Our research has shown that ABCA1 (and additionally ABCG1 in the mouse), a mediator of cholesterol efflux from macrophages, functions in macrophage deposition of unesterified cholesterol into the extracellular matrix. The drug, probucol, an inhibitor of ABCA1, blocks macrophage deposition of this cholesterol. We detected the extracellular cholesterol deposits using a unique monoclonal antibody that labels ordered arrays of unesterified cholesterol molecules. Although appearing spherical at the resolution of the standard fluorescence microscope, the cholesterol accumulates extracellularly in irregularly shaped deposits of varying size when viewed by super-resolution fluorescence, atomic force, and immunoelectron microscopy. The extracellular cholesterol deposits are shed from the plasma membrane of cholesterol-enriched macrophages. The cholesterol deposits are shed with predominantly phosphatidylcholine and lack plasma membrane protein markers such as CD14 indicating a selective removal of lipid from the plasma membrane. This research shows that macrophages clear their excess unesterified cholesterol not only by esterifying this cholesterol and storing the formed cholesteryl ester within intracellular lipid droplets, but also by depositing excess unesterified cholesterol within the extracellular matrix. However, if not mobilized, buildup of extracellular unesterified cholesterol could be cytotoxic and promote the development of plaques. We are currently investigating deposition of extracellular unesterified cholesterol in human and animal atherosclerotic plaques to learn how buildup of extracellular unesterified cholesterol contributes to atherosclerotic plaque formation and progression.
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