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Journal articles
Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice
Abstract : 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.
https://hal-agrosup-dijon.archives-ouvertes.fr/hal-01953523
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Submitted on : Thursday, December 13, 2018 - 9:36:13 AM
Last modification on : Monday, October 18, 2021 - 9:12:01 AM
Contributor : Admin Agrosupdijon Connect in order to contact the contributor
Submitted on : Thursday, December 13, 2018 - 9:36:13 AM
Last modification on : Monday, October 18, 2021 - 9:12:01 AM
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