Atherosclerosis 178 (2005) 279–286 Effect of cholesteryl ester transfer protein (CETP) expression on diet-induced hyperlipidemias in transgenic rats Zoulika Zak a,c , Thomas Gautier a , Laure Dumont a , David Masson a , Val´ erie Deckert a , Linda Duverneuil a , Jean-Paul Pais De Barros a , Naig Le Guern a , Martina Schneider a , Philippe Moulin b , Alain Bataillard c , Laurent Lagrost a,∗ a Laboratoire de Biochimie des Lipoprot´ eines, INSERM U498, Facult´ edeM´ edecine, BP 87900, Dijon Cedex 21033, France b Service d’Endocrinologie-U-11, 69500 Bron, France c D´ epartement de Physiologie et de Pharmacologie Clinique, CNRS FRE 2678, Facult´ e de Pharmacie 69373, Lyon, France Received 6 April 2004; received in revised form 19 August 2004; accepted 11 October 2004 Available online 13 December 2004 Abstract Objective: In order to determine the influence of the lipid status on the ability of cholesteryl ester transfer protein (CETP) to modify the plasma lipoprotein profile, the effect of hypercholesterolemia versus hypertriglyceridemia were compared in wild-type and CETP-transgenic (CETPTg) rats expressing CETP at a constant level. Methods and results: Wild-type and CETPTg rats were fed either a chow diet, a high fat/high cholesterol (HF/HC) diet, or a sucrose diet. As compared to wild-type rats, CETPTg rats fed the standard chow exhibited lower high-density lipoproteins (HDL)–cholesterol concentration (-65%, p < 0.01), but similar non-HDL–cholesterol concentrations. Both wild-type and CETPTg rats fed the HF/HC diet displayed pronounced increases in total and non-HDL–cholesterol levels, with no influence of CETP expression in this case. In contrast, the sucrose diet produced significant changes only in CETPTg rats which then exhibited a 82% increase in non-HDL–cholesterol in addition to a 80% reduction in HDL cholesterol when compared to sucrose-fed, wild-type rats (p < 0.01 in both cases). The triglyceride to cholesterol ratio in very low-density lipoprotein (VLDL) was 10-fold lower in ‘HF/HC’ rats than in ‘chow’ and ‘sucrose’ rats (p < 0.005 and p < 0.01, respectively), and VLDL from ‘HF/HC’ animals were proven to constitute poor cholesteryl ester acceptors. Conclusions: CETP expression modified dramatically the lipoprotein phenotype in ‘sucrose’ rats but not in ‘HF/HC’ rats. These observations suggest that a CETP inhibitor treatment is susceptible to produce profound changes in hypertriglyceridemia or combined hyperlipidemia. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Transgenic rats; CETP; Diet; Lipoprotein profile; Hypertriglyceridemia; Hypercholesterolemia; VLDL 1. Introduction Earlier studies in cholesteryl ester transfer protein (CETP)-deficient patients demonstrated that CETP is a key factor in determining the distribution of plasma cholesterol Abbreviations: CETP, cholesteryl ester transfer protein; CETPTg rats, CETP-transgenic rats; HDL, high density lipoprotein; LDL, low density lipoprotein; non-HDL, non-high-density lipoprotein; VLDL, very low- density lipoprotein; HF/HC, high fat/high cholesterol diet ∗ Corresponding author. E-mail address: laurent.lagrost@u-bourgogne.fr (L. Lagrost). between the high-density lipoproteins (HDL) and the apoB- containing lipoproteins, i.e. very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) [1,2]. Recently, pharmacological inhibition of CETP in human subjects was shown to reproduce, at least in part the CETP-deficient syn- drome that is characterized mainly by a substantial rise in plasma HDL cholesterol levels [3,4]. Human observations are in agreement with animal studies that were conducted by the means of either anti-CETP immunotherapy, anti- sense oligonucleotides or specific pharmacological inhibitors [5–8]. Overall, it appears that CETP inhibition may constitute 0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.10.006