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


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.
Westerterp
Marit
M
Department of Biomedical Research, Gaubius Laboratory, CE Leiden, The Netherlands. M.Westerterp@lumc.nl
van der Hoogt
Caroline C
CC
de Haan
Willeke
W
Offerman
Erik H
EH
Dallinga-Thie
Geesje M
GM
Jukema
J Wouter
JW
Havekes
Louis M
LM
Rensen
Patrick C N
PC
D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D053480:Cholesterol Ester Transfer Proteins; D004032:Diet; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000037:antagonists & inhibitors* / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D018955:CD36 Antigens; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; C052720:apolipoprotein E3 (Leidein); D002784:Cholesterol