Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw 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
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- Co-Autor*innen der 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