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Journal of Lipid Research, Vol. 48, 2453-2462, November 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

The roles of different pathways in the release of cholesterol from macrophages

Maria Pia Adorni^1,*, Francesca Zimetti^1,*, Jeffrey T. Billheimer, Nan Wang, Daniel J. Rader, Michael C. Phillips^* and George H. Rothblat^2,*

^* Gastroenterology, Hepatology, and Nutrition Division, Children's Hospital of Philadelphia, Philadelphia, PA
Institute of Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY

Published, JLR Papers in Press, August 29, 2007.

¹ M. P. Adorni and F. Zimetti contributed equally to this work.

² To whom correspondence should be addressed. e-mail: rothblat{at}email.chop.edu

Cholesterol efflux occurs by different pathways, including transport mediated by specific proteins. We determined the effect of enriching cells with free cholesterol (FC) on the release of FC to human serum. Loading Fu5AH cells with FC had no effect on fractional efflux, whereas enriching mouse peritoneal macrophages (MPMs) resulted in a doubling of fractional efflux. Efflux from cholesterol-normal MPM and Fu5AH cells to 15 human sera correlated well with HDL parameters. However, these relationships were reduced or lost with cholesterol-loaded MPMs. Using macrophages from scavenger receptor class B type I (SR-BI)-, ABCA1-, and ABCG1-knockout mice, together with inhibitors of SR-BI- and ABCA1-mediated efflux, we were able to quantitate efflux upon loading macrophages with excess cholesterol and to establish the contributions of the various efflux pathways in cholesterol-normal and -enriched cells. The removal of ABCA1 had essentially no effect on the total efflux when cell cholesterol levels were normal. However, in cholesterol-enriched cells, the removal of ABCA1 reduced efflux by 50%. Approximately 20% of the efflux stimulated by FC-loading MPM is attributable to ABCG1. The SR-BI contribution to efflux was small. Another pathway that is present in all cells is aqueous diffusion. Our studies demonstrate that this mechanism is one of the major contributors to efflux, particularly in cholesterol-normal cells.

Supplementary key words SR-BI • ABCA1 • ABCG1 • efflux

Abbreviations: AcLDL, acetylated low density lipoprotein; apoA-I, apolipoprotein A-I; BLT-1, 2-hexyl-1-cyclopentanone thiosemicarbazone; DPBS, phosphate-buffered saline with calcium and magnesium; FC, free cholesterol; KO, knockout; MPM, mouse peritoneal macrophage; PL, phospholipid; RCT, reverse cholesterol transport; SR-BI, scavenger receptor class B type I; WT, wild-type

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