期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 2, 页码 1079-1091出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.491522
关键词
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资金
- National Creative Research Initiatives through the National Research Foundation of Korea (NRF) [20110018305]
- Future-based Technology Development Program (BIO Fields) through the National Research Foundation of Korea (NRF) [20100019512]
- Korean government (Ministry of Science, ICT & Future Planning)
- National Research Foundation of Korea [NRF-2012M3A9B6055345, NRF-2010-0019513]
- Ministry of Science, ICT & Future Planning, Republic of Korea
- National Research Foundation of Korea [2010-0019513, 2012M3A9B6055345] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 alpha)-mediated sterol regulatory element binding protein-1c (SREBP-1c) gene expression. We found that SMILE inhibited T0901317 (T7)-induced transcriptional activity of LXR alpha, 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 alpha and represses T7-induced LXR alpha 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 alpha-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 alpha-mediated hepatic lipogenic enzyme gene expression.
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