Skip to main content
Log in

Role of the ABC transporters A1 and G1, key reverse cholesterol transport proteins, in atherosclerosis

  • Reviews
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstract

Atherosclerosis is one of the most common causes of death worldwide. Epidemiology studies firmly established an inverse relationship between atherogenesis and distorted lipid metabolism, in particular, higher levels of total cholesterol, an accumulation of CH-laden macrophages (foam cells), and lower plasma levels of antiatherogenic high density lipoprotein (HDL). It is believed that the reverse cholesterol transport, a process that removes excess cholesterol from peripheral tissues/cells including macrophages to circulating HDL, is one of the main mechanisms responsible for anti-atherogenic properties of HDL. The key proteins of reverse cholesterol transport—ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1)—mediate the cholesterol efflux from macrophages and prevent their transformation into foam cells. This review focuses on the role of ABC transporters A1 and G1 in the pathogenesis of atherosclerosis.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Feig J.E., Shamir R., Fisher E.A. 2008. Atheroprotective effects of HDL: Beyond reverse cholesterol transport. Curr. Drug. Targets. 9 (3), 196–203.

    Article  CAS  PubMed  Google Scholar 

  2. Oram J.F., Vaughan A.M. 2006. ATP-binding cassette cholesterol transporters and cardiovascular disease. Circ. Res. 99, 1031–1043.

    Article  CAS  PubMed  Google Scholar 

  3. Ono K. 2012. Current concept of reverse cholesterol transport and novel strategy for atheroprotection. J. Cardiol. 60 (5), 339–343.

    Article  PubMed  Google Scholar 

  4. Meurs I., Van Eck M., Van Berkel T.J. 2010. High-density lipoprotein: key molecule in cholesterol efflux and the prevention of atherosclerosis. Curr. Pharm. Des. 16 (13), 1445–1467.

    Article  CAS  PubMed  Google Scholar 

  5. Chen W., Silver D.L., Smith J.D., Tall A.R. 2000. Scavenger receptor-BI inhibits ATP-binding cassette transporter 1-mediated cholesterol efflux in macrophages. J. Biol. Chem. 275 (40), 30794–30800.

    Article  CAS  PubMed  Google Scholar 

  6. Singaraja R.R., Fievet C., Castro G. James E.R., Hennuyer N., Clee S.M., Bissada N., Choy J.C., Fruchart J.C., McManus B.M., Staels B., Hayden M.R. 2002. Increased ABCA1 activity protects against atherosclerosis. J. Clin. Invest. 110 (1), 35–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jessup W., Gelissen I.C., Gaus K., Kritharides L. 2006. Roles of ATP binding cassette transporters A1 and G1, scavenger receptor BI and membrane lipid domains in cholesterol export from macrophages. Curr. Opin. Lipidology. 17, 247–257.

    Article  CAS  Google Scholar 

  8. Gelissen I.C., Harris M., Rye K.A., Quinn C., Brown A.J., Kockx M., Cartland S., Packianathan M., Kritharides L., Jessup W. 2006. ABCA1 and ABCG1 synergize to mediate cholesterol export to ApoA-I. Arterioscler. Thromb. Vasc. Biol. 26, 534–540.

    Article  CAS  PubMed  Google Scholar 

  9. Kontush A., Chapman M.J. 2006. Functionally defective high-density lipoprotein: A new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacology. 58, 342–374.

    CAS  Google Scholar 

  10. Miller M., Rhyne J., Hamlette S., Birnbaum J., Rodriguez A. 2003. Genetics of HDL regulation in humans. Curr. Opin. Lipidol. 14, 273–279.

    Article  CAS  PubMed  Google Scholar 

  11. Hovingh G.K., de Groot E., van der Steeg W., Boekholdt S.M., Hutten B.A., Kuivenhoven J.A., Kastelein J.J. 2005. Inherited disorders of HDL metabolism and atherosclerosis. Curr. Opin. Lipidol. 16 (2), 139–145.

    Article  CAS  PubMed  Google Scholar 

  12. Schaefer J.R., Rader D.J., Ikewaki K., Fairwell T., Zech L.A., Kindt M.R., Davignon J., Gregg R.E., Brewer H.B. Jr. 1992. In vivo metabolism of apolipoprotein A-I in a patient with homozygous familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 12, 843–848.

    Article  CAS  Google Scholar 

  13. Frenais R., Ouguerram K., Maugeais C. Marchini J.S., Benlian P., Bard J.M., Magot T., Krempf M. 1999. Apolipoprotein A-I kinetics in heterozygous familial hypercholesterolemia: A stable isotope study. J. Lipid Res. 40, 1506–1511.

    CAS  PubMed  Google Scholar 

  14. Yokoyama S. 2006. ABCA1 and biogenesis of HDL. J. Atheroscler. Tromb. 13, 1–15.

    Article  CAS  Google Scholar 

  15. Cuchel M., Rader D.J. 2006. Macrophage reverse cholesterol transport key to the regression of atherosclerosis. Circulation. 113, 2548–2555.

    Article  PubMed  Google Scholar 

  16. Shchelkunova T.A., Morozov I.A., Rubtsov P.M., Samokhodskaya L.M., Andrianova I.V., Sobenin I.A., Orekhov A.N., Smirnov A.N. 2013. Changes in levels of gene expression in human aortal intima during atherogenesis. Biochemistry (Moscow). 78 (5), 463–470.

    CAS  PubMed  Google Scholar 

  17. Barry H., Cole S., Kuchler K., Higgins C.F. 2003. ABC Proteins: From Bacteria to Man. London: Academic.

    Google Scholar 

  18. Luciani M.F., Denizot F., Savary S., Mattei M.G., Chimini G. 1994. Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics. 21, 150–159.

    Article  CAS  PubMed  Google Scholar 

  19. Voloshyna I., Reiss A.B. 2011. The ABC transporters in lipid flux and atherosclerosis. Prog. Lipid. Res. 50 (3), 213–224.

    Article  CAS  PubMed  Google Scholar 

  20. Klucken J., Buchler C., Orso E., Kaminski W.E., Porsch-Ozcürümez M., Liebisch G., Kapinsky M., Diederich W., Drobnik W., Dean M., Allikmets R., Schmitz G. 2000. ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc. Natl. Acad. Sci. U. S. A. 97, 817–822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mauldin J.P., Nagelin M.H., Wojcik A.J. Srinivasan S., Skaflen M.D., Ayers C.R., McNamara C.A., Hedrick C.C. 2008. Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus. Circulation. 117, 2785–2792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dushkin M.I. 2006. Macrophages and atheroscletosis: Pathophysiological and therapeutic aspects. Byull. Sib. Otd. Ross. Akad. Med. Nauk. 26 (120), 47–55.

    Google Scholar 

  23. Rohatgi A., Khera A., Berry J.D., Givens E.G., Ayers C.R., Wedin K.E., Neeland I.J., Yuhanna I.S., Rader D.R., de Lemos J.A., Shaul P.W. 2014. HDL cholesterol efflux capacity and incident cardiovascular events. N. Engl. J. Med. 371 (25), 2383–2393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Van Eck M., Bos I.S., Kaminski W.E., Orsó E., Rothe G., Twisk J., Böttcher A., Van Amersfoort E.S., Christiansen-Weber T.A., Fung-Leung W.P., Van Berkel T.J., Schmitz G. 2002. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc. Natl. Acad. Sci. U. S. A. 99 (9), 6298–6303.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yvan-Charvet L., Ranalletta M., Wang N., Han S., Terasaka N., Li R., Welch C., Tall A.R. 2007. Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. J. Clin. Invest. 117 (12), 3900–3908.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Kennedy M.A., Barrera G.C., Nakamura K., Baldán A., Tarr P., Fishbein M.C., Frank J., Francone O.L., Edwards P.A. 2005. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 1, 121–131.

    Article  CAS  PubMed  Google Scholar 

  27. Engel T., Kannenberg F., Fobker M., Nofer J.R., Bode G., Lueken A., Assmann G., Seedorf U. 2007. Expression of ATP binding cassette-transporter ABCG1 prevents cell death by transporting cytotoxic 7 beta-hydroxycholesterol. FEBS Lett. 581, 1673–1680.

    Article  CAS  PubMed  Google Scholar 

  28. Terasaka N., Wang N., Yvan-Charvet L., Tall A.R. 2007. High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1. Proc. Natl. Acad. Sci. U. S. A. 104, 15093–15098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yvan-Charvet L., Welch C., Pagler T.A., Ranalletta M., Lamkanfi M., Han S., Ishibashi M., Li R., Wang N., Tall A.R. 2008. Increased Inflammatory gene expression in ABC transporter-deficient macrophages free cholesterol accumulation, increased signaling via Tolllike receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation. 118, 1837–1847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ma L., Dong F., Zaid M., Kumar A., Zha X. 2012. ABCA1 protein enhances Toll-like receptor 4 (TLR4)-stimulated interleukin-10 (IL-10) secretion through protein kinase A (PKA) activation. J. Biol. Chem. 287 (48), 40502–40512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Terasaka N., Yu S., Yvan-Charvet L., Wang N., Mzhavia N., Langlois R., Pagler T., Li R., Welch C.L., Goldberg I.J., Tall A.R. 2008. ABCG1 and HDL protect against endothelial dysfunction in mice fed a highcholesterol diet. J. Clin. Invest. 118, 3701–3713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Oram J.F., Heinecke J.W. 2005. ATP-binding cassette transporter A1: A cell cholesterol exporter that protects against cardiovascular disease. Physiol. Rev. 85 (4), 1343–1372.

    Article  CAS  PubMed  Google Scholar 

  33. Zhao C., Dahlman-Wright K. 2010. Liver X receptor in cholesterol metabolism. J. Endocrinol. 204 (3), 233–240.

    Article  CAS  PubMed  Google Scholar 

  34. Schmitz G, Buechler C. 2002. ABCA1: Regulation, trafficking and association with heteromeric proteins. Ann. Med. 34, 334–347.

    Article  CAS  PubMed  Google Scholar 

  35. Adlakha Y.K., Khanna S., Singh R., Singh V.P., Agrawal A., Saini N. 2013. Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXRa expression and cholesterol homeostasis. Cell Death Dis. 4, e780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Guay S.P., Brisson D., Munger J., Lamarche B., Gaudet D., Bouchard L. 2012. ABCA1 gene promoter DNA methylation is associated with HDL particle profile and coronary artery disease in familial hypercholesterolemia. Epigenetics. 7 (5), 464–472.

    Article  CAS  PubMed  Google Scholar 

  37. Peng P., Wang L., Yang X., Huang X., Ba Y., Chen X., Guo J., Lian J., Zhou J. 2014. A preliminary study of the relationship between promoter methylation of the ABCG1, GALNT2 and HMGCR genes and coronary heart disease. PLoS ONE. 9 (8), e102265.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Nazarenko M.S., Markov A.V., Lebedev I.N., Sleptsov A.A., Frolov A.V., Barbarash O.L., Barbarash L.S., Puzyrev V.P. 2013. DNA methylation profiling of the vascular tissues in the setting of atherosclerosis. Mol. Biol. (Moscow). 47 (3), 352–357.

    Article  CAS  Google Scholar 

  39. Seo D., Wang T., Dressman H., Herderick E.E., Iversen E.S., Dong C., Vata K., Milano C.A., Rigat F., Pittman J., Nevins J.R., West M., Goldschmidt-Clermont P.J. 2004. Gene expression phenotypes of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24, 1922–1927.

    Article  CAS  PubMed  Google Scholar 

  40. Sinnaeve P.R., Donahue M.P., Grass P., Seo D., Vonderscher J., Chibout S.D., Kraus W.E., Sketch M., Jr., Nelson C., Ginsburg G.S., Goldschmidt-Clermont P.J., Granger C.B. 2009. Gene expression patterns in peripheral blood correlate with the extent of coronary artery disease. PLoS ONE. 4 (9), e7037.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Korkor M.T., Meng G.B., Xing S.Y., Zhang M.C., Guo J.R., Zhu X.X., Yang P. 2011. Microarray analysis of differential gene expression profile in peripheral blood cells of patients with human essential hypertension. Int. J. Med. Sci. 8 (2), 168–179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sivapalaratnam S., Basart H., Watkins N.A., Maiwald S., Rendon A., Krishnan U., Sondermeijer B.M., Creemers E.E., Pinto-Sietsma S.J., Hovingh K., Ouwehand W.H., Kastelein J.J., Goodall A.H., Trip M.D. 2012. Monocyte gene expression signature of patients with early onset coronary artery disease. PLoS ONE. 7, e32166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Di Gregoli K., Johnson J.L. 2012. Role of colony-stimulating factors in atherosclerosis. Curr. Opin. Lipidol. 23 (5), 412–421.

    Article  PubMed  Google Scholar 

  44. Waldo S.W., Li Y., Buono C., Billings E.M., Chang J., Kruth H.S. 2008. Heterogeneity of human macrophages in culture and in atherosclerotic plaques. Am. J. Pathol. 172, 1112–1126.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Demina E.P., Miroshnikova V.V., Rodygina T.I., Kuriyanov P.S., Vinogradov A.G., Denisenko A.D., Schwarzman A.L. 2011. ABCA1 gene expression in peripheral blood lymphocytes and macrophages in patients with atherosclerosis. Mol. Biol. (Moscow). 45 (2), 258–262.

    Article  CAS  Google Scholar 

  46. Demina E.P., Miroshnikova V.V., Maiorov N.V. Davydenko V.V., Schwarzman A.L. 2013. ABCA1 gene mRNA and ABCA1 protein level in M-CSF-activated macrophages of patients with arterial stenosis. Tsitologiya. 55 (8), 580–585.

    CAS  Google Scholar 

  47. Wong J., Quinn C.M., Gelissen I.C., Jessup W., Brown A.J. 2008. The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation. Atherosclerosis. 196 (1), 180–189.

    Article  CAS  PubMed  Google Scholar 

  48. Genvigir F.D., Rodrigues A.C., Cerda A., Arazi S.S., Willrich M.A., Oliveira R., Hirata M.H., Dorea E.L., Bernik M.M., Curi R., Hirata R.D. 2010. Effects of lipid-lowering drugs on reverse cholesterol transport gene expressions in peripheral blood mononuclear and HepG2 cells. Pharmacogenomics. 11 (9), 1235–1246.

    Article  CAS  PubMed  Google Scholar 

  49. Albrecht C., Soumian S., Amey J.S., Sardini A., Higgins C.F., Davies A.H., Gibbs R.G. 2004. ABCA1 expression in carotid atherosclerotic plaques. Stroke. 35 (12), 2801–2806.

    Article  CAS  PubMed  Google Scholar 

  50. Liu H.F., Cui K.F., Wang J.P., Zhang M., Guo Y.P., Li X.Y., Jiang C. 2012. Significance of ABCA1 in human carotid atherosclerotic plaques. Exp. Ther. Med. 4 (2), 297–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Soumian S., Gibbs R., Davies A., Albrecht C. 2005. mRNA expression of genes involved in lipid efflux and matrix degradation in occlusive and ectatic atherosclerotic disease. J. Clin. Pathol. 58 (12), 1255–1260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Miroshnikova V.V., Demina E.P., Maiorov N.V., Davydenko V.V., Kuriyanov P.S., Vavilov V.N., Vinogradov A.G., Denisenko A.D., Schwarzman A.L. 2014. Specific features of ABCG1 transporter gene expression in peripheral plood mononuclar cells of patients with atherosclerosis. Tsitologiya. 56 (3), 234–240.

    CAS  Google Scholar 

  53. Wellington C.L., Walker E.K., Suarez A., Kwok A., Bissada N., Singaraja R., Yang Y.Z., Zhang L.H., James E., Wilson J.E., Francone O., McManus B.M., Hayden M.R. 2002. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab. Invest. 82 (3), 273–283.

    Article  CAS  PubMed  Google Scholar 

  54. Kang M.H., Singaraja R., Hayden M.R. 2010. Adenosine-triphosphate-binding cassette transporter-1 trafficking and function. Trends Cardiovasc. Med. 20 (2), 41–49.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E. P. Demina.

Additional information

Original Russian Text © E.P. Demina, V.V. Miroshnikova, A.L. Schwarzman, 2016, published in Molekulyarnaya Biologiya, 2016, Vol. 50, No. 2, pp. 223–230.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Demina, E.P., Miroshnikova, V.V. & Schwarzman, A.L. Role of the ABC transporters A1 and G1, key reverse cholesterol transport proteins, in atherosclerosis. Mol Biol 50, 193–199 (2016). https://doi.org/10.1134/S0026893316020047

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893316020047

Keywords

Navigation