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Journal of Lipid Research, Vol. 49, 2504-2512, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study

Hannelore Samyn^*, Matthijs Moerland^*, Teus van Gent^*, Rien van Haperen^*, Jari Metso, Frank Grosveld^*, Matti Jauhiainen, Arie van Tol^* and Rini de Crom^1,*,

^* Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland

Published, JLR Papers in Press, August 18, 2008.

Part of this work was supported by Zorgonderzoek Nederland Medische Wetenschappen, The Netherlands Organization for Health Research and Development (Grant 910-31-806). The Sigrid Juselius Foundation, Research Council for Health, Academy of Finland (Grant 114484), and the Finnish Foundation for Cardiovascular Research also supported this study.

¹ To whom correspondence should be addressed. e-mail: m.decrom{at}erasmusmc.nl

Plasma phospholipid transfer protein (PLTP) interacts with HDL particles and facilitates the transfer of phospholipids from triglyceride (TG)-rich lipoproteins to HDL. Overexpressing human PLTP in mice increases the susceptibility to atherosclerosis. In human plasma, high-active and low-active forms of PLTP exist. To elucidate the contribution of phospholipid transfer activity to changes in lipoprotein metabolism and atherogenesis, we developed mice expressing mutant PLTP, still able to associate with HDL but lacking phospholipid transfer activity. In mice heterozygous for the LDL receptor, effects of the mutant and normal human PLTP transgene (mutPLTP tg and PLTP tg, respectively) were compared. In PLTP tg mice, plasma PLTP activity was increased 2.9-fold, resulting in markedly reduced HDL lipid levels. In contrast, in mutPLTP tg mice, lipid levels were not different from controls. Furthermore, hepatic VLDL-TG secretion was stimulated in PLTP tg mice, but not in mutPLTP tg mice. When mice were fed a cholesterol-enriched diet, atherosclerotic lesion size in PLTP tg mice was increased more than 2-fold compared with control mice, whereas in mutPLTP tg mice, there was no change. Our findings demonstrate that PLTP transfer activity is essential for the development of atherosclerosis in PLTP transgenic mice, identifying PLTP activity as a possible target to prevent atherogenesis, independent of plasma PLTP concentration.

Supplementary key words phospholipid transfer protein • lipoproteins • atherosclerosis

Abbreviations: apoA-I, apolipoprotein A-I; AU, arbitrary unit; FPLC, fast-protein liquid chromatography; FXR, farnesoid X receptor; HFHC, high-fat, high-cholesterol; IAA, iodoacetate; LDLR, LDL receptor; mutPLTP, mutant PLTP; PLTP, phospholipid transfer protein; TC, total cholesterol; tg, transgenic; TG, triglyceride

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