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Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice

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Author: Westerterp, M. · Hoogt, C.C. van der · Haan, W. de · Offerman, E.H. · Dallinga-Thie, G.M. · Jukema, J.W. · Havekes, L.M. · Rensen, P.C.N.
Type:article
Date:2006
Institution: TNO Kwaliteit van Leven
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 11, 26, 2552-2559
Identifier: 239562
doi: doi:10.1161/01.ATV.0000243925.65265.3c
Keywords: Health · Biomedical Research · CETP · Cholesterol efflux · Hyperlipidemia · Reverse cholesterol transport · Transgenic mice cholesterol · High density lipoprotein · Low density lipoprotein · Very low density lipoprotein · Animal cell · Animal experiment · Animal model · Animal tissue · Aorta root · Atherosclerosis · Cholesterol blood level · Controlled study · Diet · Mouse · Nonhuman · Plasma · Protein expression · Transgenic mouse · Animals · Antigens, CD36 · Apolipoprotein E3 · Apolipoproteins E · Atherosclerosis · Carrier Proteins · Cell Line, Tumor · Cholesterol · Cholesterol Ester Transfer Proteins · Diet · Female · Glycoproteins · Humans · Lipids · Lipoproteins · Lipoproteins, HDL · Macrophages · Mice · Mice, Transgenic · Rats

Abstract

OBJECTIVE - The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden (E3L) mice with a humanized lipoprotein profile. METHODS AND RESULTS - E3L mice were crossbred with human CETP transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (+43%; P<0.05). To evaluate the effects of CETP on the development of atherosclerosis, mice were fed a Western-type diet containing 0.25% cholesterol, leading to 4.3-fold elevated TC levels in both E3L and CETP.E3L mice (P<0.01). On both diets, CETP expression shifted the distribution of cholesterol from high-density lipoprotein (HDL) toward very-low-density lipoprotein (VLDL)/low-density lipoprotein (LDL). Moreover, plasma of CETP.E3L mice had reduced capacity (-39%; P<0.05) to induce SR-BI-mediated cholesterol efflux from Fu5AH cells than plasma of E3L mice. After 19 weeks on the Western-type diet, CETP.E3L mice showed a 7.0-fold increased atherosclerotic lesion area in the aortic root compared with E3L mice (P<0.0001). CONCLUSIONS - CETP expression in E3L mice shifts the distribution of cholesterol from HDL to VLDL/LDL, reduces plasma-mediated SR-BI-dependent cholesterol efflux, and represents a clear pro-atherogenic factor in E3L mice. We anticipate that the CETP.E3L mouse will be a valuable model for the preclinical evaluation of HDL-raising interventions on atherosclerosis development. © 2006 American Heart Association, Inc. Chemicals / CAS: cholesterol, 57-88-5; Antigens, CD36; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; Carrier Proteins; CETP protein, human; Cholesterol Ester Transfer Proteins; Cholesterol, 57-88-5; Glycoproteins; Lipids; Lipoproteins; Lipoproteins, HDL