6533b855fe1ef96bd12b1490
RESEARCH PRODUCT
Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice
Theo J.c. Van BerkelLaurent LagrostJacques GroberFolkert KuipersThierry ClaudelThierry ClaudelMatthias J. BahrMichael P. MannsPatrick C.n. RensenStefan M. WillemsWilleke De HaanDan YeUwe J. F. TietgeNiels NijstadPancras C.w. HogendoornMiranda Van EckLouis M. HavekesThomas GautierThomas Gautiersubject
Male[SDV]Life Sciences [q-bio]Receptors Cytoplasmic and Nuclear030204 cardiovascular system & hematologyInbred C57BLBiochemistryTransgenicchemistry.chemical_compoundMice0302 clinical medicineEndocrinologyHigh-density lipoproteinLifeReceptorsnuclear receptorResearch ArticlesCells Cultured0303 health sciencesCulturedbiologyMiddle AgedUp-RegulationCytoplasmic and Nuclear/agonistslipids (amino acids peptides and proteins)FemaleEELS - Earth Environmental and Life SciencesMHR - Metabolic Health ResearchHealthy Livingmedicine.medical_specialtyTransgeneCellsMice TransgenicQD415-436macrophageReceptors Cytoplasmic and Nuclear/agonists03 medical and health sciencesDownregulation and upregulationInternal medicineCholesterylester transfer proteinmedicinehepatocyteFood and NutritionAnimalsHumans[SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology030304 developmental biologyNutritionbile acidsCholesterolGene Expression ProfilingCell BiologyCholesterol Ester Transfer Proteinscarbohydrates (lipids)Mice Inbred C57BLlipoproteinsEndocrinologyNuclear receptorchemistrybiology.proteinFarnesoid X receptor[SDV.AEN]Life Sciences [q-bio]/Food and NutritionLipoproteinCholesterol Ester Transfer Proteins/geneticsdescription
International audience; 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-08-01 |