FXRα down-regulates LXRα 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 α (FXRα; NR1H4) down-regulates CETP expression in HepG2 cells. A FXRα 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 FXRα could bind to the liver X receptor α (LXRα; NR1H3) binding site (LXRE; DR4RE) located within the CETP 5′ promoter region. FXRα suppressed LXRα-induced DR4RE-luciferase activity and this effect was mediated by a binding competition between FXRα and LXRα for DR4RE. Furthermore, the addition of CDCA together with a LXRα 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 FXRα down-regulates CETP gene expression via binding to the DR4RE sequence within the CETP 5′ promoter and this FXRα binding is essential for FXRα inhibition of LXRα-induced CETP expression.