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Article Dans Une Revue Journal of Lipid Research Année : 2013

Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice

Résumé

Cholesteryl ester transfer protein (CETP) activity results in a proatherogenic lipoprotein profile. In cholestatic conditions, farnesoid X receptor (FXR) signaling by bile acids (BA) is activated and plasma HDL cholesterol (HDL-C) levels are low. This study tested the hypothesis that FXR-mediated induction of CETP contributes to this phenotype. Patients with cholestasis and high plasma BA had lower HDL-C levels and higher plasma CETP activity and mass compared with matched controls with low plasma BA (each P < 0.01). BA feeding in APOE3*Leiden transgenic mice expressing the human CETP transgene controlled by its endogenous promoter increased cholesterol within apoB-containing lipoproteins and decreased HDL-C (each P < 0.01), while hepatic CETP mRNA expression and plasma CETP activity and mass increased (each P < 0.01). In vitro studies confirmed that FXR agonists substantially augmented CETP mRNA expression in hepatocytes and macrophages dependent on functional FXR expression (each P < 0.001). These transcriptional effects are likely mediated by an ER8 FXR response element (FXRE) in the first intron. In conclusion, using a translational approach, this study identifies CETP as novel FXR target gene. By increasing CETP expression, FXR activation leads to a proatherogenic lipoprotein profile. These results have clinical relevance, especially when considering FXR agonists as emerging treatment strategy for metabolic disease and atherosclerosis.

Dates et versions

hal-01953523 , version 1 (13-12-2018)

Identifiants

Citer

Thomas Gautier, Willeke de Haan, Jacques Grober, Dan Ye, Matthias Bahr, et al.. Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice. Journal of Lipid Research, 2013, 54 (8), pp.2195-2205. ⟨10.1194/jlr.M038141⟩. ⟨hal-01953523⟩
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