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Atorvastatin increases HDL cholesterol by reducing CETP expression in cholesterol-fed APOE*3-Leiden.CETP mice

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Author: Haan, W. de · Hoogt, C.C. van der · Westerterp, M. · Hoekstra, M. · Dallinga-Thie, G.M. · Princen, H.M.G. · Romijn, J.A. · Jukema, J.W. · Havekes, L.M. · Rensen, P.C.N.
Type:article
Date:2008
Institution: TNO Kwaliteit van Leven
Source:Atherosclerosis, 1, 197, 57-63
Identifier: 240676
doi: doi:10.1016/j.atherosclerosis.2007.08.001
Keywords: Health · CETP · High-density lipoprotein · HMGCoA reductase · Statin · Transgenic mice · ABC transporter A1 · apolipoprotein A1 · apolipoprotein E3 · atorvastatin · cholesterol ester transfer protein · high density lipoprotein · high density lipoprotein cholesterol · messenger RNA · phospholipid transfer protein · scavenger receptor BI · very low density lipoprotein · very low density lipoprotein cholesterol · animal experiment · animal model · article · cholesterol blood level · cholesterol diet · controlled study · drug effect · gene expression · hypercholesterolemia · lipoprotein blood level · lipoprotein metabolism · male · mouse · nonhuman · priority journal · protein expression · transgenic mouse · Animals · Apolipoprotein E3 · Cholesterol Ester Transfer Proteins · Cholesterol, Dietary · Cholesterol, HDL · Cholesterol, VLDL · Dose-Response Relationship, Drug · Female · Gene Expression · Heptanoic Acids · Humans · Hydroxymethylglutaryl-CoA Reductase Inhibitors · Hypercholesterolemia · Liver · Male · Mice · Mice, Inbred C57BL · Mice, Transgenic · Pyrroles · RNA, Messenger

Abstract

Objective: In addition to lowering low-density lipoprotein (LDL)-cholesterol, statins modestly increase high-density lipoprotein (HDL)-cholesterol in humans and decrease cholesteryl ester transfer protein (CETP) mass and activity. Our aim was to determine whether the increase in HDL depends on CETP expression. Methods and results: APOE*3-Leiden (E3L) mice, with a human-like lipoprotein profile and a human-like responsiveness to statin treatment, were crossbred with mice expressing human CETP under control of its natural flanking regions resulting in E3L.CETP mice. E3L and E3L.CETP mice were fed a Western-type diet with or without atorvastatin. Atorvastatin (0.01% in the diet) reduced plasma cholesterol in both E3L and E3L.CETP mice (-26 and -33%, P < 0.05), mainly in VLDL, but increased HDL-cholesterol only in E3L.CETP mice (+52%). Hepatic mRNA expression levels of genes involved in HDL metabolism, such as phospholipid transfer protein (Pltp), ATP-binding cassette transporter A1 (Abca1), scavenger receptor class B type I (Sr-b1), and apolipoprotein AI (Apoa1), were not differently affected by atorvastatin in E3L.CETP mice as compared to E3L mice. However, in E3L.CETP mice, atorvastatin down-regulated the hepatic CETP mRNA expression (-57%; P < 0.01) as well as the total CETP level (-29%) and cholesteryl esters (CE) transfer activity (-36%; P < 0.05) in plasma. Conclusions: Atorvastatin increases HDL-cholesterol in E3L.CETP mice by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool. © 2007 Elsevier Ireland Ltd. All rights reserved.