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

作者：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^*

来源：The Journal of Lipid Research, 2013, 54(8): 2195-2205.

DOI：10.1194/jlr.M038141

• nuclear receptor
• lipoproteins
• bile acids
• hepatocyte
• macrophage

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 %26lt; 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 %26lt; 0.01), while hepatic CETP mRNA expression and plasma CETP activity and mass increased (each P %26lt; 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 %26lt; 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.

• 出版日期2013-8