title: Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice.
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.
authors.affiliation: Department of Pediatrics and University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Lipides, Nutrition, Cancer - Faculté de Médecine, Université de Bourgogne - INSERM UMR866, Dijon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.affiliation: Department of Endocrinology, and Metabolic Diseases and Einthoven Laboratory for Experimental Vascular Medicine and Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Willeke
authors.initials: W
authors.lastname: de Haan
authors.affiliation: Lipides, Nutrition, Cancer - Faculté de Médecine, Université de Bourgogne - INSERM UMR866, Dijon, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Grober
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany; and.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Bahr
authors.affiliation: Department of Pediatrics and University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria.
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.affiliation: Department of Pediatrics and University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Nijstad
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Theo J C
authors.initials: TJC
authors.lastname: Van Berkel
authors.affiliation: Department of Endocrinology, and Metabolic Diseases and Einthoven Laboratory for Experimental Vascular Medicine and Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany; and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Willems
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pancras C W
authors.initials: PCW
authors.lastname: Hogendoorn
authors.affiliation: Lipides, Nutrition, Cancer - Faculté de Médecine, Université de Bourgogne - INSERM UMR866, Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.affiliation: Department of Pediatrics and University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.affiliation: Department of Endocrinology, and Metabolic Diseases and Einthoven Laboratory for Experimental Vascular Medicine and Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Patrick C N
authors.initials: PCN
authors.lastname: Rensen
authors.affiliation: Department of Pediatrics and University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: u_tietge@yahoo.com.
authors.forename: Uwe J F
authors.initials: UJF
authors.lastname: Tietge
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated
keywords: bile acids; hepatocyte; lipoproteins; macrophage; nuclear receptor