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Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element
Thierry Claudel, … , Folkert Kuipers, Bart Staels
Thierry Claudel, … , Folkert Kuipers, Bart Staels
Published April 1, 2002
Citation Information: J Clin Invest. 2002;109(7):961-971. https://doi.org/10.1172/JCI14505.
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Article Endocrinology

Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

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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.

Authors

Thierry Claudel, Ekkehard Sturm, Hélène Duez, Inés Pineda Torra, Audrey Sirvent, Vladimir Kosykh, Jean-Charles Fruchart, Jean Dallongeville, Dean W. Hum, Folkert Kuipers, Bart Staels

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Figure 1

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Low serum apoA-I in patients with progressive familial intrahepatic chol...
Low serum apoA-I in patients with progressive familial intrahepatic cholestasis. Serum apoA-I was determined in patients with low GGT-type PFIC (n = 15) in patients with BA (n = 15) or in normal control individuals (CON; n = 110). Serum apoA-I concentrations were normalized to CHE activities; data are expressed as means ± SEM. Serum total bile acid concentrations were also determined in the different groups as a marker of cholestasis. Bile acid concentration is expressed in micromoles per liter. Statistical analysis was performed by ANOVA (P < 0.001) followed by Dunnett’s T3 test. *P < 0.001 versus control.

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