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Journal of Lipid Research, Vol. 49, 24-32, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Macrophage PLTP is atheroprotective in LDLr-deficient mice with systemic PLTP deficiency

David T. Valenta, Joshua J. Bulgrien, David J. Bonnet and Linda K. Curtiss¹

Department of Immunology, Scripps Research Institute, La Jolla, CA 92037

Published, JLR Papers in Press, October 10, 2007.

¹ To whom correspondence should be addressed. e-mail: lcurtiss{at}scripps.edu

Systemic phospholipid transfer protein (PLTP) is a recognized risk factor for coronary heart disease. In apolipoprotein E-deficient mice, systemic PLTP deficiency is atheroprotective, whereas PLTP overexpression is proatherogenic. As expected, we also observed significantly smaller lesions (P < 0.0001) in hypercholesterolemic double mutant low density lipoprotein receptor-deficient (LDLr^–/–) PLTP-deficient (PLTP^–/–) mice compared with LDLr^–/– mice expressing systemic PLTP. To assess the specific contribution of only macrophage-derived PLTP to atherosclerosis progression, bone marrow transplantation was performed in LDLr^–/– mice that also lacked systemic PLTP. Groups of double mutant PLTP^–/–LDLr^–/– mice were irradiated with 1,000 rad and injected with bone marrow (BM) cells collected from either PLTP^–/– or wild-type mice. When fed a high-fat diet, BM cell expression of PLTP decreased plasma cholesterol of PLTP^–/–LDLr^–/– mice from 878 ± 220 to 617 ± 183 mg/dl and increased HDL cholesterol levels from 54 ± 11 to 117 ± 19 mg/dl. This decreased total plasma cholesterol and increased HDL cholesterol contributed to the significantly smaller atherosclerotic lesions in both aortas and heart sinus valves observed in these mice. Thus, unlike total systemic PLTP, locally produced macrophage-derived PLTP beneficially alters lipoprotein metabolism and reduces lesion progression in hyperlipidemic mice.

Supplementary key words phospholipid transfer protein • atherosclerosis • bone marrow transplant • inflammation • low density lipoprotein receptor

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