Nuclear receptor-mediated repression of human cholesterol 7 alpha-hydroxylase gene transcription by bile acids

Hydrophobic bile acids strongly repressed transcription of the human choles terol 7 alpha -hydroxylase gene (CYP7A1) in the bile acid biosynthetic path way in the Ever. Farnesoid X receptor (FXR) repressed CYP7A1/Luc reporter a ctivity in a transfection assay in human liver-derived HepG2 cells, but not in human embryonic kidney (HEK) 293 cells. FXR-binding activity was requir ed for bile acid repression of CYP7A1 transcription despite the fact that F XR did not bind to the CYP7A1 promoter. FXR-induced liver-specific factors must be required for mediating bile acid repression. Bile acids and FXR rep ressed endogenous CYP7A1 but stimulated a-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) mRNA expression in HepG2 cells. F eeding of rats with chenodeoxycholic acid repressed CYP7A1, induced FIT, bu t had no effect on SHP mRNA expression in the liver. FIT strongly repressed CYP7A1 transcription in a dose-dependent manner, and SHP further inhibited CYP7A1 in HepG2 cells, but not in HEK 293 cells. FXR only moderately stimu lated SHP transcription, whereas FIT strongly inhibited SHP transcription i n HepG2 cells. Results revealed that FTF was a dominant negative factor tha t was induced by bile acid-activated FXR to inhibit both CYP7A1 and SHP tra nscription. Differential regulation of FTF and SHP expression by bile acids may explain the wide variation in CYP7A1 expression and the rate of bile a cid synthesis and regulation in different species.