Abstract 534: Abca1 Mediates Macrophage Deposition of Cholesterol Into the Extracellular Matrix
ABCG1 and ABCA1 both function in reverse cholesterol transport. We previously reported that cholesterol-enriched macrophages deposit cholesterol into the extracellular space and this process depends in part on ABCG1. The extracellular cholesterol deposits can be mobilized by HDL. The objective of the current study was to determine whether ABCA1 also contributes to macrophage deposition of extracellular cholesterol. A monoclonal antibody that detects cholesterol microdomains, and not isolated cholesterol molecules, labels these extracellular deposits. First, to confirm the specificity of the cholesterol labeling, we treated cholesterol-enriched macrophages cultures with cholesterol oxidase and found that antibody labeling of deposits was eliminated. Many biochemical studies assume that cholesterol oxidase susceptible cholesterol indicates this cholesterol is within the plasma membrane. However, as we show here, the extracellular pool of cholesterol also contributes to cholesterol oxidase susceptible cholesterol. Second, concerning ABCA1 function in cholesterol deposition, we observed that the LXR agonist, TO901317, an ABCA1-inducing agent, restored cholesterol deposition that was absent in ABCG1-/- mouse macrophages. In addition, probucol, an agent that inhibits ABCA1 function, partially inhibited cholesterol deposited by wild-type mouse macrophages, and completely inhibited deposition from TO901317-treated ABCG1-/- mouse macrophages. These results suggest that ABCA1 contributes to macrophage cholesterol deposition. We confirmed this conclusion by testing cholesterol deposition in ABCA1-/- mouse macrophages. Extracellular cholesterol deposition by these macrophages was substantially reduced compared with wild-type mouse macrophages. Thus, our findings demonstrate a novel function of ABCA1 in contributing to macrophage export of cholesterol into the extracellular space where this cholesterol can be stored until mobilized by HDL.
Author Disclosures: X. Jin: None. S.R. Freeman: None. B. Vaisman: None. Y. Liu: None. J. Chang: None. N. Varsano: None. L. Addadi: None. A. Remaley: None. H.S. Kruth: None.
- © 2015 by American Heart Association, Inc.