J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on March 1, 2007

Papers In Press, published online ahead of print December 5, 2006
J. Lipid Res., doi:10.1194/jlr.M600470-JLR200
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Submitted on October 25, 2006
Revised on November 27, 2006
Accepted on December 5, 2006

Different intracellular trafficking of LDL- and acetylated LDL-derived cholesterol lead to distinct reverse cholesterol transport mechanisms

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

Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7

Corresponding Author: ylmarcel{at}ottawaheart.ca

Endocytosis of low density lipoprotein (LDL) and modified LDL is classically described as regulated and unregulated cholesterol delivery to macrophages, respectively. 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-LDL (acLDL), and the intracellular cholesterol trafficking pathways were examined. Confocal microscopy using fluorescently labeled DiO-LDL and DiD-acLDL, clearly demonstrated their discrete intracellular traffic pathways leading to accumulation in distinct endosome compartments. ABCA1-mediated cholesterol efflux to apoA-I was much greater for acLDL-loaded macrophages as compared to LDL. Treatment of LXR ligand 22-OH failed to significantly increase cholesterol efflux to apoA-I in LDL treated cells, but significantly increase efflux in acLDL loaded cells. In contrast, at equivalent levels of cellular cholesterol loading, LDL-derived cholesterol was preferentially effluxed by diffusional pathways, as indicated by increased ABCG1 expression and specificity for HDL. 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 as compared to acLDL-derived cholesterol. This contrasts with in vitro cholesterol efflux to apoA-I but is consistent with in vitro cholesterol efflux to HDL, indicating a greater efficiency of HDL than lipid-poor apoA-I in interstitial fluid in controlling the in vivo RCT. These assays, taken together, emphasize the importance of mediators of diffusional cholesterol efflux in reverse cholesterol transport and the role of ABCA1-mediated efflux in foam cell regression.


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