Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element.
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.
Claudel
Thierry
T
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.
Sturm
Ekkehard
E
Duez
Hélène
H
Torra
Inés Pineda
IP
Sirvent
Audrey
A
Kosykh
Vladimir
V
Fruchart
Jean-Charles
JC
Dallongeville
Jean
J
Hum
Dean W
DW
Kuipers
Folkert
F
Staels
Bart
B
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
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