestingly, UDCA treatment significantly increased SMILE promoter activity and gene expression in an adenosine monophosphate-activated kinase-dependent manner. Furthermore, UDCA treatment repressed T7-induced SREBP-1c, FAS, and ACC protein levels, whereas knockdown of endogenous SMILE gene expression by adenovirus SMILE shRNA (Ad-shSMILE) significantly reversed UDCA-mediated repression of SREBP-1c, FAS, and ACC protein levels. Collectively, these results demonstrate that UDCA activates SMILE gene expression through adenosine monophosphate-activated kinase phosphorylation, which leads to repression of LXR-mediated hepatic lipogenic enzyme gene expression.

KEYWORDS:

AMP-activated Kinase (AMPK); Bile Acid; Corepressor; Lipogenesis; Liver X Receptor (LXR); Nuclear Receptors; Small Heterodimer Partner Interacting Leucine Zipper Protein (SMILE); Sterol Regulatory Element-binding Protein-1 (SREBP-1c); Transcription Repressor

PMID:
24265317
[PubMed - indexed for MEDLINE]
PMCID:
PMC3887176
[Available on 2015/1/10]
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