Atherosclerosis 206 (2009) 153–158 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Human CETP aggravates atherosclerosis by increasing VLDL-cholesterol rather than by decreasing HDL-cholesterol in APOE*3-Leiden mice Jitske de Vries-van der Weij a,b,∗ , Susanne Zadelaar a , Karin Toet a , Louis M. Havekes a,c , Teake Kooistra a , Patrick C.N. Rensen d a The Netherlands Organization for Applied Scientific Research - BioSciences, Gaubius Laboratory, P.O. Box 2215, 2301 CE Leiden, The Netherlands b The Dept. of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands c The Dept. of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands d The Dept. of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands article info Article history: Received 10 December 2008 Received in revised form 23 February 2009 Accepted 23 February 2009 Available online 19 March 2009 Keywords: Atherosclerosis Cholesteryl ester transfer protein Lipoproteins Lesion stability abstract 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. Methods and 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. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Atherosclerosis is a disease affecting the large arteries and is one of the leading causes of death in the Western world. An important risk factor for the development of atherosclerosis is dyslipidemia, as characterized by high levels of (very) low density lipoprotein- cholesterol ((V)LDL-C) and low levels of high density lipoprotein- cholesterol (HDL-C). The cholesteryl ester transfer protein (CETP) plays a role in the regulation of both (V)LDL-C and HDL-C levels, as CETP transfers cholesteryl esters from HDL to (V)LDL in exchange for triglycerides (TG) [1]. In this way, CETP lowers HDL-C and at the same time increases (V)LDL-C, thereby unfavorably modifying two risk factors for atherosclerosis development [2]. ∗ Corresponding author at: Leiden University Medical Center, Dept. Endocrinology and Metabolic Diseases, Room C4-R, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 71 518 5462; fax: +31 71 524 8136. E-mail address: a.j.de vries@lumc.nl (J. de Vries-van der Weij). Indeed, in established hyperlipidemic mouse models for atherosclerosis, CETP expression aggravated atherosclerosis devel- opment [3,4]. However, contradicting effects of CETP on atheroscle- rosis development have been reported in humans. In studies where a reduced CETP mass led to increased HDL-C a beneficial effect on CHD was found only with concomitantly reduced (V)LDL-C [2,5–7], while in studies where (V)LDL-C was not affected an increased CHD prevalence was observed [8–10]. These studies suggest that (V)LDL- C levels are of great importance in determining the effect of CETP on CHD. On the other hand, a recent meta-analysis suggests that mutations in CETP that are associated with reduced CETP activ- ity and increased HDL-C coincided with a reduced CHD risk [11]. Together, these studies demonstrate the complex role of CETP in atherosclerosis. This complexity is further illustrated by the RADIANCE 1 [12] and 2 [13], ILLUSTRATE [14] and ILLUMINATE [15] trials, which evaluated the CETP inhibitor torcetrapib in combination with the LDL-C lowering drug atorvastatin. Combination therapy led to a strong increase in HDL-C (up to +63%) that was accompanied by 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.02.038