Title: Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice
Authors: Gautier, Thomas ×
de Haan, Willeke
Grober, Jacques
Ye, Dan
Bahr, Matthias J
Claudel, Thierry
Nijstad, Niels
Van Berkel, Theo J C
Havekes, Louis M
Manns, Michael P
Willems, Stefan M
Hogendoorn, Pancras C W
Lagrost, Laurent
Kuipers, Folkert
Van Eck, Miranda
Rensen, Patrick C N
Tietge, Uwe J F #
Issue Date: Aug-2013
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Lipid Research vol:54 issue:8 pages:2195-205
Article number: 10.1194/jlr.M038141
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.
ISSN: 0022-2275
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

Files in This Item:

There are no files associated with this item.

Request a copy


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science