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Journal of Lipid Research, Vol. 45, 805-811, May 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Elevation of plasma phospholipid transfer protein increases the risk of atherosclerosis despite lower apolipoprotein B-containing lipoproteins

Jessica Lie^*, Rini de Crom^1,,, Teus van Gent^*,, Rien van Haperen, Leo Scheek^*, Farah Sadeghi-Niaraki^* and Arie van Tol^1,*,

^* Departments of Biochemistry, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
Cell Biology and Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
Vascular Surgery, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

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

Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins and mediates HDL conversion. PLTP-overexpressing mice have increased atherosclerosis. However, mice do not express cholesteryl ester transfer protein (CETP), which is involved in the same metabolic pathways as PLTP. Therefore, we studied atherosclerosis in heterozygous LDL receptor-deficient (LDLR^+/–) mice expressing both human CETP and human PLTP. We used two transgenic lines with moderately and highly elevated plasma PLTP activity. In LDLR^+/–/huCETPtg mice, cholesterol is present in both LDL and HDL. Both are decreased in LDLR^+/–/huCETPtg/huPLTPtg mice (>50%). An atherogenic diet resulted in high levels of VLDL+LDL cholesterol. PLTP expression caused a strong PLTP dose-dependent decrease in VLDL and LDL cholesterol (–26% and –69%) and a decrease in HDL cholesterol (–70%). Surprisingly, atherosclerosis was increased in the two transgenic lines with moderately and highly elevated plasma PLTP activity (1.9-fold and 4.4-fold, respectively), indicating that the adverse effect of the reduction in plasma HDL outweighs the beneficial effect of the reduction in apolipoprotein B (apoB)-containing lipoproteins. The activities of the antiatherogenic enzymes paraoxonase and platelet-activating factor acetyl hydrolase were both PLTP dose-dependently reduced ( –33% and –65%, respectively).

We conclude that expression of PLTP in this animal model results in increased atherosclerosis in spite of reduced apoB-containing lipoproteins, by reduction of HDL and of HDL-associated antioxidant enzyme activities.

Abbreviations: apoB, apolipoprotein B; CETP, cholesteryl ester transfer protein; HFHC, high fat, high cholesterol; LDLR, LDL receptor; PAF-AH, platelet-activating factor acetyl hydrolase; PLTP, phospholipid transfer protein; PON, paraoxonase

Supplementary key words apolipoprotein B • high density lipoprotein • cholesteryl ester transfer protein • cholesterol • transgenic • paraoxonase • platelet activating factor acetyl hydrolase

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