title: Nuclear receptor-mediated repression of human cholesterol 7alpha-hydroxylase gene transcription by bile acids.
abstract: Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7alpha-hydroxylase gene (CYP7A1) in the bile acid biosynthetic pathway in the liver. Farnesoid X receptor (FXR) repressed CYP7A1/Luc reporter activity in a transfection assay in human liver-derived HepG2 cells, but not in human embryonic kidney (HEK) 293 cells. FXR-binding activity was required for bile acid repression of CYP7A1 transcription despite the fact that FXR did not bind to the CYP7A1 promoter. FXR-induced liver-specific factors must be required for mediating bile acid repression. Bile acids and FXR repressed endogenous CYP7A1 but stimulated alpha-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) mRNA expression in HepG2 cells. Feeding of rats with chenodeoxycholic acid repressed CYP7A1, induced FTF, but had no effect on SHP mRNA expression in the liver. FTF 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 stimulated SHP transcription, whereas FTF strongly inhibited SHP transcription in HepG2 cells. Results revealed that FTF was a dominant negative factor that was induced by bile acid-activated FXR to inhibit both CYP7A1 and SHP transcription. Differential regulation of FTF and SHP expression by bile acids may explain the wide variation in CYP7A1 expression and the rate of bile acid synthesis and regulation in different species.
authors.affiliation: Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: E
authors.initials: E
authors.lastname: Owsley
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: D
authors.initials: D
authors.lastname: Stroup
authors.forename: J Y
authors.initials: JY
authors.lastname: Chiang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D016466:CHO Cells; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D007668:Kidney; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D008562:Membrane Glycoproteins; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013656:Taurocholic Acid / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099150:Receptor, Farnesoid X-Activated; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002790:Cholesterol 7-alpha-Hydroxylase; D004247:DNA; D004268:DNA-Binding Proteins; D006913:Hydroxysteroid Dehydrogenases; D008156:Luciferases; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D013656:Taurocholic Acid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C037643:bile acid binding proteins; C099948:fetoprotein transcription factor; C099713:nuclear receptor subfamily 0, group B, member 2; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)