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Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice.
Arterioscler Thromb Vasc Biol. 2006 Nov; 26(11):2552-9.AT

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.

Authors+Show Affiliations

Department of Biomedical Research, Gaubius Laboratory, CE Leiden, The Netherlands. M.Westerterp@lumc.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16946130

Citation

Westerterp, Marit, et al. "Cholesteryl Ester Transfer Protein Decreases High-density Lipoprotein and Severely Aggravates Atherosclerosis in APOE*3-Leiden Mice." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 11, 2006, pp. 2552-9.
Westerterp M, van der Hoogt CC, de Haan W, et al. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice. Arterioscler Thromb Vasc Biol. 2006;26(11):2552-9.
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. (2006). Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(11), 2552-9.
Westerterp M, et al. Cholesteryl Ester Transfer Protein Decreases High-density Lipoprotein and Severely Aggravates Atherosclerosis in APOE*3-Leiden Mice. Arterioscler Thromb Vasc Biol. 2006;26(11):2552-9. PubMed PMID: 16946130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice. AU - Westerterp,Marit, AU - van der Hoogt,Caroline C, AU - de Haan,Willeke, AU - Offerman,Erik H, AU - Dallinga-Thie,Geesje M, AU - Jukema,J Wouter, AU - Havekes,Louis M, AU - Rensen,Patrick C N, Y1 - 2006/08/31/ PY - 2006/9/2/pubmed PY - 2006/11/14/medline PY - 2006/9/2/entrez SP - 2552 EP - 9 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 26 IS - 11 N2 - 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/16946130/Cholesteryl_ester_transfer_protein_decreases_high_density_lipoprotein_and_severely_aggravates_atherosclerosis_in_APOE_3_Leiden_mice_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.ATV.0000243925.65265.3c?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -