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Selected Publication:
Claudel, T; Sturm, E; Duez, H; Torra, IP; Sirvent, A; Kosykh, V; Fruchart, JC; Dallongeville, J; Hum, DW; Kuipers, F; Staels, B.
Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element.
J Clin Invest. 2002; 109(7):961-971
Doi: 10.1172/JCI14505
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- Leading authors Med Uni Graz
- Claudel Thierry
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apolipoprotein A-I - blood
- Bile Acids and Salts - metabolism
- Binding Sites - metabolism
- Blood Proteins - metabolism
- Cells, Cultured - metabolism
- Cholestasis, Intrahepatic - metabolism
- Chromosome Mapping - metabolism
- DNA-Binding Proteins - metabolism
- Dimerization - metabolism
- Gene Expression Regulation - metabolism
- Hepatocytes - cytology
- Humans - cytology
- Isoxazoles - pharmacology
- Liver - metabolism
- Mice - metabolism
- Mice, Inbred C57BL - metabolism
- Mice, Transgenic - metabolism
- Promoter Regions, Genetic - metabolism
- RNA, Messenger - metabolism
- Receptors, Cytoplasmic and Nuclear - metabolism
- Response Elements - metabolism
- Transcription Factors - metabolism
- Transcription, Genetic - metabolism
- Tumor Cells, Cultured - metabolism
- gamma-Glutamyltransferase - metabolism