FXRalpha down-regulates LXRalpha signaling at the CETP promoter via a common element.
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 (FXRalpha; NR1H4) down-regulates CETP expression in HepG2 cells. A FXRalpha 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 FXRalpha could bind to the liver X receptor alpha (LXRalpha; NR1H3) binding site (LXRE; DR4RE) located within the CETP 5' promoter region. FXRalpha suppressed LXRalpha-induced DR4RE-luciferase activity and this effect was mediated by a binding competition between FXRalpha and LXRalpha for DR4RE. Furthermore, the addition of CDCA together with a LXRalpha 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 FXRalpha down-regulates CETP gene expression via binding to the DR4RE sequence within the CETP 5' promoter and this FXRalpha binding is essential for FXRalpha inhibition of LXRalpha-induced CETP expression.
Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, Korea.
Sung-Soo
SS
Park
Hojung
H
Choi
Seung-Jin
SJ
Kim
Ok Jin
OJ
Kim
Kwon-Seok
KS
Chae
Eungseok
E
Kim
D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D020218:Response Elements; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D053480:Cholesterol Ester Transfer Proteins; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C506642:CETP protein, human; C000605213:NR1H3 protein, human