The roles of different pathways in the release of cholesterol from macrophages
Cholesterol efflux occurs by different pathways, including transport mediated by specific proteins. We determined the effect of enriching cells with free cholesterol (FC) on the release of FC to human serum. Loading Fu5AH cells with FC had no effect on fractional efflux, whereas enriching mouse peritoneal macrophages (MPMs) resulted in a doubling of fractional efflux. Efflux from cholesterol-normal MPM and Fu5AH cells to 15 human sera correlated well with HDL parameters. However, these relationships were reduced or lost with cholesterol-loaded MPMs. Using macrophages from scavenger receptor class B type I (SR-BI)-, ABCA1-, and ABCG1-knockout mice, together with inhibitors of SR-BI- and ABCA1-mediated efflux, we were able to quantitate efflux upon loading macrophages with excess cholesterol and to establish the contributions of the various efflux pathways in cholesterol-normal and -enriched cells. The removal of ABCA1 had essentially no effect on the total efflux when cell cholesterol levels were normal. However, in cholesterol-enriched cells, the removal of ABCA1 reduced efflux by 50%. Approximately 20% of the efflux stimulated by FC-loading MPM is attributable to ABCG1. The SR-BI contribution to efflux was small. Another pathway that is present in all cells is aqueous diffusion. Our studies demonstrate that this mechanism is one of the major contributors to efflux, particularly in cholesterol-normal cells. Cholesterol efflux occurs by different pathways, including transport mediated by specific proteins. We determined the effect of enriching cells with free cholesterol (FC) on the release of FC to human serum. Loading Fu5AH cells with FC had no effect on fractional efflux, whereas enriching mouse peritoneal macrophages (MPMs) resulted in a doubling of fractional efflux. Efflux from cholesterol-normal MPM and Fu5AH cells to 15 human sera correlated well with HDL parameters. However, these relationships were reduced or lost with cholesterol-loaded MPMs. Using macrophages from scavenger receptor class B type I (SR-BI)-, ABCA1-, and ABCG1-knockout mice, together with inhibitors of SR-BI- and ABCA1-mediated efflux, we were able to quantitate efflux upon loading macrophages with excess cholesterol and to establish the contributions of the various efflux pathways in cholesterol-normal and -enriched cells. The removal of ABCA1 had essentially no effect on the total efflux when cell cholesterol levels were normal. However, in cholesterol-enriched cells, the removal of ABCA1 reduced efflux by 50%. Approximately 20% of the efflux stimulated by FC-loading MPM is attributable to ABCG1. The SR-BI contribution to efflux was small. Another pathway that is present in all cells is aqueous diffusion. Our studies demonstrate that this mechanism is one of the major contributors to efflux, particularly in cholesterol-normal cells. acetylated low density lipoprotein apolipoprotein A-I 2-hexyl-1-cyclopentanone thiosemicarbazone phosphate-buffered saline with calcium and magnesium free cholesterol knockout mouse peritoneal macrophage phospholipid reverse cholesterol transport scavenger receptor class B type I wild-type Several epidemiological studies have shown an inverse correlation between HDL plasma level and the risk of coronary heart disease (1.Linsel-Nitschke P. Tall A.R. HDL as a target in the treatment of atherosclerotic cardiovascular disease.Nat. Rev. 2005; 4: 193-205Google Scholar, 2.Nofer J-R. Kehrel B. Fobker M. Levkau B. Assmann G. Eckardstein A.Von HDL and arteriosclerosis: beyond reverse cholesterol transport.Atherosclerosis. 2002; 161: 1-16Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar). One of the mechanisms by which HDL is antiatherogenic is the ability to promote reverse cholesterol transport (RCT) (3.Von Eckardstein A. Nofer J-R. Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 13-27Crossref PubMed Scopus (646) Google Scholar, 4.Lewis G.F. Rader D.J. New insights into the regulation of HDL metabolism and reverse cholesterol transport.Circ. Res. 2005; 96: 1221-1232Crossref PubMed Scopus (828) Google Scholar). In RCT, excess cholesterol is returned from the peripheral cells, such as the lipid-laden macrophages of an atherosclerotic plaque, to the liver for excretion in the bile. RCT begins with cholesterol export from macrophages to serum lipoproteins, which serve as extracellular cholesterol acceptors. It has been demonstrated that the efflux of cholesterol from cells can occur by several mechanisms, including unmediated aqueous diffusion and specific receptor-mediated processes. Among the latter is the unidirectional flux of cholesterol promoted by a transporter belonging to the ATP binding cassette superfamily, specifically ABCA1, which mediates the efflux of cholesterol to lipid-free or lipid-poor apolipoproteins (5.Attie A.D. Kastelein J.P. Hayden M.R. Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis.J. Lipid Res. 2001; 42: 1717-1726Abstract Full Text Full Text PDF PubMed Google Scholar, 6.Hayden M.R. Clee S.M. Brooks-Wilson A. Genest Jr., J. Attie A. Kastelein J.J.P. Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency.Curr. Opin. Lipidol. 2000; 11: 117-122Crossref PubMed Scopus (109) Google Scholar, 7.Oram J.F. Vaughan A.M. ABC1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins.Curr. Opin. Lipidol. 2000; 11: 253-260Crossref PubMed Scopus (241) Google Scholar). Recently, the half-transporter ABCG1 was identified as a protein involved in the efflux of cholesterol, mainly to lipid-rich acceptor particles (8.Brewer Jr., H.B. Santamarina-Fojo S. New insights into the role of the adenosine triphosphate-binding cassette transporters in high-density lipoprotein metabolism and reverse cholesterol transport.Am. J. Cardiol. 2003; 91: 3E-11EAbstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 9.Jessup W. Gelissen I.C. Gaus K. Kritharides L. Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages.Curr. Opin. Lipidol. 2006; 17: 247-257Crossref PubMed Scopus (226) Google Scholar). In addition, scavenger receptor class B type I (SR-BI) facilitates the bidirectional flux of free cholesterol (FC) between cells and lipoprotein (10.Kellner-Weibel G. de la Llera-Moya M. Connelly M.A. Stoudt G. Christian A.E. Haynes M.P. Williams D.L. Rothblat G.H. Expression of scavenger receptor BI in COS-7 cells alters cholesterol content and distribution.Biochemistry. 2000; 39: 221-229Crossref PubMed Scopus (133) Google Scholar, 11.de la Llera-Moya M. Connelly M.A. Drazul D. Klein S.M. Favari E. Yancey P.G. Williams D.L. Rothblat G.H. Scavenger receptor, class B, type I (SR-BI) affects cholesterol homeostasis by magnifying cholesterol flux between cells and HDL.J. Lipid Res. 2001; 42: 1969-1978Abstract Full Text Full Text PDF PubMed Google Scholar). The flux of FC between lipoproteins and cells expressing SR-BI is closely linked to the phospholipid (PL) content and composition of the lipoprotein (12.Yancey P.G. de la Llera-Moya M. Swarnakar S. Monzo P. Klein S.M. Connelly M.A. Johnson W.J. Williams D.L. Rothblat G.H. HDL phospholipid composition is a major determinant of the bi-directional flux and net movement of cellular free cholesterol mediated by scavenger receptor-BI (SR-BI).J. Biol. Chem. 2000; 275: 36596-36604Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar, 13.Yancey P.G. Kawashiri M. Moore R. Glick J.M. Williams D.L. Connelly M.A. Rader D.J. Rothblat G.H. In vivo modulation of HDL phospholipid has opposing effects on SR-BI- an ABCA1-mediated cholesterol efflux.J. Lipid Res. 2004; 45: 337-346Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). The aim of this investigation arose from the observation that fractional efflux of cholesterol from Fu5AH hepatoma cells when these cells were in the net of cholesterol from cholesterol-loaded Fu5AH cells was that from cholesterol-normal cells the cellular of cholesterol was that the cholesterol efflux in and Fu5AH cells was However, when studies were cholesterol-normal and mouse peritoneal macrophages we an in fractional efflux upon cholesterol In addition, the flux from cells was by cholesterol In the in fractional efflux when were cholesterol-enriched that such treatment a in the of efflux mechanisms and that this was linked to cell cholesterol In the present we the of and cholesterol-loaded Fu5AH and MPM cells in of the fractional release of cholesterol, as cholesterol 15 sera from human or a of human serum. cell we the between the efflux and HDL and we determined a of of the efflux mechanisms cholesterol loading these we different to the contributions of the different efflux pathways to efflux from cholesterol-normal and cholesterol-enriched MPMs. we efflux to human serum from from wild-type and in which ABCA1, and ABCG1 were Using these cells, we the with to ABCA1-mediated efflux or 2-hexyl-1-cyclopentanone thiosemicarbazone to efflux E. 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However, these or when with We demonstrate to different aqueous ABCA1 and ABCG1 a role in the of efflux to human serum with cholesterol-enriched whereas SR-BI has a role in this In addition, we that in cholesterol-normal aqueous diffusion of cholesterol from the plasma membrane is the major pathway for cholesterol release to serum. was from and from and phosphate-buffered saline with calcium and magnesium were from and from was from was from The was by The Cholesterol to cell cholesterol was from was from and from were in to a The was to a and a a with and was to a of with in of the of to the hepatoma cell Fu5AH was by as la Llera-Moya M. Rothblat G.H. Connelly M.A. G. Williams D.L. Scavenger receptor BI (SR-BI) mediates free cholesterol flux of HDL to the cell Lipid Res. Full Text Full Text PDF PubMed Google Scholar). was to acetylated low density lipoprotein as by of low density lipoprotein and regulation of cholesterol metabolism in familial PubMed Scopus Google and the was by serum was from 15 with and or and levels were on a levels were an on the ABCA1 knockout were on the and were from the SR-BI mice, on a were from the and to SR-BI were from ABCG1 mice, on a were from the of were a The macrophages were from the peritoneal of as Rothblat G.H. of cholesterol bidirectional flux between cells and Lipid Res. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). were with the were and macrophages were by of the with were on a density of in Fu5AH hepatoma cells were in serum cells were and a density of on cells were for with in the of loading of cells with cholesterol the by the of to the were for in or with or or the of and efflux of cholesterol was by for with human serum or serum from to FC efflux was by the release of cholesterol into the as G.H. de la Llera-Moya M. 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Biol. 2006; PubMed Scopus Google and by the in efflux between and MPMs. of cholesterol-normal and cholesterol-enriched and were for with to or cholesterol-enriched by a in the of this were to or or to the of and were for with a of human serum The contribution of ABCA1 to efflux was determined by the in efflux upon to W. Favari E. Rothblat G.H. The contributions of ABCA1 and SR-BI to cholesterol efflux to serum from and Thromb. Vasc. Biol. 2006; PubMed Scopus Google Scholar). The in total efflux by to was as the contribution of SR-BI W. Favari E. Rothblat G.H. The contributions of ABCA1 and SR-BI to cholesterol efflux to serum from and Thromb. Vasc. Biol. 2006; PubMed Scopus Google Scholar). The level of efflux treatment with inhibitors was a of ABCG1 aqueous diffusion. aqueous diffusion or as demonstrated and cells A.M. J.F. ABCA1 and ABCG1 or to cellular cholesterol and HDL.J. Lipid Res. 2006; Full Text Full Text PDF PubMed Scopus Google The contribution of aqueous diffusion was as the efflux present in cholesterol-normal or and this was to the in cholesterol-enriched cells. The efflux for the contributions of ABCA1, and aqueous diffusion was to that by ABCG1. However, is that this the contribution to cholesterol efflux of pathways that have been The were in and as correlation were to between cholesterol efflux and various serum parameters. were with the In cell of cells with excess cholesterol cholesterol fractional efflux W.J. Rothblat G.H. The of cellular and lipoprotein cholesterol on the flux of cholesterol between and density Biol. Chem. Full Text PDF PubMed Google Scholar). Cholesterol of Fu5AH cells was by of cells with Efflux was upon the of 15 sera from In cells, we an cholesterol of with cells. the cholesterol efflux from cells was to that of cells that the major efflux mechanism in the hepatoma cells of the cell cholesterol We relationships between the efflux of cholesterol from Fu5AH cells and in the 15 human serum The fractional efflux of cholesterol from these cells from to we P.G. Kawashiri M. Moore R. Glick J.M. Williams D.L. Connelly M.A. Rader D.J. Rothblat G.H. In vivo modulation of HDL phospholipid has opposing effects on SR-BI- an ABCA1-mediated cholesterol efflux.J. Lipid Res. 2004; 45: 337-346Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, B. de la Llera-Moya M. L. Rothblat G. of the cholesterol efflux of human serum by with Lipid Res. Full Text PDF PubMed Google Scholar, P.G. D. Williams D.L. Connelly M.A. Rothblat G.H. SR-BI- and ABCA1-mediated cholesterol efflux to serum from with Lipid Res. 2004; 45: Full Text Full Text PDF PubMed Scopus Google with these cells, a correlation was between efflux and and Fu5AH cells have levels of SR-BI the between efflux and the HDL were P.G. Kawashiri M. Moore R. Glick J.M. Williams D.L. Connelly M.A. Rader D.J. Rothblat G.H. In vivo modulation of HDL phospholipid has opposing effects on SR-BI- an ABCA1-mediated cholesterol efflux.J. Lipid Res. 2004; 45: 337-346Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, P.G. D. Williams D.L. Connelly M.A. Rothblat G.H. SR-BI- and ABCA1-mediated cholesterol efflux to serum from with Lipid Res. 2004; 45: Full Text Full Text PDF PubMed Scopus Google Scholar). The 15 sera in the Fu5AH were as to ability in efflux from or cholesterol-enriched MPMs. Loading of was by with to the cells the which efflux to sera was for The of cholesterol efflux promoted by the 15 sera from was the the fractional release in an efflux of the efflux in as cholesterol The cholesterol that was to the 15 sera from cholesterol-normal was was by upon cholesterol of the cells. the in cholesterol was a of an cell cholesterol the of cholesterol have been to protein, the protein that was that the efflux cholesterol loading was to a cholesterol the of an efflux linked to the of a cholesterol efflux. with Fu5AH cells we the relationships between cholesterol efflux from to the of serum. shown in of to the 15 for efflux of cholesterol correlated with and the for of the was to that with Fu5AH cells. However, enriching with cholesterol, the relationships between efflux and HDL were lost or as shown for and with Fu5AH cells and we the cholesterol efflux from cholesterol-normal cholesterol efflux from Fu5AH cells. shown in the correlation between fractional efflux was with the in which the of cells in of the of cholesterol efflux to serum. was lost loading with the of efflux pathways when were with We the role of SR-BI in the of fractional cholesterol release from macrophages in We efflux from and SR-BI mice, for to a of human serum The efflux from to the serum was for and cells and Loading of macrophages with a doubling in fractional cholesterol with the in and SR-BI cells and that the SR-BI receptor to the of efflux we cholesterol of MPMs. cholesterol-normal cells, or SR-BI the major to efflux was aqueous diffusion. cholesterol the contribution to efflux the ABCA1 with a contribution from ABCG1 In studies to for we cholesterol efflux from and from or ABCA1 and for to the of human serum The of the was to establish the contribution of the ABCA1 receptor to the of cholesterol efflux from cholesterol-enriched and to the contributions of pathways to total efflux in and ABCA1 cells. In cholesterol-normal cells, or of the efflux was the aqueous diffusion Loading macrophages with cholesterol efflux from to to the of ABCA1 and ABCG1. In the ABCA1 cells, the loading with FC stimulated the efflux from to The in total efflux from cholesterol-enriched ABCA1 cells with cholesterol-enriched can to the of the ABCA1 of efflux the role of ABCG1 in the stimulated fractional release of cholesterol loading of with we efflux on macrophages from and ABCG1 The fractional release of cholesterol to serum from to in of ABCG1 reduced the of cholesterol efflux in cholesterol-enriched cells with cells to ABCG1 reduced the of efflux upon cholesterol the of the removal of ABCG1 was that with ABCA1 macrophages The that cholesterol loading fractional efflux was with the efflux Fu5AH cells and by Johnson W.J. Rothblat G.H. The of cellular and lipoprotein cholesterol on the flux of cholesterol between and density Biol. Chem. Full Text PDF PubMed Google Scholar). was cholesterol-normal and -enriched ABCG1 cells. these cells were with and aqueous was essentially the pathway and aqueous diffusion was in cholesterol-normal and -enriched ABCG1 macrophages The contribution of ABCG1 was as the efflux from total efflux the contributions of aqueous ABCA1, and The efflux of cholesterol from macrophages in the atherosclerotic one of the of RCT G.F. Rader D.J. New insights into the regulation of HDL metabolism and reverse cholesterol transport.Circ. Res. 2005; 96: 1221-1232Crossref PubMed Scopus (828) Google Scholar). The regulation of the movement of cholesterol of macrophages is by the of extracellular and the cholesterol of the cells. studies have lipoproteins or apolipoproteins as cholesterol and have with of lipoproteins and In the present we the of enriching with cholesterol in of the serum lipoprotein composition and the of the various efflux pathways that have been identified in MPMs. we specifically on the efflux of the bidirectional flux of cholesterol that occurs when cells to The mechanisms cholesterol efflux to cholesterol which the of FC and cholesterol by a of different mechanisms Rothblat G.H. of cholesterol bidirectional flux between cells and Lipid Res. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). Our studies cholesterol-normal and cholesterol-enriched Fu5AH hepatoma cells and determined fractional efflux when these cells were to 15 of human serum. We that fractional efflux to the sera when the cells were with cholesterol cholesterol fractional efflux were to cholesterol efflux, was an in this for by efflux from an of the cell cholesterol The Fu5AH hepatoma cells in SR-BI B. de la M. Rothblat G.H. Tall A.R. Scavenger receptor density cellular cholesterol efflux.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and efflux from these cells occurs by the SR-BI pathway and a contribution by the aqueous diffusion pathway G.H. de la Llera-Moya M. G. Williams D.L. cholesterol of and Lipid Res. Full Text Full Text PDF PubMed Google Scholar). of these pathways for efflux to the level of HDL to which the cells and the between efflux and the shown in with that efflux from these hepatoma cells is closely linked to HDL and composition de la Llera-Moya M. Rothblat G.H. effects of HDL on cellular and cholesterol efflux.J. Lipid Res. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The fractional efflux with cholesterol-normal and -enriched cells is with a in which the for efflux upon In to the from the hepatoma cells, cholesterol of resulted in a in fractional efflux when these cells were to the 15 serum the efflux to cholesterol is a in efflux from the cells, with of this attributable to cell cholesterol The in fractional efflux upon cholesterol loading that the the contribution to efflux of pathways or of the relationships between efflux from cholesterol-normal and -enriched and HDL this between efflux from cholesterol-normal cells to and were all and to with Fu5AH cells However, when the was efflux with cholesterol-enriched the relationships between efflux and HDL were lost or reduced can to the of ABCA1, which lipid-free or lipid-poor apolipoproteins as cholesterol A.E. Rothblat G.H. Stoudt G. J. The correlation of levels with cholesterol efflux from various cell Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J.F. 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It can that free in human serum is and the correlation between efflux and level specifically to in this these we correlated the efflux from Fu5AH cells to the efflux with cholesterol-normal and cholesterol-enriched The between the efflux with the hepatoma is whereas the correlation with efflux from cholesterol-loaded is the that was upon cholesterol loading of we macrophages from or mice, in which ABCA1, or ABCG1 were quantitate the contributions of different efflux pathways in and we to ABCA1 and to efflux. The of efflux by cholesterol was determined with and MPMs. can from the removal of SR-BI had no effect on the fractional efflux from cholesterol-normal or -enriched cells. In addition, ABCA1, or ABCG1 had or no effect on efflux from cholesterol-normal cells. demonstrated that the mechanism for efflux from cholesterol-normal is aqueous from to of total efflux, whereas SR-BI or no contribution to efflux. to that for SR-BI was to ABCA1 to the fractional cholesterol efflux from The efflux was for cholesterol-normal and ABCA1 cells, was of efflux with the ABCA1 cells upon cholesterol The removal of ABCA1 had essentially no effect on total efflux when cell cholesterol levels were removal of the contribution of ABCA1 in cells reduced total efflux by 50%. that ABCA1 has or no on efflux from cholesterol-normal mediates a of the efflux that is stimulated when cholesterol The contribution of ABCG1 to total cholesterol efflux from was in a the ABCG1 cells, was a in efflux in the cholesterol-normal and cholesterol-enriched was essentially no ABCG1 contribution in cholesterol-normal cells and efflux or of the total efflux in cells, the in efflux with the ABCG1 macrophages a in efflux all pathways cholesterol-normal with cholesterol-normal and with in in all efflux mechanisms was in the SR-BI and ABCA1 cells and linked to a in which ABCG1 as an transporter that the plasma membrane with cholesterol that can by a of different W. Gelissen I.C. Gaus K. Kritharides L. Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages.Curr. Opin. Lipidol. 2006; 17: 247-257Crossref PubMed Scopus (226) Google Scholar). on the we that ABCA1-mediated efflux to human serum of the stimulated of total cholesterol efflux, with efflux for the 20% of the of efflux. It that aqueous diffusion is for the in efflux from upon cholesterol essentially all of this can to ABCA1 and ABCG1. ABCA1-mediated efflux is with lipid-poor acceptor particles and such particles a of the total HDL A. D. D. A. J. effects of plasma from human apolipoprotein on cholesterol efflux from macrophages and Fu5AH hepatoma Thromb. Vasc. Biol. 2002; PubMed Scopus Google Scholar, B. W. L. Role of free apolipoprotein A-I in cholesterol of density lipoprotein Thromb. Vasc. Biol. 17: PubMed Scopus Google Scholar). 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Rothblat G.H. the flux of cholesterol between cells and density lipoprotein in K. of the on of Scholar). in the level of efflux in receptor with different of and to different of mice, a efflux was can that the mechanism for cholesterol efflux to serum from cholesterol-normal is aqueous with a contribution from SR-BI a role in efflux from cholesterol-normal or cholesterol of a in the contribution of ABCA1 to total and ABCG1 to efflux from cholesterol-normal cells is upon cholesterol and between and of the total efflux to human serum. In the present we to human serum as an was for the levels of lipoproteins that present in in serum and of of human peripheral of cholesterol by HDL in Lipid Res. 2001; 42: Full Text Full Text PDF PubMed Google and the of lipoproteins to cell is with cells in in and of human serum to mouse cells, as a of the of that with on mouse cells S. of human serum on and of human and with Biol. Google Scholar, S. J. of human serum on in human Google Scholar). The contributions of the various pathways to cholesterol efflux with human serum. were in the contributions of the pathways when human serum from to The was a in the contributions of ABCA1 and ABCG1 as serum in the contribution of pathways as serum to ABCA1-mediated efflux L. A.E. M. P. P. S. Rothblat G.H. of apolipoprotein A-I on cassette transporter efflux of macrophage phospholipid and Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google whereas such as SR-BI and aqueous demonstrate M. Rothblat G.H. in stimulated cholesterol efflux from macrophages to Thromb. Vasc. Biol. 2000; PubMed Scopus Google Scholar). was by and from the of and and an HDL from