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. The extracellular cholesterol deposits can be mobilized by agents such as HDL, ApoA-I, and ApoA-I mimetic peptides that mediate reverse cholesterol transport from tissues. Mobilization of the extracellular cholesterol deposits by ApoA-I and ApoA-I mimetic peptide depends on ABCA1 function, which is known to complex these agents with phospholipid, a cholesterol solubilizing agent. Our 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 whether, despite lowering HDL levels, probucol's anti-atherogenic property could be due to its blocking macrophage deposition of extracellular unesterified cholesterol.
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