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Journal of Lipid Research, Vol. 47, 356-365, February 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Human apoA-I expression in CETP transgenic rats leads to lower levels of apoC-I in HDL and to magnification of CETP-mediated lipoprotein changes¹

David Masson^2,*,, Jean-Paul Pais de Barros^*,, Zoulika Zak^*,, Thomas Gautier^*,, Naig Le Guern^*,, Mahfoud Assem, Jeffrey W. Chisholm^**, James R. Paterniti, Jr. and Laurent Lagrost^2,*,

^* Laboratoire de Biochimie des Lipoprotéines, INSERM U498, Faculté de Médecine, BP87900, 21079 Dijon Cedex, France
Institut Fédératif de Recherche 100, Faculté de Médecine, BP87900, 21079 Dijon Cedex, France
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105
^** CV Therapeutics, Inc., 3172 Porter Dr., Palo Alto, CA 94304
and Amylin Pharmaceuticals, Inc., San Diego, CA 92121

¹ In memory of our friend and colleague, Dr. Peter Dolphin (Dalhousie University, Halifax), who contributed to the initiation of the present study.

Published, JLR Papers in Press, November 10, 2005.

² To whom correspondence should be addressed. e-mail: laurent.lagrost{at}u-bourgogne.fr(L.L.); david.masson{at}chu-dijon.fr (D.M.)

Plasma cholesteryl ester transfer protein (CETP) has a profound effect on neutral lipid transfers between HDLs and apolipoprotein B (apoB)-containing lipoproteins when it is expressed in combination with human apoA-I in HuAI/CETP transgenic (Tg) rodents. In the present study, human apoA-I-mediated lipoprotein changes in HuAI/CETPTg rats are characterized by 3- to 5-fold increments in the apoB-containing lipoprotein-to-HDL cholesterol ratio, and in the cholesteryl ester-to-triglyceride ratio in apoB-containing lipoproteins. These changes occur despite no change in plasma CETP concentration in HuAI/CETPTg rats, as compared with CETPTg rats. A number of HDL apolipoproteins, including rat apoA-I and rat apoC-I are removed from the HDL surface as a result of human apoA-I overexpression. Rat apoC-I, which is known to constitute a potent inhibitor of CETP, accounts for approximately two-thirds of CETP inhibitory activity in HDL from wild-type rats, and the remainder is carried by other HDL-bound apolipoprotein inhibitors. It is concluded that human apoA-I overexpression modifies HDL particles in a way that suppresses their ability to inhibit CETP. An apoC-I decrease in HDL of HuAI/CETPTg rats contributes chiefly to the loss of the CETP-inhibitory potential that is normally associated with wild-type HDL.

Supplementary key words apolipoprotein A-I • cholesteryl ester transfer protein • apolipoprotein C-I

Abbreviations: apoA-I, apolipoprotein A-I; CETP, cholesteryl ester transfer protein; LCAT, lecithin:cholesterol acyltransferase; PLTP, phospholipid transfer protein

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