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KMID : 0578320080260040409
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Molecules and Cells
2008 Volume.26 No. 4 p.409 ~ p.414
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FXR alpha Down-Regulates LXR alpha Signaling at the CETP Promoter via a Common Element
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Park Sung-Soo
Choi Ho-Jung
Kim Seung-Jin
Kim Ok-Jin
Chae Kwon-Seok
Kim Eung-Seok
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Abstract
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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.
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KEYWORD
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CETP, DR4RE, FXR, LXR
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