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

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., Nov-2006, In : Arteriosclerosis, thrombosis, and vascular biology. 26, 11, p. 2552-2559 8 p.

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

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DOI

  • 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

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.

Original languageEnglish
Pages (from-to)2552-2559
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume26
Issue number11
Publication statusPublished - Nov-2006

    Keywords

  • Animals, Apolipoprotein E3, Apolipoproteins E/genetics, Atherosclerosis/blood, CD36 Antigens/metabolism, Carrier Proteins/metabolism, Cell Line, Tumor, Cholesterol/blood, Cholesterol Ester Transfer Proteins, Diet, Female, Glycoproteins/metabolism, Humans, Lipids/blood, Lipoproteins/blood, Lipoproteins, HDL/antagonists & inhibitors, Macrophages/metabolism, Mice, Mice, Transgenic, Rats

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