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Journal of Lipid Research, Vol. 47, 1725-1732, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Absence of endogenous phospholipid transfer protein impairs ABCA1-dependent efflux of cholesterol from macrophage foam cells

Miriam Lee-Rueckert^1,*, Riikka Vikstedt^1,, Jari Metso, Christian Ehnholm, Petri T. Kovanen^2,* and Matti Jauhiainen

^* Wihuri Research Institute, Helsinki, Finland
Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland

Published, JLR Papers in Press, May 10, 2006.

¹ M. Lee-Rueckert and R. Vikstedt contributed equally to this work.

² To whom correspondence should be addressed. e-mail: petri.kovanen{at}wri.fi

In vitro experiments have demonstrated that exogenous phospholipid transfer protein (PLTP), i.e. purified PLTP added to macrophage cultures, influences ABCA1-mediated cholesterol efflux from macrophages to HDL. To investigate whether PLTP produced by the macrophages (i.e., endogenous PLTP) is also part of this process, we used peritoneal macrophages derived from PLTP-knockout (KO) and wild-type (WT) mice. The macrophages were transformed to foam cells by cholesterol loading, and this resulted in the upregulation of ABCA1. Such macrophage foam cells from PLTP-KO mice released less cholesterol to lipid-free apolipoprotein A-I (apoA-I) and to HDL than did the corresponding WT foam cells. Also, when plasma from either WT or PLTP-KO mice was used as an acceptor, cholesterol efflux from PLTP-KO foam cells was less efficient than that from WT foam cells. After cAMP treatment, which upregulated the expression of ABCA1, cholesterol efflux from PLTP-KO foam cells to apoA-I increased markedly and reached a level similar to that observed in cAMP-treated WT foam cells, restoring the decreased cholesterol efflux associated with PLTP deficiency. These results indicate that endogenous PLTP produced by macrophages contributes to the optimal function of the ABCA1-mediated cholesterol efflux-promoting machinery in these cells. Whether macrophage PLTP acts at the plasma membrane or intracellularly or shuttles between these compartments needs further study.

Supplementary key words cholesterol loading • cholesterol efflux • ATP binding cassette transporter protein-1 upregulation • cyclic AMP • PLTP deficiency

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