Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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FXRα Down-Regulates LXRα Signaling at the CETP Promoter via a Common Element

  • Park, Sung-Soo (Department of Biological Sciences, College of Natural Sciences, Chonnam National University) ;
  • Choi, Hojung (Department of Biological Sciences, College of Natural Sciences, Chonnam National University) ;
  • Kim, Seung-Jin (Department of Biological Sciences, College of Natural Sciences, Chonnam National University) ;
  • Kim, Ok Jin (Department of Biological Sciences, College of Natural Sciences, Chonnam National University) ;
  • Chae, Kwon-Seok (Department of Biology Education, Teachers' College, Kyungpook National University) ;
  • Kim, Eungseok (Department of Biological Sciences, College of Natural Sciences, Chonnam National University)
  • Received : 2008.05.22
  • Accepted : 2008.06.12
  • Published : 2008.10.31
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Abstract

The cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism, has been shown to promote the transfer of triglycerides from very low density lipoprotein (VLDL) and low density lipoprotein (LDL) to high density lipoprotein (HDL) in exchange for cholesterol ester. Here we demonstrate that farnesoid X receptor ${\alpha}$ ($FXR{\alpha}$; NR1H4) down-regulates CETP expression in HepG2 cells. A $FXR{\alpha}$ ligand, chenodeoxycholic acid (CDCA), suppressed basal mRNA levels of the CETP gene in HepG2 cells in a dose-dependent manner. Using gel shift and chromatin immunoprecipitation (ChIP) assays, we found that $FXR{\alpha}$ could bind to the liver X receptor ${\alpha}$ ( $LXR{\alpha}$; NR1H3) binding site (LXRE; DR4RE) located within the CETP 5' promoter region. $FXR{\alpha}$ suppressed $LXR{\alpha}$-induced DR4RE-luciferase activity and this effect was mediated by a binding competition between $FXR{\alpha}$ and $LXR{\alpha}$ for DR4RE. Furthermore, the addition of CDCA together with a $LXR{\alpha}$ ligand, GW3965, to HepG2 cells was shown to substantially decrease mRNA levels of hepatic CETP gene, which is typically induced by GW3965. Together, our data demonstrate that $FXR{\alpha}$ down-regulates CETP gene expression via binding to the DR4RE sequence within the CETP 5' promoter and this $FXR{\alpha}$ binding is essential for $FXR{\alpha}$ inhibition of $LXR{\alpha}$-induced CETP expression.

Keywords

Acknowledgement

Supported by : Chonnam National University

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