HDL biology
Bile-acid-activated farnesoid X receptor identified as a novel driver of CETP expression, explaining low HDL-C in cholestasis (J Lipid Res 2013)
Original title: Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice
Testing the hypothesis that farnesoid X receptor (FXR) signaling by bile acids explains the low HDL-C seen in cholestasis, researchers found cholestatic patients with high plasma bile acids had lower HDL-C and higher plasma CETP activity and mass than matched low-bile-acid controls (each P less than 0.01). Feeding bile acids to APOE3*Leiden mice carrying the human CETP transgene under its own promoter increased apoB-lipoprotein cholesterol and decreased HDL-C, while raising hepatic CETP mRNA and plasma CETP activity and mass (each P less than 0.01). In vitro, FXR agonists substantially increased CETP mRNA in hepatocytes and macrophages in an FXR-dependent manner (each P less than 0.001), an effect likely mediated by an FXR response element in CETP's first intron, identifying CETP as a novel FXR target gene with implications for FXR agonists under development as metabolic disease therapies.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.