Skip to main content
SpringerLink
Log in

ATP binding cassette transporter A1 - key roles in cellular lipid transport and atherosclerosis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

ATP-binding cassette transporter A1 (ABCA1) was recently recognized as the mutant molecule responsible for Tangier disease with low HDL levels, accumulation of cholesteryl esters in tissues, and increased risk of cardiovascular disease. Extensive studies for the past 2 years have recognized the critical role of ABCA1 in cholesterol and phospholipid trafficking. Since the removal of cholesterol from tissues is a key step in the prevention of atherosclerosis, significant attention has been focused on this molecule. Natural ABCA1 mutations in Tangier disease (TD) patients and WHAM chickens together with induced mutation in ABCA1 knock-out mice unequivocally established the important role of ABCA1 in maintaining circulating HDL levels and promoting cholesterol efflux from the arterial wall. Mice lacking ABCA1 showed similar phenotypes observed in Tangier disease patients with low levels of HDL. Further understanding of the roles of ABCA1 in lipid transport and atherosclerosis became clear from studies with ABCA1 transgenic mice. These mice showed enhanced cholesterol efflux from macrophages and reduced atherosclerotic lesion formation. The promoter of the ABCA1 gene has been mapped to a large extent, with the exception of cAMP response element. The present review summarizes recent developments on the role of ABCA1 in cholesterol efflux and prevention of atherosclerosis. Given the antiatherogenic properties of ABCA1, this molecule can serve as an appropriate target for developing drugs to treat individuals with low levels of HDL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bailey JM: Lipid metabolism in cultured cells IV: Serum alpha globulins and cellular cholesterol exchange. Exp Cell Res 37: 175–182, 1965

    Google Scholar 

  2. Glomset JA: The plasma lecithin:cholesterol acyltransferase reaction. J Lipid Res 9: 155–167, 1968

    Google Scholar 

  3. Kilsdonk EPC, Yancey P, Stoudt G, Bangerter FW, Johnson WJ, Phillipis MC, Rothblat GH: Cellular cholesterol efflux mediated by cyclodextrins. J Biol Chem 270: 17250–17256, 1995

    Google Scholar 

  4. Rothblat GH, de la Llera-Moya M, Atger V, Kellner-Weibel G, Williams DL, Phillipis MC: Cell cholesterol efflux: Integration of old and new observations provides new insights. J Lipid Res 40: 781–796, 1999

    Google Scholar 

  5. Li Q, Yakoyama S: Independent regulation of cholesterol incorporation into free apolipoprotein-mediated cellular lipid efflux in rat vascular smooth muscle cells. J Biol Chem 270: 26216–26223, 1995

    Google Scholar 

  6. Oram JF, Yakoyama S: Apolipoprotein-mediated removal of cellular cholesterol and phospholipids. J Lipid Res 9: 155–167, 1996

    Google Scholar 

  7. Johnson WJ, Mahlberg FH, Rothblat GH, Phillipis MC: Cholesterol transport between cells and high density lipoprotein. Biochim Biophys Acta 1085: 273–298, 1991

    Google Scholar 

  8. Fournier N, Llera-Moya MDL, Burkey B, Swaney J, Peterniti J Jr, Moatti N, Atger V, Rothblat GH: The role of HDL phospholipids in efflux of cell cholesterol to whole serum: Studies with human apoA1 transgenic rats. J Lipid Res 37: 1704–1711, 1996

    Google Scholar 

  9. Bielicki JK, Johnson WJ, Weinberg RB, Glick JM, Rothblat GH: Efflux of lipid from fibroblasts to apolipoproteins: Dependence on elevated levels of cellular unesterified cholesterol. J Lipid Res 33: 1699–1710, 1992

    Google Scholar 

  10. Smith JD, Miyata M, Ginsberg M, Grigaux C, Shmookeler E, Plump AS: Cyclic AMP induces apolipoprotein E binding activity and promoted cholesterol efflux from a macrophage cell line to apolipoprotein acceptors. J Biol Chem 271: 30647–30655, 1996

    Google Scholar 

  11. Sakr SW, Williams DL, Stoudt GW, Phillipis MC, Rothblat GH: Cholesterol efflux from macrophages. Biochim Biophys Acta 1438: 85–98, 1999

    Google Scholar 

  12. Li Q, Czamecka H, Yokoyama S: Involvement of a cellular surface factor(s) in lipid-free apolipoprotein-mediated cellular cholesterol efflux. Biochim Biophys Acta 1259: 227–234, 1995

    Google Scholar 

  13. Mendez AJ, Oram JF: Limited proteolysis of high density lipoprotein abolished its interaction with cell-surface binding sites that promote cholesterol efflux. Biochim Biophys Acta 1346: 285–299, 1997

    Google Scholar 

  14. Sakata N, Phillipis TE, Dixon JL: Distribution, transport, and degradation of apolipoprotein B-100 in HepG2 cells. J Lipid Res 42: 1947–1958, 2001

    Google Scholar 

  15. Adeli K, Wettesten M, Asp L, Mohammadi A, Macri J, Olofsson SO: Intracellular assembly and degradation of apolipoprotein B-100–containing lipoproteins in digitonin-permeabilized HepG2 cells. J Biol Chem 272: 5031–5039, 1997

    Google Scholar 

  16. Srivastava RAK, Srivastava N, Averna M, Cefalu AB, Schonfeld G: Molecular bases of low production rates of apolipoprotein B-100 and truncated apoB-82 in a mutant HepG2 cell line generated by targeted modification of the apolipoprotein B gene. J Lipid Res 40: 901–912, 1999

    Google Scholar 

  17. Attie AD, Brooks-Wilson A, Gray-Keller ME, Zhang LH, Tebon A, Mulligan J, Bitgood JJ, Cook ME, Kastelein JJ, Hayden MR: Circulation 102: II-312, 2000

    Google Scholar 

  18. Srivastava RAK, Srivastava N: High density lipoprotein, apolipoprotein A1, and coronary artery disease. Mol Cell Biochem 209: 131–144, 2000

    Google Scholar 

  19. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, Dam MV, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Csherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Hayden MR: Mutations in ABCA1 in Tangier disease and familial high density lipoprotein deficiency. Nat Genet 22: 336–345, 1999

    Google Scholar 

  20. Bodzioch M, Orso M, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G: The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22: 347–351, 1999

    Google Scholar 

  21. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assman G: Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22: 352–355, 1999

    Google Scholar 

  22. Remaley AT, Stonik JA, Demosky SJ, Neufeld EB, Bocharov AV, Vishnyakova TG, Eggerman TL, Patterson AP, Duverger NJ, Santamarina-Fojo S, Brewer HB Jr: Apolipoprotein specificity for lipid efflux by the human ABCA1 transporter. Biochem Biophys Res Commun 280: 818–823, 2001

    Google Scholar 

  23. Remaley AT, Thomas F, Stonik J, Demosky SJ Jr, Neufeld EB, Bocharov AV, Vishnyakova TG, Patterson AP, Eggerman T, Santamarina-Fojo S, Brewer HB Jr: ABCA1 transporter dependent and independent lipid efflux to synthetic peptide acceptors. Abstract #709. Scientific Session of the American Heart Association, November, 2001

  24. Oram JF, Lawn RM, Garvin MR, Wade DP: ABCA1 is the cyclic AMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem 275: 34508–34511, 2000

    Google Scholar 

  25. Klein I, Sarkadi B, Varadi A: An inventory of the human ABC proteins. Biochim Biophys Acta 1461: 237–262, 1999

    Google Scholar 

  26. Kielar D, Dietmaier W, Langmann T, Aslanidis C, Probst M, Naruszewicz M, Schmitz G: Rapid quantification of human ABCA1 mRNA in various cell types and tissues by real-time reverse transcription-PCR. Clin Chem 47: 2089–2097, 2001

    Google Scholar 

  27. Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF: The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Res 104: R25–R31, 1999

    Google Scholar 

  28. Heyden M, Kastelein J, Attie A: Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J Lipid Res 42: 1717–1726, 2001

    Google Scholar 

  29. Orso E, Broccardo C, Kaminiski WE, Bottcher A, Liebisch G, Drobnik W, Gotz A, Chambenoit O, Diedrich W, Langmann T, Spruss T, Luciani MF, Rothe G, Lackner KJ, Chimini G, Schmitz G: Transport of lipids from golgi to plasma membrane is defective in Tangier disease patients and Abc1–deficient mice. Nat Genet 24: 192–196, 2000

    Google Scholar 

  30. McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, Wet JD, Broccardo C, Chimini G, Francone OL: High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci USA 97: 4245–4350, 2000

    Google Scholar 

  31. Christiansen-Weber TA, Voland JR, Wu Y, Ngo K, Roland BL, Nguyen S, Peterson PA, Fung-Leung WP: Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high density lipoprotein cholesterol deficiency. Am J Pathol 157: 1017–1029, 2000

    Google Scholar 

  32. Acton S, Rigotti A, Landschulz K, Xu S, Hobbs H, Krieger M: Identification of scavenger receptor SR-B1 as a high density lipoprotein receptor. Science 271: 518–520, 1996

    Google Scholar 

  33. Oram JF, Vaughan AM, Stocker R: ATP-binding cassette transporter A1 mediates cellular secretion of α-tocopherol. J Biol Chem 276: 39898–39902, 2001

    Google Scholar 

  34. Wang N, Silver DL, Costet P, Tall AR: Specific binding of apoA1 enhanced cholesterol efflux and altered plasma membrane morphology in cells expressing ABC1. J Biol Chem 275: 33053–33058, 2000

    Google Scholar 

  35. Remaley AT, Rust S, Rosier M, Knapper C, Naudin L, Broccardo C, Peterson KM, Koch C, Arnould I, Pradesh C, Duverger N, Funke H, Assmann G, Dinger M, Dean M, Chimini G, Santamarina-Fojo S, Fredrickson DS, Denefle P, Brewer HB Jr: Human ATP-binding cassette transporter 1 (ABC1): Genomic organization and identification of the genetic defect in the original Tangier disease kindred. Proc Natl Acad Sci USA 96: 12685–12690, 1999

    Google Scholar 

  36. Cavalier LB, Qui Y, Bielicki JK, Afzal V, Cheng J, Rubin EM: Regulation and activity of the human ABCA1 gene in transgenic mice. J Biol Chem 276: 18046–18051, 2001

    Google Scholar 

  37. Singaraja RR, Bocher V, James ER, Clee SM, Zhang L, Leavitt BR, Tan B, Brooks-Wilson A, Kwok A, Bissada N, Yang Y, Liu G, Tafuri SR, Fievet C, Wellington CL, Staels B, Hayden MR: Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and apoA1–dependent efflux stimulated by an internal promoter containing liver X receptor response element in intron 1. J Biol Chem 276: 33969–33979, 2001

    Google Scholar 

  38. Vaisman BL, Lambert G, Amar M, Joyce C, Ito T, Shamburek RD, Cain WJ, Fruchart-Najib J, Neufeld ED, Remaley AT, Brewer HB Jr, Santamarina-Fojo S: ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice. J Clin Res 108: 303–309, 2001

    Google Scholar 

  39. Srivastava RAK, Jiao S, Tang J, Pfleger B, Kitchens RT, Schonfeld G: In vivo regulation of low density lipoprotein receptor and apolipoprotein B gene expression by dietary fat and cholesterol in inbred strains of mice. Biochim Biophys Acta 1086: 29–43, 1991

    Google Scholar 

  40. Srivastava RAK, Tang J, Krul ES, Pfleger BA, Kitchens RT, Schonfeld G: Dietary fatty acids and cholesterol differ in their effects on the in vivo regulation of apoA1 and apoAII gene expression in inbred strains of mice. Biochim Biophys Acta 1125: 251–261, 1992

    Google Scholar 

  41. Srivastava RAK, Srivastava N, Averna M: Dietary cholate lowers plasma levels of mouse and human apolipoprotein A1 primarily via a transcriptional mechanism. Eur J Biochem 267: 4272–4280, 2000

    Google Scholar 

  42. Srivastava RAK, Averna M, Srivastava N, Pape ME: Dietary cholate increases plasma levels of apolipoprotein B in mice by posttranscriptional mechanisms. Intern J Biochem Cell Biol (Lond) 33: 1215–1226, 2001

    Google Scholar 

  43. Claudel T, Duez H, Torra IP, Fruchart J, Staels B: Bile acids suppresses human apolipoprotein A-I gene expression via a negative response element for the nuclear receptor FXR. Abstract 1399, American Heart Association's Scientific Meeting, Anaheim, November, 2001

  44. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ: Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731–744, 2000

    Google Scholar 

  45. Baroukh N, Ostos MA, Vergnes L, Recalde D, Staels B, Fruchart J, Ochoa A, Castro G, Zakin MM: Expression of human apolipoprotein AI/CIII/AIV gene cluster in mice reduces atherogenesis in response to a high fat-high cholesterol diet. FEBS Lett 502: 16–20, 2001

    Google Scholar 

  46. Srivastava RAK, Srivastava N, Averna M, Lin RC, Korach K, Lubahn D, Schonfeld G: Regulation of apolipoprotein E gene expression by estrogen occurs by translational mechanism via estrogen receptormediated pathway. J Biol Chem 272: 33360–33366, 1997

    Google Scholar 

  47. Repa JJ, Turley SD, Lobaccaro JMA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ: Regulation of absorption and ABC1–mediated efflux of cholesterol by RXR heterodimers. Science 289: 1524–1529, 2000

    Google Scholar 

  48. Haghpassand M, Bourassa PK, Francone OL, Aiello RJ: Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J Clin Res 108: 1315–1320, 2001

    Google Scholar 

  49. Abe-Domae S, Suzuki S, Wada Y: Characterization of apolipoproteinmediated HDL generation induced by cAMP in a murine macrophage cell line. Biochemistry 39: 11092–11099, 2000

    Google Scholar 

  50. Takahashi Y, Miyata M, Zheng P: Identification of cAMP analog inducible genes in RAW264 macrophages. Biochim Biophys Acta 1492: 385–394, 2000

    Google Scholar 

  51. Langmann T, Klucken J, Reil M: Molecular cloning of the human ATPbinding cassette transporter 1 (hABC1): Evidence for sterol-dependent regulation in macrophages. Biochem Biophys Res Commun 257: 29–33, 1999

    Google Scholar 

  52. Costel P, Luo Y, Wang N, Tall AR: Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275: 28240–28245, 2000

    Google Scholar 

  53. Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG: 27–hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276: 38378–38387, 2001

    Google Scholar 

  54. Venkateshwaran A, Laffitte BA, Joseph SB: Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA 97: 12097–12102, 2000

    Google Scholar 

  55. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB Jr, Fruchart JC, Clavey V, Staels B: PPAR-α and PPAR-α activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 7: 53–58, 2001

    Google Scholar 

  56. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P: A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7: 161–171, 2001

    Google Scholar 

  57. Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, Collins JL, Tontonoz P: Autoregulation of the human liver X receptor alpha promoter. Mol Cell Biol 22: 7558–7568, 2001

    Google Scholar 

  58. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM: A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 98: 5306–5311, 2001

    Google Scholar 

  59. Panousis CG, Zuckerman SH: Interferon gamma induces down regulation of Tangier disease gene (ATP-binding cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc Biol 20: 1565–1571, 2000

    Google Scholar 

  60. Gan X, Kaplan R, Menke JG, MacNaul K, Chen Y, Sparrow CP, Zhou G, Wright SD, Cai T: Dual mechanisms of ABCA1 regulation by geranylgeranyl pyrophosphate. J Biol Chem 276: 48702–48708, 2001

    Google Scholar 

  61. Wang Y, Oram JF: Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1. J Biol Chem 277: 5692–5697, 2002

    Google Scholar 

  62. Reaven GM, Chen YD: Role of abnormal free fatty acid metabolism in the development of non-insulin-dependent diabetes mellitus. Am J Med 85: 106–112, 1988

    Google Scholar 

  63. Yang X, Freeman L, Peterson K, Knapper C, Remaley A, Francois T, Blackmon E, Duverger N, Denefle P, Brewer HB Jr, Santamarina-Fojo S: Abstract. Circulation 102: II-310, 2000

    Google Scholar 

  64. Porsch-Ozcurumez M, Langmann T, Heimerl S, Borsukowa H, Kaminiski WE, Drobnik W, Honer C, Schumacher C, Schmitz G: The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux. J Biol Chem 276: 12427–12433, 2001

    Google Scholar 

  65. Clee SM, Kastelein JJ, van Dam M, Marcil M, Roomp K, Zwarts KY, Collins JA, Roelants R, Tamasawa N, Stulc T, Suda T, Caska R, Boucher B, Rondeau C, DeSouich C, Brook-Wilson A, Molhuiszen HO, Frohlich J, Genest J, Hayden MR: Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Invest 106: 1263–1270, 2000

    Google Scholar 

  66. Joyce CW, Amar MJ, Lambert G, Vaisman BL, Najib-Fruchart J, Hoyt RF Jr, Neufeld ED, Remaley AT, Fredrickson DS, Brewer HB Jr, Santamarina-Fojo S: The ATP-binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 mice and apoE-knock out mice. Proc Natl Acad Sci USA 99: 407–412, 2002

    Google Scholar 

  67. Eck MV, Bos S, Kaminiski W, Orso E, Rothe G, Twisk J, Bottcher A, Amersfoort ESV, Christiansen-Weber TA, Fung-Leung W, Van Berkel TJC: Leukocyte ATP-binding cassette transporter A1 (ABCA1) deficiency promotes atherosclerotic lesion development. Scientific Session of the American Heart Association, Anaheim, #465, November, 2001

  68. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B: Role of LXR in control of lipogenesis. Genes Dev 14: 2831–2838, 2000

    Google Scholar 

  69. Luo Y, Liang CP, Tall AR: The orphan nuclear receptor LRH-1 potentiates the sterol-mediated induction of the human CETP gene by liver X-receptor. J Biol Chem 276: 24767–24773, 2001

    Google Scholar 

  70. Tu AY, Albers JJ: Functional analysis of the transcriptional activity of the mouse phospholipid transfer protein. Biochem Biophys Res Commun 287: 921–926, 2001

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiovascular Molecular Sciences and Technology, Pfizer Global Research & Development, Ann Arbor, MI, USA

    Neelam Srivastava

Authors
  1. Neelam Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Srivastava, N. ATP binding cassette transporter A1 - key roles in cellular lipid transport and atherosclerosis. Mol Cell Biochem 237, 155–164 (2002). https://doi.org/10.1023/A:1016506221047

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016506221047

Search

Navigation