Title
Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice
Author
Gautier, T.
de Haan, W.
Grober, J.
Ye, D.
Bahr, M.J.
Claudel, T.
Nijstad, N.
van Berkel, T.J.
Havekes, L.M.
Manns, M.P.
Willems, S.M.
Hogendoorn, P.C.
Lagrost, L.
Kuipers, F.
van Eck, M.
Rensen, P.C.
Tietge, U.J.
Publication year
2013
Abstract
Cholesteryl ester transfer protein (CETP) activity results in a proatherogenic lipoprotein profi le. 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 apoBcontaining 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 confi rmed 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 fi rst intron. In conclusion, using a translational approach, this study identifi es CETP as novel FXR target gene. By increasing CETP expression, FXR activation leads to a proatherogenic lipoprotein profi le. These results have clinical relevance, especially when considering FXR agonists as emerging treatment strategy for metabolic disease and atherosclerosis.
Subject
Nutrition
Food and Nutrition
Healthy Living
Life
MHR - Metabolic Health Research
EELS - Earth, Environmental and Life Sciences
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http://resolver.tudelft.nl/uuid:a97a7416-95ca-4d00-8e36-b08d344acc55
DOI
https://doi.org/10.1194/jlr.m038141
TNO identifier
525799
Source
Journal of Lipid Research, 54 (54), 2195-2205
Document type
article