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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / genetics
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Blotting, Western
  • Cells, Cultured
  • Diet, High-Fat
  • Fatty Acid Synthase, Type I / genetics
  • Fatty Acid Synthase, Type I / metabolism
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Hydrocarbons, Fluorinated / pharmacology
  • Lipogenesis / drug effects*
  • Liver / cytology
  • Liver / drug effects*
  • Liver / metabolism
  • Liver X Receptors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism*
  • Protein Binding / drug effects
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Sulfonamides / pharmacology
  • Transcriptional Activation / drug effects
  • Ursodeoxycholic Acid / pharmacology*

Substances

  • Basic-Leucine Zipper Transcription Factors
  • CREBZF protein, human
  • Hydrocarbons, Fluorinated
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Sterol Regulatory Element Binding Protein 1
  • Sulfonamides
  • T0901317
  • Ursodeoxycholic Acid
  • FASN protein, human
  • Fatty Acid Synthase, Type I
  • Acetyl-CoA Carboxylase