ABCA1 contributes to macrophage deposition of extracellular cholesterol

Abstract

This article is available online at http://www.jlr.org it can be mobilized from these cells by components of the HDL system. In this process, either preformed plasmaderived HDL or HDL generated by cells such as macrophages within atherosclerotic plaques, function as acceptors of excess cellular cholesterol. Excess cellular cholesterol is believed to be transferred to HDL from either intracellular or plasma membrane pools of cholesterol.ABCA1 and ABCG1 both function in mediating cellular cholesterol effl ux and contributing to reverse cholesterol transport ( 3-5 ). ABCA1 mediates phospholipidation of ApoA-I, which then functions as an HDL cholesterol acceptor, stimulating cholesterol effl ux. In contrast, ABCG1 mediates cellular cholesterol effl ux to preformed HDL. HDL binds poorly to ABCA1 and ABCG1; nevertheless, both proteins mediate transfer of cholesterol from cells to HDL ( 6-10 ). While ABCA1 can mediate cholesterol effl ux by generating nascent HDL from the simultaneous effl ux of phospholipid and cholesterol, ABCA1 can also effl ux cholesterol to preformed mature HDL ( 11 ). The possible molecular mechanisms for these cholesterol transfers have been recently reviewed ( 4 ). Hypothetical cholesterol microdomains are featured in some of the models of cellular cholesterol effl ux.Besides cellular cholesterol effl ux to HDL, under certain conditions, cells release cholesterol in the form of spherical microparticles. Microparticles containing cholesterol and phospholipid are released into culture medium by cAMP-treated J774 mouse macrophages ( 12, 13 ), cholesterol-enriched human monocyte-derived macrophages ( 14 ), and BHK cells following increased expression of ABCA1 ( 12 ). All these microparticles lack HDL-associated apolipoproteins and do not appear to be precursors to HDL.Previously, we described an extracellular matrix-associated pool of cholesterol that functions in delivering 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. Macrophage 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 fi ndings demonstrate a novel functi...

Allicin induces the upregulation of ABCA1 expression via PPARγ/LXRα signaling in THP-1 macrophage-derived foam cells

“…The cells (2×10 6 cells/well) were transfected using Lipofectamine 2000 (Invitrogen) as previously described (16). The effeciency of transfection was examined bys by RT-qPCR and western blot analysis.…”

ABCA1 (ATP-Binding Cassette Transporter A1) Mediates ApoA-I (Apolipoprotein A-I) and ApoA-I Mimetic Peptide Mobilization of Extracellular Cholesterol Microdomains Deposited by Macrophages

“…In conclusion, previously we showed that both ABCA1 and ABCG1 mediate macrophage deposition of extracellular cholesterol microdomains 4, 5 . Our finding here that ABCA1 is necessary for mobilization of this cholesterol demonstrates an interesting concerted action of ABCA1, both to deposit and then effect mobilization of extracellular cholesterol microdomains.…”

“…We have shown previously that ABCA1 and ABCG1 mediate macrophage deposition of cholesterol microdomains into the extracellular matrix 4, 5 . Thus, ABCA1 shows two separate functions; one that mediates deposition of the extracellular cholesterol microdomains, and another that mediates ApoA-I’s mobilization of the extracellular microdomains.…”

“…Therefore, we examined whether peptide 5A could mobilize extracellular cholesterol microdomains in the absence of macrophages. First, human macrophages were cholesterol-enriched by incubation with AcLDL as described above except that incubation was for 2 days with the LXR agonist, TO901317 (TO9), added to induce maximally ABCA1 and ABCG1 that we previously showed mediate macrophage deposition of extracellular cholesterol microdomains 4, 5 . Then, macrophages were removed from one set of cultures leaving only the extracellular macrophage deposited cholesterol.…”

“…We have visualized these cholesterol microdomains with a unique monoclonal antibody that immunolabels an ordered array of cholesterol molecules 7 . Both ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) mediate extracellular deposition of the cholesterol microdomains by mouse bone marrow-derived macrophages, while ABCA1 mediates their deposition by human M-CSF differentiated monocyte-derived macrophages 4, 5 .…”