Print Email Facebook Twitter PXR agonism decreases plasma HDL levels in ApoE*3-Leiden.CETP mice Title PXR agonism decreases plasma HDL levels in ApoE*3-Leiden.CETP mice Author de Haan, W. de Vries-van der Weij, J. Mol, I.M. Hoekstra, M. Romijn, J.A. Jukema, J.W. Havekes, L.M. Princen, H.M.G. Rensen, P.C.N. TNO Kwaliteit van Leven Publication year 2009 Abstract Pregnane X receptor (PXR) agonism has been shown to affect multiple steps in both the synthesis and catabolism of HDL, but its integrated effect on HDL metabolism in vivo remains unclear. The aim of this study was to evaluate the net effect of PXR agonism on HDL metabolism in ApoE*3-Leiden (E3L) and E3L.CETP mice, well-established models for human-like lipoprotein metabolism. Female mice were fed a diet with increasing amounts of the potent PXR agonist 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN). In E3L and E3L.CETP mice, PCN increased liver lipids as well as plasma cholesterol and triglycerides. However, whereas PCN increased cholesterol contained in large HDL-1 particles in E3L mice, it dose-dependently decreased HDL-cholesterol in E3L.CETP mice, indicating that CETP expression dominates the effect of PCN on HDL metabolism. Analysis of the hepatic expression of genes involved in HDL metabolism showed that PCN decreased expression of genes involved in HDL synthesis (Abca1, Apoa1), maturation (Lcat, Pltp) and clearance (Sr-b1). The HDL-increasing effect of PCN, observed in E3L mice, is likely caused by a marked decrease in hepatic SR-BI protein expression, and completely reversed by CETP expression. We conclude that chronic PXR agonism dose-dependently reduces plasma HDL-cholesterol in the presence of CETP. © 2008 Elsevier B.V. All rights reserved. Subject BiologyBiomedical ResearchCholesteryl ester transfer proteinGene expressionHigh density lipoproteinPregnane X ReceptorTransgenic miceTriglycerides5 pregnen 3beta ol 20 one 16alpha carbonitrileABC transporter A1apolipoprotein E3cholesterolcholesterol ester transfer proteincholesterol oleatecomplementary DNAhigh density lipoproteinlow density lipoproteinmessenger RNApregnane X receptorpregnenolone derivativetriacylglyceroltritiumunclassified druganimal experimentanimal tissuearticleatherosclerosischolesterol blood levelcontrolled studyfemalegene expressionlipid liver levellipoprotein metabolismmousenonhumanplasmapolyacrylamide gel electrophoresispriority journalreverse transcription polymerase chain reactiontransgenic mousetriacylglycerol blood levelAnimalsApolipoprotein E3ATP-Binding Cassette TransportersCholesterol Ester Transfer ProteinsCholesterol, HDLFemaleImmunoblottingLipidsLipoproteinsLiverMiceMice, TransgenicPregnenolone CarbonitrileReceptors, SteroidRNA, MessengerScavenger Receptors, Class BMusMus musculus To reference this document use: http://resolver.tudelft.nl/uuid:478349d0-ea18-4685-9067-e7ffc173eb93 DOI https://doi.org/10.1016/j.bbalip.2008.12.008 TNO identifier 241422 ISSN 1388-1981 Source Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1791 (3), 191-197 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.