on August 31, 2006
Published online before print August 31, 2006, doi: 10.1161/01.ATV.0000243925.65265.3c
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Submitted on June 1, 2006
Accepted on August 16, 2006
Cholesteryl Ester Transfer Protein Decreases High-Density Lipoprotein and Severely Aggravates Atherosclerosis in APOE*3-Leiden Mice
Marit Westerterp *;
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.
* To whom correspondence should be addressed. 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.
Key words: CETP • cholesterol efflux • hyperlipidemia • reverse cholesterol transport • transgenic mice
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