Human CETP aggravates atherosclerosis by increasing VLDL-cholesterol rather than by decreasing HDL-cholesterol in APOE*3-Leiden mice.
OBJECTIVE
Cholesteryl ester transfer protein (CETP) adversely affects the plasma lipoprotein profile by increasing VLDL-cholesterol and decreasing HDL-cholesterol. The relative contribution of either of these changes to atherosclerosis development is not known. We investigated to what extent the increase in VLDL-cholesterol can explain the atherogenic action of human CETP expression in APOE*3-Leiden (E3L) mice, a model for human-like lipoprotein metabolism.


RESULTS
E3L mice and E3L.CETP mice were fed a low cholesterol (LC) diet, resulting in a 4-fold increased VLDL-cholesterol level as well as a 9-fold increased atherosclerotic lesion area in the aortic root in E3L.CETP mice compared to E3L-LC mice. E3L mice fed a high cholesterol (HC) diet to match the increased VLDL-cholesterol levels in E3L.CETP mice, displayed a similar atherosclerotic lesion area as observed in E3L.CETP mice. Hence, the CETP-induced raise in atherosclerosis can largely be explained by increased VLDL-cholesterol. Despite similar atherosclerosis development, E3L.CETP mice had lower HDL-cholesterol as compared to E3L-HC mice (-49%) indicating that the HDL-cholesterol lowering effect of CETP is unlikely to contribute to atherosclerosis development in this experimental setting. Remarkably, atherosclerotic lesions in CETP-expressing mice were enriched in collagen, suggesting a role of CETP or the diet in modifying lesion collagen content.


CONCLUSIONS
In this experimental setting, the proatherogenic effect of CETP is largely explained by increased VLDL-cholesterol.
The Netherlands Organization for Applied Scientific Research-BioSciences, Gaubius Laboratory, Leiden, The Netherlands. a.j.de vries@lumc.nl
Jitske
J
de Vries-van der Weij
Susanne
S
Zadelaar
Karin
K
Toet
Louis M
LM
Havekes
Teake
T
Kooistra
Patrick C N
PC
Rensen
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000473:pathology*; D053480:Cholesterol Ester Transfer Proteins / Q000494:pharmacology*; D008076:Cholesterol, HDL / Q000097:blood*; D015243:Cholesterol, VLDL / Q000097:blood*; D019040:E-Selectin / Q000097:blood; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood; D051379:Mice; D000685:Serum Amyloid A Protein / Q000378:metabolism
D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D019040:E-Selectin; D000685:Serum Amyloid A Protein; D005340:Fibrinogen