title: Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element.
abstract: Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associated with diminished apoA-I serum levels. In human apoA-I transgenic mice, treatment with the FXR agonist taurocholic acid strongly decreased serum concentrations and liver mRNA levels of human apoA-I, which was associated with reduced serum HDL levels. Incubation of human primary hepatocytes and hepatoblastoma HepG2 cells with bile acids resulted in a dose-dependent downregulation of apoA-I expression. Promoter mutation analysis and gel-shift experiments in HepG2 cells demonstrated that bile acid-activated FXR decreases human apoA-I promoter activity by a negative FXR response element mapped to the C site. FXR bound this site and repressed transcription in a manner independent of retinoid X receptor. The nonsteroidal synthetic FXR agonist GW4064 likewise decreased apoA-I mRNA levels and promoter activity in HepG2 cells.
authors.affiliation: Unité de Recherche 545, Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, and the Faculté de Pharmacie, Université de Lille II, Lille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Sturm
authors.forename: Hélène
authors.initials: H
authors.lastname: Duez
authors.forename: Inés Pineda
authors.initials: IP
authors.lastname: Torra
authors.forename: Audrey
authors.initials: A
authors.lastname: Sirvent
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kosykh
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
authors.forename: Jean
authors.initials: J
authors.lastname: Dallongeville
authors.forename: Dean W
authors.initials: DW
authors.lastname: Hum
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002780:Cholestasis, Intrahepatic / Q000378:metabolism; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D005723:gamma-Glutamyltransferase / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016632:Apolipoprotein A-I; D001647:Bile Acids and Salts; D001798:Blood Proteins; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D005723:gamma-Glutamyltransferase; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064