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

Thomas Gautier 1 Willeke de Haan 2 Jacques Grober 3 Dan Ye 4 Matthias Bahr 5 Thierry Claudel 6, 3 Niels Nijstad 7 Theo van Berkel 4 Louis Havekes 2 Michael Manns 5 Stefan Willems Pancras Hogendoorn 8 Laurent Lagrost 3 Folkert Kuipers 6 Miranda van Eck 4 Patrick Rensen 2 Uwe Tietge 6
1 UMCG - University Medical Center Groningen [Groningen]
2 ELEVM - LEIDEN - Einthoven Laboratory for Experimental Vascular Medicine
3 LNC - Lipides - Nutrition - Cancer (U866)
4 Division of Biopharmaceutics
5 Dept. of Gastroenterology, Hepatology, and Endocrinology
6 Dept. of Pediatrics
7 University Medical Centre Groningen, University of Groningen, Groningen
8 Department of Pathology
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.
Keywords : Bile acids Hepatocyte Lipoproteins Macrophage Nuclear receptor
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Journal articles
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Submitted on : Thursday, December 13, 2018 - 9:36:13 AM
Last modification on : Friday, December 14, 2018 - 1:15:37 AM

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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, American Society for Biochemistry and Molecular Biology, 2013, 54 (8), pp.2195-2205. ⟨10.1194/jlr.M038141⟩. ⟨hal-01953523⟩

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