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PXR agonism decreases plasma HDL levels in ApoE*3-Leiden.CETP mice

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Author: Haan, W. de · Vries-van der Weij, J. de · Mol, I.M. · Hoekstra, M. · Romijn, J.A. · Jukema, J.W. · Havekes, L.M. · Princen, H.M.G. · Rensen, P.C.N.
Institution: TNO Kwaliteit van Leven
Source:Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 3, 1791, 191-197
Identifier: 241422
doi: doi:10.1016/j.bbalip.2008.12.008
Keywords: Biology · Biomedical Research · Cholesteryl ester transfer protein · Gene expression · High density lipoprotein · Pregnane X Receptor · Transgenic mice · Triglycerides · 5 pregnen 3beta ol 20 one 16alpha carbonitrile · ABC transporter A1 · apolipoprotein E3 · cholesterol · cholesterol ester transfer protein · cholesterol oleate · complementary DNA · high density lipoprotein · low density lipoprotein · messenger RNA · pregnane X receptor · pregnenolone derivative · triacylglycerol · tritium · unclassified drug · animal experiment · animal tissue · article · atherosclerosis · cholesterol blood level · controlled study · female · gene expression · lipid liver level · lipoprotein metabolism · mouse · nonhuman · plasma · polyacrylamide gel electrophoresis · priority journal · reverse transcription polymerase chain reaction · transgenic mouse · triacylglycerol blood level · Animals · Apolipoprotein E3 · ATP-Binding Cassette Transporters · Cholesterol Ester Transfer Proteins · Cholesterol, HDL · Female · Immunoblotting · Lipids · Lipoproteins · Liver · Mice · Mice, Transgenic · Pregnenolone Carbonitrile · Receptors, Steroid · RNA, Messenger · Scavenger Receptors, Class B · Mus · Mus musculus


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.