title: ABCA1 contributes to macrophage deposition of extracellular cholesterol.
abstract: We previously reported that cholesterol-enriched macrophages excrete cholesterol into the extracellular matrix. A monoclonal antibody that detects cholesterol microdomains labels the deposited extracellular particles. Macro-phage deposition of extracellular cholesterol depends, in part, on ABCG1, and this cholesterol can be mobilized by HDL components of the reverse cholesterol transport process. The objective of the current study was to determine whether ABCA1 also contributes to macrophage deposition of extracellular cholesterol. ABCA1 functioned in extracellular cholesterol deposition. The liver X receptor agonist, TO901317 (TO9), an ABCA1-inducing factor, restored cholesterol deposition that was absent in cholesterol-enriched ABCG1(-/-) mouse macrophages. In addition, the ABCA1 inhibitor, probucol, blocked the increment in cholesterol deposited by TO9-treated wild-type macrophages, and completely inhibited deposition from TO9-treated ABCG1(-/-) macrophages. Lastly, ABCA1(-/-) macrophages deposited much less extracellular cholesterol than wild-type macrophages. These findings demonstrate a novel function of ABCA1 in contributing to macrophage export of cholesterol into the extracellular matrix.
authors.affiliation: Section of Experimental Atherosclerosis National Institutes of Health, Bethesda, MD 20892.
authors.forename: Xueting
authors.initials: X
authors.lastname: Jin
authors.affiliation: Section of Experimental Atherosclerosis National Institutes of Health, Bethesda, MD 20892.
authors.forename: Sebastian R
authors.initials: SR
authors.lastname: Freeman
authors.affiliation: Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Boris
authors.initials: B
authors.lastname: Vaisman
authors.affiliation: Section of Experimental Atherosclerosis National Institutes of Health, Bethesda, MD 20892.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Section of Experimental Atherosclerosis National Institutes of Health, Bethesda, MD 20892.
authors.forename: Janet
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Varsano
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Lia
authors.initials: L
authors.lastname: Addadi
authors.affiliation: Lipoprotein Metabolism Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Alan
authors.initials: A
authors.lastname: Remaley
authors.affiliation: Section of Experimental Atherosclerosis National Institutes of Health, Bethesda, MD 20892.
authors.forename: Howard S
authors.initials: HS
authors.lastname: Kruth
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics; D011341:Probucol / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011341:Probucol; D013449:Sulfonamides; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: ATP binding cassette transporter A1; ATP binding cassette transporter G1; TO901317; apolipoprotein A-I; atherosclerosis; high density lipoprotein; probucol