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Keywords:

Animals, Cells, Cultured, Cholesterol Ester Transfer Proteins, Female, Gene Expression Profiling, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Receptors, Cytoplasmic and Nuclear, Up-Regulation, Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, nuclear receptor, lipoproteins, bile acids, hepatocyte, macrophage, HIGH-DENSITY-LIPOPROTEIN, STEROL UP-REGULATION, BILE-ACID RECEPTORS, NUCLEAR RECEPTOR, MYOCARDIAL-INFARCTION, CHENODEOXYCHOLIC ACID, RESPONSE ELEMENT, HDL CHOLESTEROL, DEFICIENT MICE, PLASMA-LEVELS, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

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.