Title
Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice
Author
Westerterp, M.
van der Hoogt, C.C.
de Haan, W.
Offerman, E.H.
Dallinga-Thie, G.M.
Jukema, J.W.
Havekes, L.M.
Rensen, P.C.N.
TNO Kwaliteit van Leven
Publication year
2006
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
Subject
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
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DOI
https://doi.org/10.1161/01.atv.0000243925.65265.3c
TNO identifier
239562
ISSN
1079-5642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 26 (11), 2552-2559
Document type
article