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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2552.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Cholesteryl Ester Transfer Protein Decreases High-Density Lipoprotein and Severely Aggravates Atherosclerosis in APOE*3-Leiden Mice

Marit Westerterp; Caroline C. van der Hoogt; Willeke de Haan; Erik H. Offerman; Geesje M. Dallinga-Thie; J. Wouter Jukema; Louis M. Havekes; Patrick C.N. Rensen

From The Netherlands Organization for Applied Scientific Research-Quality of Life (M.W., C.C.v.d.H., W.d.H., J.W.J., L.M.H., P.C.N.R.), Department of Biomedical Research, Gaubius Laboratory, CE Leiden, The Netherlands; Departments of General Internal Medicine, Endocrinology, and Metabolic Diseases (M.W., C.C.v.d.H., W.d.H., E.H.O., L.M.H., P.C.N.R.), and Cardiology (J.W.J.), Leiden University Medical Center, RC Leiden, The Netherlands; Laboratory of Vascular Medicine (G.M.D.-T.), Erasmus Medical Center, DR Rotterdam, The Netherlands.

Correspondence to Marit Westerterp, Leiden University Medical Center, Department Endocrinology and Metabolism, C4-R, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail M.Westerterp{at}lumc.nl

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.

The effect of CETP on lipoprotein metabolism and atherosclerosis development was investigated in APOE*3-Leiden mice with a humanized lipoprotein profile. CETP expression shifted the distribution of cholesterol from HDL to VLDL/LDL, and severely aggravated atherosclerosis. The CETP·E3L mouse may be a valuable model for the preclinical evaluation of HDL-raising interventions on atherosclerosis development.

Key Words: CETP • cholesterol efflux • hyperlipidemia • reverse cholesterol transport • transgenic mice

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