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• W2129578969 abstract "Cholesterol efflux from macrophage foam cells, a key step in reverse cholesterol transport, requires trafficking of cholesterol from intracellular sites to the plasma membrane. Sphingomyelin is a cholesterol-binding molecule that transiently exists with cholesterol in endosomes and lysosomes but is rapidly hydrolyzed by lysosomal sphingomyelinase (L-SMase), a product of the acid sphingomyelinase (ASM) gene. We therefore hypothesized that sphingomyelin hydrolysis by L-SMase enables cholesterol efflux by preventing cholesterol sequestration by sphingomyelin. Macrophages from wild-type and ASM knockout mice were incubated with [3H]cholesteryl ester-labeled acetyl-LDL and then exposed to apolipoprotein A-I or high density lipoprotein. In both cases, [3H]cholesterol efflux was decreased substantially in the ASM knockout macrophages. Similar results were shown for ASM knockout macrophages labeled long-term with [3H]cholesterol added directly to medium, but not for those labeled for a short period, suggesting defective efflux from intracellular stores but not from the plasma membrane. Cholesterol trafficking to acyl-coenzyme A:cholesterol acyltransferase (ACAT) was also defective in ASM knockout macrophages. Using filipin to probe cholesterol in macrophages incubated with acetyl-LDL, we found there was modest staining in the plasma membrane of wild-type macrophages but bright, perinuclear fluorescence in ASM knockout macrophages. Last, when wild-type macrophages were incubated with excess sphingomyelin to “saturate” L-SMase, [3H]cholesterol efflux was decreased. Thus, sphingomyelin accumulation due to L-SMase deficiency leads to defective cholesterol trafficking and efflux, which we propose is due to sequestration of cholesterol by sphingomyelin and possibly other mechanisms. This model may explain the low plasma high density lipoprotein found in ASM-deficient humans and may implicate L-SMase deficiency and/or sphingomyelin enrichment of lipoproteins as novel atherosclerosis risk factors. Cholesterol efflux from macrophage foam cells, a key step in reverse cholesterol transport, requires trafficking of cholesterol from intracellular sites to the plasma membrane. Sphingomyelin is a cholesterol-binding molecule that transiently exists with cholesterol in endosomes and lysosomes but is rapidly hydrolyzed by lysosomal sphingomyelinase (L-SMase), a product of the acid sphingomyelinase (ASM) gene. We therefore hypothesized that sphingomyelin hydrolysis by L-SMase enables cholesterol efflux by preventing cholesterol sequestration by sphingomyelin. Macrophages from wild-type and ASM knockout mice were incubated with [3H]cholesteryl ester-labeled acetyl-LDL and then exposed to apolipoprotein A-I or high density lipoprotein. In both cases, [3H]cholesterol efflux was decreased substantially in the ASM knockout macrophages. Similar results were shown for ASM knockout macrophages labeled long-term with [3H]cholesterol added directly to medium, but not for those labeled for a short period, suggesting defective efflux from intracellular stores but not from the plasma membrane. Cholesterol trafficking to acyl-coenzyme A:cholesterol acyltransferase (ACAT) was also defective in ASM knockout macrophages. Using filipin to probe cholesterol in macrophages incubated with acetyl-LDL, we found there was modest staining in the plasma membrane of wild-type macrophages but bright, perinuclear fluorescence in ASM knockout macrophages. Last, when wild-type macrophages were incubated with excess sphingomyelin to “saturate” L-SMase, [3H]cholesterol efflux was decreased. Thus, sphingomyelin accumulation due to L-SMase deficiency leads to defective cholesterol trafficking and efflux, which we propose is due to sequestration of cholesterol by sphingomyelin and possibly other mechanisms. This model may explain the low plasma high density lipoprotein found in ASM-deficient humans and may implicate L-SMase deficiency and/or sphingomyelin enrichment of lipoproteins as novel atherosclerosis risk factors. cholesteryl ester acyl-CoA:cholesterol acyltransferase apolipoprotein A-I acid sphingomyelinase bovine serum albumin Dulbecco's modified Eagle's medium fetal bovine serum high-density lipoprotein low-density lipoprotein lysosomal sphingomyelinase Niemann-Pick C phosphate-buffered saline phosphatidylserine sphingomyelinase scavenger receptor BI Cholesteryl ester (CE)1-loaded macrophages, or foam cells, are prominent features of atherosclerotic lesions and play important roles in lesion progression (1Ross R. Annu. Rev. Physiol. 1995; 57: 791-804Crossref PubMed Scopus (889) Google Scholar, 2Libby P. Clinton S.K. Curr. Opin. Lipidol. 1993; 4: 355-363Crossref Scopus (124) Google Scholar). During atherogenesis, intimal macrophages internalize atherogenic lipoproteins, including modified forms of LDL, that have been retained in the arterial subendothelium (1Ross R. Annu. Rev. Physiol. 1995; 57: 791-804Crossref PubMed Scopus (889) Google Scholar, 3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar, 4Williams K.J. Tabas I. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar). This event directly leads to esterification of cellular cholesterol by acyl-coenzyme A:cholesterolO-acyltransferase (ACAT), resulting in “foam cell” formation (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar, 5Brown M.S. Goldstein J.L. Annu. Rev. Biochem. 1983; 52: 223-261Crossref PubMed Google Scholar). Foam cell formation can be prevented or reversed by the process known as cellular cholesterol efflux (6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar). Cholesterol efflux is the initial step of reverse cholesterol transport, a process whereby excess cholesterol in peripheral cells is delivered to the liver for excretion (6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar). Thus, the elucidation of cellular molecules and pathways that facilitate and regulate cholesterol efflux is a major goal of research in the area of atherosclerosis.Atherogenic lipoproteins internalized by macrophages deliver their stores of cholesterol, which are mostly in the form of CE, to late endosomes and/or lysosomes (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar). Here, lysosomal acid lipase hydrolyzes the CE to free cholesterol, which is then transported by poorly defined mechanisms to various sites in the cell (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar). A major site of transport is the plasma membrane, and from there the cholesterol can be effluxed to extracellular acceptors, such as apoA-I and HDL, or transported to ACAT in the endoplasmic reticulum for re-esterification (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar, 6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar). Efflux to apoA-I involves the initial formation of phospholipid-apoA-I particles by ABCA1-mediated phospholipid efflux, followed by cholesterol efflux to these phospholipid-rich particles (7Wang N. Silver D.L. Thiele C. Tall A.R. J. Biol. Chem. 2001; 276: 23742-23747Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 8Fielding P.E. Nagao K. Hakamata H. Chimini G. Fielding C.J. Biochemistry. 2000; 39: 14113-14120Crossref PubMed Scopus (182) Google Scholar). Cholesterol efflux to HDL can be mediated by scavenger receptor type B1 (SR-B1) in those cell types that have relatively high levels of this receptor, such as human monocyte-derived macrophages, but another mechanism must be involved in cells that have very low expression of SR-B1, such as mouse peritoneal macrophages 2Y. Sun and A. R. Tall, unpublished data.2Y. Sun and A. R. Tall, unpublished data. (6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar, 9Ji Y. Jian B. Wang N. Sun Y. Moya M.L. Phillips M.C. Rothblat G.H. Swaney J.B. Tall A.R. J. Biol. Chem. 1997; 272: 20982-20985Crossref PubMed Scopus (631) Google Scholar, 10Rothblat G.H. Llera-Moya M. Atger V. Kellner-Weibel G. Williams D.L. Phillips M.C. J. Lipid Res. 1999; 40: 781-796Abstract Full Text Full Text PDF PubMed Google Scholar).Given that all pathways of cholesterol efflux require cholesterol transport to the plasma membrane, the identification of molecules mediating or regulating this transport process is an important goal. Thus far, only the molecules npc1, npc2 (HE1), and possibly lysobisphosphatidic acid have been shown to play a role in cholesterol transport to the plasma membrane, and the molecular mechanisms are poorly understood (11Liscum L. Klansek J.J. Curr. Opin. Lipidol. 1998; 9: 131-135Crossref PubMed Scopus (96) Google Scholar, 12Blanchette-Mackie E.J. Biochim. Biophys. Acta. 2000; 1486: 171-183Crossref PubMed Scopus (98) Google Scholar, 13Ory D.S. Biochim. Biophys. Acta. 2000; 1529: 331-339Crossref PubMed Scopus (119) Google Scholar, 14Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Science. 2000; 290: 2298-2301Crossref PubMed Scopus (689) Google Scholar, 15Kobayashi T. Beuchat M.H. Lindsay M. Frias S. Palmiter R.D. Sakuraba H. Parton R.G. Gruenberg J. Nat. Cell Biol. 1999; 1: 113-118Crossref PubMed Scopus (247) Google Scholar). We reasoned that another molecule, lysosomal sphingomyelinase (L-SMase), may also be involved in cholesterol transport from lysosomes to the plasma membrane. L-SMase, a product of the acid sphingomyelinase (ASM) gene, hydrolyzes sphingomyelin in late endosomes and lysosomes (16Schuchman E.H. Desnick R.J. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2601-2624Google Scholar). Because SM avidly binds cholesterol (17Slotte J.P. Chem. Phys. Lipids. 1999; 102: 13-27Crossref PubMed Scopus (174) Google Scholar, 18Ridgway N.D. Biochim. Biophys. Acta. 2000; 1484: 129-141Crossref PubMed Scopus (119) Google Scholar), we hypothesized that sphingomyelin hydrolysis by L-SMase enables cholesterol transport by preventing cholesterol sequestration by sphingomyelin. Of interest, humans with ASM deficiency (types A and B Niemann-Pick disease) have low plasma HDL levels (19Viana M.B. Giugliani R. Leite V.H. Barth M.L. Lekhwani C. Slade C.M. Fensom A. J. Med. Genet. 1990; 27: 499-504Crossref PubMed Scopus (38) Google Scholar, 20Worgall T.S. McGovern M.M. Jiang X.C. Berglund L. Shea S. Tabas I. Deckelbaum R.J. Circulation. 2001; 102: II-30Google Scholar), which could result from defective cholesterol efflux (cf. Ref. 21Tall A.R. Wang N. J. Clin. Invest. 2000; 106: 1205-1207Crossref PubMed Scopus (101) Google Scholar).In this context, we show herein that macrophages from ASM knockout mice, which lack L-SMase (22Horinouchi K. Erlich S. Perl D. Ferlinz K. Bisgaier C.L. Sandhoff K. Desnick R.J. Stewart C.L. Schuchman E.H. Nature Gen. 1995; 10: 288-293Crossref PubMed Scopus (406) Google Scholar, 23Otterbach B. Stoffel W. Cell. 1995; 81: 1053-1061Abstract Full Text PDF PubMed Scopus (189) Google Scholar), have a defect in cholesterol efflux to both apoA-I and HDL, a decrease in the esterification of cellular cholesterol, and an accumulation of cholesterol in perinuclear vesicles. Moreover, a defect in cholesterol efflux was also observed in wild-type macrophages that internalized a large amount of sphingomyelin. These data support the hypothesis that intracellular accumulation of sphingomyelin due to L-SMase deficiency or to internalization of excess sphingomyelin leads to cholesterol sequestration and defective cholesterol trafficking and efflux.DISCUSSIONThe results of this study have implications ranging from the basic cellular biology of lipid trafficking to the important physiologic area of macrophage cholesterol efflux in atherosclerosis. The mechanisms and regulation of cholesterol trafficking from lysosomes to the plasma membrane are poorly understood. Data from mutant cells indicate that the proteins npc1 and npc2 (HE1) have functions along this pathway (11Liscum L. Klansek J.J. Curr. Opin. Lipidol. 1998; 9: 131-135Crossref PubMed Scopus (96) Google Scholar, 12Blanchette-Mackie E.J. Biochim. Biophys. Acta. 2000; 1486: 171-183Crossref PubMed Scopus (98) Google Scholar, 13Ory D.S. Biochim. Biophys. Acta. 2000; 1529: 331-339Crossref PubMed Scopus (119) Google Scholar, 14Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Science. 2000; 290: 2298-2301Crossref PubMed Scopus (689) Google Scholar, 15Kobayashi T. Beuchat M.H. Lindsay M. Frias S. Palmiter R.D. Sakuraba H. Parton R.G. Gruenberg J. Nat. Cell Biol. 1999; 1: 113-118Crossref PubMed Scopus (247) Google Scholar), and antibody experiments may suggest a role for the lipid lysobisphosphatidic acid (15Kobayashi T. Beuchat M.H. Lindsay M. Frias S. Palmiter R.D. Sakuraba H. Parton R.G. Gruenberg J. Nat. Cell Biol. 1999; 1: 113-118Crossref PubMed Scopus (247) Google Scholar). The mechanism of action of these molecules, however, is not known. The idea that the sphingomyelin content of lysosomes could be an important regulatory factor is based upon the ability of this lipid to bind cholesterol (17Slotte J.P. Chem. Phys. Lipids. 1999; 102: 13-27Crossref PubMed Scopus (174) Google Scholar, 18Ridgway N.D. Biochim. Biophys. Acta. 2000; 1484: 129-141Crossref PubMed Scopus (119) Google Scholar). Indeed, Aviram and colleagues (42Maor I. Mandel H. Aviram M. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1378-1387Crossref PubMed Scopus (65) Google Scholar) suggested that the ability of oxysterols in oxidized LDL to inhibit L-SMase in murine and human macrophages may account for the accumulation of lysosomal FC under these conditions, although molecular genetic proof was not provided to support their hypothesis. In contrast, cholesterol esterification and trafficking to the plasma membrane were reported as being normal in several lines of fibroblasts from humans with types A and B Niemann-Pick disease (43Liscum L. Ruggiero R.M. Faust J.R. J. Cell Biol. 1989; 108: 1625-1636Crossref PubMed Scopus (241) Google Scholar,44Pentchev P.G. Comly M.E. Kruth H.S. Vanier M.T. Wenger D.A. Patel S. Brady R.O. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 8247-8251Crossref PubMed Scopus (320) Google Scholar). It is possible that the human fibroblasts data could have been influenced by residual L-SMase activity in these cells (16Schuchman E.H. Desnick R.J. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2601-2624Google Scholar) or by inherent differences in cholesterol trafficking between fibroblasts and macrophages.Our working hypothesis states that defective cholesterol trafficking in ASM knockout macrophages is due to sequestration of cholesterol by sphingomyelin. This model can readily explain the acetyl-LDL-cholesterol trafficking data, because acetyl-LDL-derived cholesterol traffics through lysosomes, which is a known site of SM accumulation in ASM-deficient cells (16Schuchman E.H. Desnick R.J. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2601-2624Google Scholar). With regard to those experiments in which the macrophages were labeled by long-term incubation with [3H]cholesterol-containing medium, it is possible that this method also labels lysosomal pools of cholesterol. However, when a similar method was used in Chinese hamster ovary cells to incorporate the fluorescent sterol dehydroergosterol or cholesterol itself, followed by filipin labeling, the major sites of accumulation were the endosomal recycling compartment and the trans-Golgi network (35Mukherjee S. Zha X. Tabas I. Maxfield F.R. Biophys. J. 1998; 75: 1915-1925Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar). If this were the case in macrophages, it would indicate defective trafficking and efflux of non-lysosomal cholesterol and therefore might imply that ASM deficiency leads to SM accumulation in the endosomal recycling compartment, trans-Golgi network, or other nonlysosomal sites (cf. Refs. 15Kobayashi T. Beuchat M.H. Lindsay M. Frias S. Palmiter R.D. Sakuraba H. Parton R.G. Gruenberg J. Nat. Cell Biol. 1999; 1: 113-118Crossref PubMed Scopus (247) Google Scholar, 34Lange Y. Ye J. Rigney M. Steck T.L. J. Biol. Chem. 2000; 275: 17468-17475Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, and 45Cruz J.C. Sugii S. Yu C. Chang T.Y. J. Biol. Chem. 2000; 275: 4013-4021Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). This idea might also provide an explanation for our finding that not all of the acetyl-LDL-derived free cholesterol that accumulates in ASM-deficient macrophages is in dextran-containing late endosomes and lysosomes (Fig.6). Detailed sphingomyelin localization studies in ASM knockout macrophages will be required to sort out these possibilities.One must also consider the possibility that direct sequestration of cholesterol by SM is not the only mechanism behind defective cholesterol trafficking in ASM knockout macrophages. In this context, there is evidence that initial accumulation of unesterified cholesterol in lysosomes or late endosomes can lead to secondary defects in vesicular trafficking. For example, the defective trafficking of lactosyl ceramide in ASM-deficient fibroblasts and the defects in late endosomal tubulovesicular trafficking observed in NPC cells can be corrected by cellular cholesterol depletion (46Puri V. Watanabe R. Dominguez M. Sun X. Wheatley C.L. Marks D.L. Pagano R.E. Nat. Cell Biol. 1999; 1: 386-388Crossref PubMed Scopus (253) Google Scholar, 47Zhang M. Dwyer N.K. Neufeld E.B. Love D.C. Cooney A. Comly M. Patel S. Watari H. Strauss III, J.F. Pentchev P.G. Hanover J.A. Blanchette-Mackie E.J. J. Biol. Chem. 2001; 276: 3417-3425Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar), and defects in the trafficking of sucrose can be induced in normal cells by cellular cholesterol enrichment (48Zhang M. Dwyer N.K. Love D.C. Cooney A. Comly M. Neufeld E. Pentchev P.G. Blanchette-Mackie E.J. Hanover J.A. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4466-4471Crossref PubMed Scopus (118) Google Scholar). Thus, it is possible that abnormal SM accumulation in ASM knockout macrophages causes an initial accumulation of FC in lysosomes or some other site, but that at least some of the trafficking and efflux defects observed in our studies are due to membrane vesiculation defects secondary to this initial cholesterol accumulation.The cholesterol trafficking defect described in this report is similar to that which occurs in fibroblasts from patients with Niemann-Pick C (NPC) disease (11Liscum L. Klansek J.J. Curr. Opin. Lipidol. 1998; 9: 131-135Crossref PubMed Scopus (96) Google Scholar, 12Blanchette-Mackie E.J. Biochim. Biophys. Acta. 2000; 1486: 171-183Crossref PubMed Scopus (98) Google Scholar, 13Ory D.S. Biochim. Biophys. Acta. 2000; 1529: 331-339Crossref PubMed Scopus (119) Google Scholar, 14Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Science. 2000; 290: 2298-2301Crossref PubMed Scopus (689) Google Scholar). Moreover, recent work from our groups has shown that macrophages from NPC mice have a defect in cholesterol trafficking (49Chen W. Sun Y. Welch C. Gorelik A. Leventhal A.R. Tabas I. Tall A.R. J. Biol. Chem. 2001; 276: 43564-43569Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Although the molecular etiologies are distinct, important interrelationships between the cholesterol trafficking defects in ASM deficiency and Niemann-Pick C disease may exist. For example, Reaganet al. (50Reagan Jr., J.W. Hubbert M.L. Shelness G.S. J. Biol. Chem. 2000; 275: 38104-38110Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar) made the interesting observation that lysosomal cholesterol accumulation in Chinese hamster ovary cells induced by either the NPC mutation or progesterone causes a decrease in the enzymatic activity of L-SMase. Therefore, in view of our data, it is possible that the cholesterol trafficking defects in NPC cells and progesterone-treated cells may be amplified by secondary inhibition of L-SMase.The findings in this report may have important implications for foam cell biology. Macrophages in advanced lesions are known to accumulate large amount of free cholesterol, much of which appears to be in lysosomes (51Lundberg B. Atherosclerosis. 1985; 56: 93-110Abstract Full Text PDF PubMed Scopus (149) Google Scholar, 52Small D.M. Bond M.G. Waugh D. Prack M. Sawyer J.K. J. Clin. Invest. 1984; 73: 1590-1605Crossref PubMed Scopus (144) Google Scholar, 53Rapp J.H. Connor W.E. Lin D.S. Inahara T. Porter J.M. J. Lipid Res. 1983; 24: 1329-1335Abstract Full Text PDF PubMed Google Scholar, 54Shio H. Haley N.J. Fowler S. Lab. Invest. 1979; 41: 160-167PubMed Google Scholar, 55Tangirala R.K. Mahlberg F.H. Glick J.M. Jerome W.G. Rothblat G.H. J. Biol. Chem. 1993; 268: 9653-9660Abstract Full Text PDF PubMed Google Scholar). On the one hand, it is possible that exposure of these macrophages to oxidized LDL or oxysterols, by inhibiting L-SMase (42Maor I. Mandel H. Aviram M. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1378-1387Crossref PubMed Scopus (65) Google Scholar), or SM-rich lipoproteins, by “saturating” L-SMase (see Fig.6), may contribute to this event. Regarding this latter possibility, Jiang et al. (56Jiang X.C. Paultre F. Pearson T.A. Reed R.G. Francis C.K. Lin M. Berglund L. Tall A.R. Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2614-2618Crossref PubMed Scopus (304) Google Scholar) recently found that a high plasma SM level is an independent risk factor for coronary artery disease in humans. On the other hand, the accumulation of lysosomal cholesterol, even if caused by another process, might be expected to secondarily inhibit L-SMase (50Reagan Jr., J.W. Hubbert M.L. Shelness G.S. J. Biol. Chem. 2000; 275: 38104-38110Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar), which could further exacerbate the accumulation of lysosomal cholesterol and inhibit cholesterol efflux.The findings in this study raise additional questions related to lipoprotein abnormalities and atherosclerotic risk in humans with ASM deficiency (types A and B Niemann-Pick disease). These subjects have markedly low plasma HDL levels (19Viana M.B. Giugliani R. Leite V.H. Barth M.L. Lekhwani C. Slade C.M. Fensom A. J. Med. Genet. 1990; 27: 499-504Crossref PubMed Scopus (38) Google Scholar, 20Worgall T.S. McGovern M.M. Jiang X.C. Berglund L. Shea S. Tabas I. Deckelbaum R.J. Circulation. 2001; 102: II-30Google Scholar). Given that low plasma HDL can result from defective cellular cholesterol efflux (21Tall A.R. Wang N. J. Clin. Invest. 2000; 106: 1205-1207Crossref PubMed Scopus (101) Google Scholar), our current data may provide a mechanism that contributes to this lipoprotein abnormality. Regarding atherosclerotic risk, one must focus on type B Niemann-Pick patients, who survive to adulthood due to low levels of residual ASM activity, and type A or type B obligate heterozygotes, who are reported to be “normal” (16Schuchman E.H. Desnick R.J. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2601-2624Google Scholar). In considering the potential atherogenic effects of L-SMase deficiency in these subjects, it is interesting to consider that the ASM gene also gives rise to secretory SMase (57Tabas I. Chem. Phys. Lipids. 1999; 102: 131-139Crossref PubMed Scopus (96) Google Scholar). Because secretory SMase promotes the subendothelial aggregation and retention of lipoproteins, leading to enhanced foam cell formation, S-SMase deficiency, unlike L-SMase deficiency, may decrease cholesterol accumulation in lesional macrophages (57Tabas I. Chem. Phys. Lipids. 1999; 102: 131-139Crossref PubMed Scopus (96) Google Scholar). Therefore, while the deficiency of S-SMase in these subjects might be protective, defective L-SMase activity, by inhibiting cholesterol efflux from lesional macrophages and possibly by leading to low HDL levels, may promote atherosclerotic vascular disease. Cholesteryl ester (CE)1-loaded macrophages, or foam cells, are prominent features of atherosclerotic lesions and play important roles in lesion progression (1Ross R. Annu. Rev. Physiol. 1995; 57: 791-804Crossref PubMed Scopus (889) Google Scholar, 2Libby P. Clinton S.K. Curr. Opin. Lipidol. 1993; 4: 355-363Crossref Scopus (124) Google Scholar). During atherogenesis, intimal macrophages internalize atherogenic lipoproteins, including modified forms of LDL, that have been retained in the arterial subendothelium (1Ross R. Annu. Rev. Physiol. 1995; 57: 791-804Crossref PubMed Scopus (889) Google Scholar, 3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar, 4Williams K.J. Tabas I. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar). This event directly leads to esterification of cellular cholesterol by acyl-coenzyme A:cholesterolO-acyltransferase (ACAT), resulting in “foam cell” formation (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar, 5Brown M.S. Goldstein J.L. Annu. Rev. Biochem. 1983; 52: 223-261Crossref PubMed Google Scholar). Foam cell formation can be prevented or reversed by the process known as cellular cholesterol efflux (6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar). Cholesterol efflux is the initial step of reverse cholesterol transport, a process whereby excess cholesterol in peripheral cells is delivered to the liver for excretion (6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar). Thus, the elucidation of cellular molecules and pathways that facilitate and regulate cholesterol efflux is a major goal of research in the area of atherosclerosis. Atherogenic lipoproteins internalized by macrophages deliver their stores of cholesterol, which are mostly in the form of CE, to late endosomes and/or lysosomes (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar). Here, lysosomal acid lipase hydrolyzes the CE to free cholesterol, which is then transported by poorly defined mechanisms to various sites in the cell (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar). A major site of transport is the plasma membrane, and from there the cholesterol can be effluxed to extracellular acceptors, such as apoA-I and HDL, or transported to ACAT in the endoplasmic reticulum for re-esterification (3Tabas I. Biochim. Biophys. Acta. 2000; 1529: 164-174Crossref PubMed Scopus (118) Google Scholar, 6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar). Efflux to apoA-I involves the initial formation of phospholipid-apoA-I particles by ABCA1-mediated phospholipid efflux, followed by cholesterol efflux to these phospholipid-rich particles (7Wang N. Silver D.L. Thiele C. Tall A.R. J. Biol. Chem. 2001; 276: 23742-23747Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar, 8Fielding P.E. Nagao K. Hakamata H. Chimini G. Fielding C.J. Biochemistry. 2000; 39: 14113-14120Crossref PubMed Scopus (182) Google Scholar). Cholesterol efflux to HDL can be mediated by scavenger receptor type B1 (SR-B1) in those cell types that have relatively high levels of this receptor, such as human monocyte-derived macrophages, but another mechanism must be involved in cells that have very low expression of SR-B1, such as mouse peritoneal macrophages 2Y. Sun and A. R. Tall, unpublished data.2Y. Sun and A. R. Tall, unpublished data. (6Tall A.R. Eur. Heart J. 1998; 19: A31-A35PubMed Google Scholar, 9Ji Y. Jian B. Wang N. Sun Y. Moya M.L. Phillips M.C. Rothblat G.H. Swaney J.B. Tall A.R. J. Biol. Chem. 1997; 272: 20982-20985Crossref PubMed Scopus (631) Google Scholar, 10Rothblat G.H. Llera-Moya M. Atger V. Kellner-Weibel G. Williams D.L. Phillips M.C. J. Lipid Res. 1999; 40: 781-796Abstract Full Text Full Text PDF PubMed Google Scholar). Given that all pathways of cholesterol efflux require cholesterol transport to the plasma membrane, the identification of molecules mediating or regulating this transport process is an important goal. Thus far, only the molecules npc1, npc2 (HE1), and possibly lysobisphosphatidic acid have been shown to play a role in cholesterol transport to the plasma membrane, and the molecular mechanisms are poorly understood (11Liscum L. Klansek J.J. Curr. Opin. Lipidol. 1998; 9: 131-135Crossref PubMed Scopus (96) Google Scholar, 12Blanchette-Mackie E.J. Biochim. Biophys. Acta. 2000; 1486: 171-183Crossref PubMed Scopus (98) Google Scholar, 13Ory D.S. Biochim. Biophys. Acta. 2000; 1529: 331-339Crossref PubMed Scopus (119) Google Scholar, 14Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Science. 2000; 290: 2298-2301Crossref PubMed Scopus (689) Google Scholar, 15Kobayashi T. Beuchat M.H. Lindsay M. Frias S. Palmiter R.D. Sakuraba H. Parton R.G. Gruenberg J. Nat. Cell Biol. 1999; 1: 113-118Crossref PubMed Scopus (247) Google Scholar). We reasoned that another molecule, lysosomal sphingomyelinase (L-SMase), may also be involved in cholesterol transport from lysosomes to the plasma membrane. L-SMase, a product of the acid sphingomyelinase (ASM) gene, hydrolyzes sphingomyelin in late endosomes and lysosomes (16Schuchman E.H. Desnick R.J. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York1995: 2601-2624Google Scholar). Because SM avidly binds cholesterol (17Slotte J.P. Chem. Phys. Lipids. 1999; 102: 13-27Crossref" @default.
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• W2129578969 cites W1507071836 @default.
• W2129578969 cites W1508282658 @default.
• W2129578969 cites W1606057223 @default.
• W2129578969 cites W1608305635 @default.
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• W2129578969 cites W1967516512 @default.
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• W2129578969 cites W1974511187 @default.
• W2129578969 cites W1974864595 @default.
• W2129578969 cites W1976058911 @default.
• W2129578969 cites W1976072602 @default.
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• W2129578969 cites W1992898297 @default.
• W2129578969 cites W1996483226 @default.
• W2129578969 cites W2001392137 @default.
• W2129578969 cites W2012008185 @default.
• W2129578969 cites W2016884991 @default.
• W2129578969 cites W2017956091 @default.
• W2129578969 cites W2033909730 @default.
• W2129578969 cites W2037821728 @default.
• W2129578969 cites W2038735303 @default.
• W2129578969 cites W2042213171 @default.
• W2129578969 cites W2046493105 @default.
• W2129578969 cites W2049312906 @default.
• W2129578969 cites W2053203314 @default.
• W2129578969 cites W2054680310 @default.
• W2129578969 cites W2062030534 @default.
• W2129578969 cites W2062058915 @default.
• W2129578969 cites W2066483219 @default.
• W2129578969 cites W2067397226 @default.
• W2129578969 cites W2075127544 @default.
• W2129578969 cites W2077252911 @default.
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• W2129578969 cites W2099064770 @default.
• W2129578969 cites W2108660588 @default.
• W2129578969 cites W2112925983 @default.
• W2129578969 cites W2117566834 @default.
• W2129578969 cites W2119324119 @default.
• W2129578969 cites W2120626817 @default.
• W2129578969 cites W2126500773 @default.
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• W2129578969 cites W2134271396 @default.
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• W2129578969 cites W2151426663 @default.
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• W2129578969 cites W2336481777 @default.
• W2129578969 cites W2412232087 @default.
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