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Journal of Lipid Research, Vol. 43, 2164-2171, December 2002
Copyright © 2002 by Lipid Research, Inc.

Expression of simian CETP in normolipidemic Fisher rats has a profound effect on large sized apoE-containing HDL

Zoulika Zak^*, Laurent Lagrost^1,, Thomas Gautier, David Masson, Valérie Deckert, Linda Duverneuil, Jean-Paul Pais de Barros, Naig Le Guern, Laure Dumont, Martina Schneider, Valérie Risson^*, Philippe Moulin, Delphine Autran^**, Gillian Brooker, Jean Sassard^** and Alain Bataillard^*

^* Département de Physiologie et de Pharmacologie Clinique, CNRS UMR 5014, IFR 39, Université Claude Bernard Lyon I, 69008 Lyon, France
Laboratoire de Biochimie des Lipoprotéines, INSERM U498, Faculté de Médecine, BP87900, 21079 Dijon Cedex, France
Service d'Endocrinologie-U11, 69500 Bron, France
^** Laboratoire de Métabolisme des Lipides, Hôpital de l'Antiquaille, Lyon, France
University of Edinburgh Medical School, Edinburgh, Scotland, UK

¹ To whom correspondence should be addressed. e-mail: laurent.lagrost{at}u-bourgogne.fr

In order to investigate the direct effect of cholesteryl ester transfer protein (CETP) on the structure and composition of HDL in vivo, simian CETP was expressed in Fisher rat that spontaneously displays high plasma levels of HDL1. In the new CETPTg rat line, the production of active CETP by the liver induced a significant 48% decrease in plasma HDL cholesterol, resulting in a 34% decrease in total cholesterol level (P < 0.01 in both cases). Among the various plasma HDL subpopulations, the largest HDL were those mostly affected by CETP, with a 74% decrease in HDL1 versus a significantly weaker 38% decrease in smaller HDL2 (P < 0.0001). Apolipoprotein E (apoE)-containing HDL1 were selectively affected by CETP expression, whereas apoA content of HDL remained unmodified. The reduction in the apoE content of serum HDL observed in CETPTg rats compared to controls (53%, P < 0.02) suggests that apoE in HDL may constitute in vivo a major determinant of their ability to interact with CETP.

These results bring new insight into the lack of HDL1 in plasma from CETP-deficient heterozygotes despite their substantial 50% decrease in CETP activity. In addition, they indicate that HDL1 constitute reliable and practicable sensors of very low plasma CETP activity in vivo.

Abbreviations: CETP, cholesteryl ester transfer protein; TC, total cholesterol; TG, triglycerides

Supplementary key words CETP deficiency • transgenesis • apolipoprotein E

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