title: Ursodeoxycholic acid inhibits liver X receptor α-mediated hepatic lipogenesis via induction of the nuclear corepressor SMILE.
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.
authors.affiliation: From the National Creative Research Initiatives Center for Nuclear Receptor Signals and.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D059305:Diet, High-Fat; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000103:Acetyl-CoA Carboxylase; D050976:Basic-Leucine Zipper Transcription Factors; D054890:Fatty Acid Synthase, Type I; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014580:Ursodeoxycholic Acid; C411104:CREBZF protein, human; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C518729:FASN protein, human
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