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SHR Neuro Cancer Cardio Lipid Metab Microb

Gautier, T; de Haan, W; Grober, J; Ye, D; Bahr, MJ; Claudel, T; Nijstad, N; Van Berkel, TJ; Havekes, LM; Manns, MP; Willems, SM; Hogendoorn, PC; Lagrost, L; Kuipers, F; Van Eck, M; Rensen, PC; Tietge, UJ.
Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice.
J Lipid Res. 2013; 54(8):2195-2205 Doi: 10.1194/jlr.M038141 [OPEN ACCESS]
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Co-authors Med Uni Graz: Claudel Thierry
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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.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Cells, Cultured -; Cholesterol Ester Transfer Proteins - genetics; Female -; Gene Expression Profiling -; Humans -; Male -; Mice -; Mice, Inbred C57BL -; Mice, Transgenic -; Middle Aged -; Receptors, Cytoplasmic and Nuclear - agonists; Up-Regulation -
Find related publications in this database (Keywords): nuclear receptor; lipoproteins; bile acids; hepatocyte; macrophage