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Journal of Lipid Research, Vol. 48, 633-645, March 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Different cellular traffic of LDL-cholesterol and acetylated LDL-cholesterol leads to distinct reverse cholesterol transport pathways

Ming-Dong Wang, Robert S. Kiss, Vivian Franklin, Heidi M. McBride, Stewart C. Whitman and Yves L. Marcel¹

Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, and Departments of Biochemistry, Microbiology, Immunology, and Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada

The online version of this article (available at http://www.jlr.orgf) contains supplemental data in the form of two figures.

Published, JLR Papers in Press, December 5, 2006.

¹ To whom correspondence should be addressed. e-mail: ylmarcel{at}ottawaheart.ca

Endocytosis of LDL and modified LDL represents regulated and unregulated cholesterol delivery to macrophages. To elucidate the mechanisms of cellular cholesterol transport and egress under both conditions, various primary macrophages were labeled and loaded with cholesterol or cholesteryl ester from LDL or acetylated low density lipoprotein (AcLDL), and the cellular cholesterol traffic pathways were examined. Confocal microscopy using fluorescently labeled 3,3'-dioctyldecyloxacarbocyanine perchlorate-labeled LDL and 1,1'-dioctyldecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate-labeled AcLDL demonstrated their discrete traffic pathways and accumulation in distinct endosomes. ABCA1-mediated cholesterol efflux to apolipoprotein A-I (apoA-I) was much greater for AcLDL-loaded macrophages compared with LDL. Treatment with the liver X receptor ligand 22-OH increased efflux to apoA-I in AcLDL-loaded but not LDL-loaded cells. In contrast, at a level equivalent to AcLDL, LDL-derived cholesterol was preferentially effluxed to HDL, in keeping with increased ABCG1. In vivo studies of reverse cholesterol transport (RCT) from cholesterol-labeled macrophages injected intraperitoneally demonstrated that LDL-derived cholesterol was more efficiently transported to the liver and secreted into bile than AcLDL-derived cholesterol. This indicates a greater efficiency of HDL than lipid-poor apoA-I in interstitial fluid in controlling in vivo RCT. These assays, taken together, emphasize the importance of mediators of diffusional cholesterol efflux in RCT.

Supplementary key words cholesterol efflux • ATP binding cassette transporter A1 • ATP binding cassette transporter G1 • scavenger receptor class B type I • low density lipoprotein

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