Advertisement

ATP Binding Cassette A1 Transporter Function and Tangier Disease

  • Ernst J. Schaefer
  • H. Bryan Brewer
Chapter

Abstract

The ATP binding cassette A1 (ABCA1) transporter facilitates the efflux of free cholesterol and phospholipid onto high density lipoprotein (HDL) particles, mainly very small discoidal precursor HDL particles, known as prebeta 1 HDL. Once these particles pick up these lipids, they are converted to small discoidal alpha 4 migrating HDL and with cholesterol esterification mature into larger spherical alpha 3 and 2 HDL particles. Separate chapters in this book are devoted to HDL particle metabolism. Patients with Tangier Disease, named after the Chesapeake Bay island home of the first two cases described, have marked HDL deficiency, moderate hypertriglyceridemia, and low density lipoprotein (LDL) cholesterol levels that are about 50% of normal values. The only HDL particle detectable in the plasma of homozygotes is the very small precursor prebeta 1 HDL particle, which in these patients is rapidly catabolized by the kidneys. Homozygotes have lipid laden macrophages in their tonsils, spleen, liver, arterial wall, other tissues, and Schwann cells, which can result in enlarged orange tonsils, hepatosplenomegaly, premature coronary heart disease (CHD), and neuropathy. Their LDL is about 50% of normal, is smaller and more triglyceride enriched than normal LDL, and its protein component is cleared from plasma at twice the normal fractional rate. Heterozygotes with this disease have about 50% of normal HDL cholesterol, lack large alpha 1 HDL, and have an increased risk of premature CHD when compared to control subjects. Findings in this disease underscore the importance of ABCA1 in promoting free cholesterol efflux from a variety of cells and maintaining cellular cholesterol homeostasis.

Keywords

High Density Lipoprotein Cholesteryl Ester Beta Carotene High Density Lipoprotein Particle Premature Coronary Heart Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Fredrickson DS, Altrocchi PH, Avioli LC, Goodman DS, Goodman HC (1961) Tangier disease: combined clinical staff conference at the National Institute of Health. Ann Intern Med 55:1016–1122Google Scholar
  2. 2.
    Fredrickson DS (1964) The inheritance of high density lipoprotein deficiency (Tangier disease). J Clin Invest 43:228–243CrossRefPubMedGoogle Scholar
  3. 3.
    Lux SE, Levy RI, Gotto AM, Fredrickson DS (1972) Studies on the protein defect in Tangier disease: isolation and Characterization of an abnormal high density lipoprotein. J Clin Invest 51:2505–2514CrossRefPubMedGoogle Scholar
  4. 4.
    Ferrans VJ, Fredrickson DS (1975) The pathology of Tangier disease. A light and electron microscopic study. Am J Pathol 78:101–158PubMedGoogle Scholar
  5. 5.
    Schaefer EJ, Triche TJ, Zech LA, Stein E, Kemeny MM, Brennan MF, Brewer HB Jr (1983) Massive omental reticuloendothelial cell lipid uptake in Tangier disease following splenectomy. Am J Med 75:521–526CrossRefPubMedGoogle Scholar
  6. 6.
    Chu FC, Kuwabara T, Cogan PG, Schaefer EJ, Brewer HB Jr (1979) Ocular manifestations of familial high density lipoprotein deficiency (Tangier disease). Arch Opthalmol 97:1926–1928Google Scholar
  7. 7.
    Engel WK, Dorman JD, Levy RI, Fredrickson DS (1967) Neuropathy in Tangier disease: alpha lipoprotein deficiency manifesting as familial recurrent neuropathy and intestinal lipid storage. Arch Neurol 17:1–10PubMedGoogle Scholar
  8. 8.
    Kocen RS, Lloyd JK, Lascelles PT, Fosbrooke AS, Williams D (1967) Familial alpha lipoprotein deficiency (Tangier disease) with neurologic abnormalities. Lancet 1:1341–1344CrossRefPubMedGoogle Scholar
  9. 9.
    Schaefer EJ, Zech LA, Schwartz DS, Brewer HB Jr (1980) Coronary heart disease prevalence and other clinical features in familial high density lipoprotein deficiency (Tangier disease). Ann Int Med 93:261–266PubMedGoogle Scholar
  10. 10.
    Serfaty-Lacrosniere C, Lanzberg A, Civeira F, Isaia P, Berg J, Janus ED, Smith MP, Pritchard PH, Frohlich J, Lees RS, Ordovas JM, Schaefer EJ (1994) Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 107:85–98CrossRefPubMedGoogle Scholar
  11. 11.
    Asztalos BF, Brousseau ME, McNamara JR, Horvath KV, Roheim PS, Schaefer EJ (2001) Subpopulations of high-density lipoproteins in homozygous and heterozygous Tangier disease. Atherosclerosis 156:217–225CrossRefPubMedGoogle Scholar
  12. 12.
    Assmann G, Herbert PN, Fredrickson DS, Forte T (1977) Isolation and characterization of an abnormal high density lipoprotein in Tangier disease. J Clin Invest 60:242–251CrossRefPubMedGoogle Scholar
  13. 13.
    Schaefer EJ, Blum CB, Levy RI, Jenkins LL, Alaupovic P, Foster DM, Brewer HB Jr (1978) Metabolism of high density lipoprotein apolipoproteins in Tangier disease. N Eng J Med 299:905–910CrossRefGoogle Scholar
  14. 14.
    Assmann G, Smootz E (1978) High density lipoprotein infusion and partial plasma exchange in Tangier disease. Eur J Clin Invest 8:131–140CrossRefPubMedGoogle Scholar
  15. 15.
    Schaefer EJ, Anderson DW, Zech LA, Lindgren FT, Bronzert TJ, Rubalcaba EA, Brewer HB Jr (1981) Metabolism of high density lipoprotein subfractions and constituents in Tangier disease following the infusion of high density lipoproteins. J Lipid Res 22:217–226PubMedGoogle Scholar
  16. 16.
    Schaefer EJ, Brousseau ME, Diffenderfer MR, Cohn JS, Welty FK, O’Connor J, Dolnikowski GG, Wang J, Hegele RA, Jones PJ (2001) Cholesterol and apolipoprotein B metabolism in Tangier disease. Atherosclerosis 159:231–236CrossRefPubMedGoogle Scholar
  17. 17.
    Alaupovic P, Schaefer EJ, McConathy WJ, Fesmire JD, Brewer HB Jr (1981) Plasma apolipoprotein concentrations in familial apolipoprotein A-I and A-II deficiency (Tangier disease). Metabolism 30:805–809CrossRefPubMedGoogle Scholar
  18. 18.
    Schaefer EJ (1984) The clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 4:303–322PubMedGoogle Scholar
  19. 19.
    Schaefer EJ, Lamon-Fava S, Ordovas JM, Cohn SD, Schaefer MM, Castelli WP, Wilson PWF (1994) Factors associated with low and elevated plasma high density lipoprotein cholesterol and apolipoprotein A-1 levels in the Framingham Offspring Study. J Lipid Res 35:871–882PubMedGoogle Scholar
  20. 20.
    Oram JF, Brinton EA, Bierman EL (1983) Regulation of high density lipoprotein receptor activity in cultured human skin fibroblasts and human arterial smooth muscle cells. J Clin Invest 72:1611–1621CrossRefPubMedGoogle Scholar
  21. 21.
    Luciani MF, Denizot F, Savary S, Mattei MG, Chimini G (1994) Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics 21:150–159CrossRefPubMedGoogle Scholar
  22. 22.
    Francis GA, Knopp RH, Oram JF (1995) Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease. J Clin Invest 96:78–87CrossRefPubMedGoogle Scholar
  23. 23.
    Rogler G, Trumbach B, Klima B, Lackner KJ, Schmitz G (1995) HDL-mediated efflux of intracellular cholesterol is impaired in fibroblasts from Tangier disease patients. Arterioscler Thromb Vasc Biol 15:683–689PubMedGoogle Scholar
  24. 24.
    Rust S, Walter M, Funke H, von Eckhardstein A et al (1998) Assignment of Tangier disease To chromosome 9q31 by a graphical linkage exclusion strategy. Nat Genet 20:96–98CrossRefPubMedGoogle Scholar
  25. 25.
    Langmann T, Klucken J, Reil M, Liebisch U et al (1999) Molecular cloning of the human ATP binding cassette transporter 1 (hABC1): evidence for sterol dependent regulation. Biochem Biohys Res Comm 257:29–33CrossRefGoogle Scholar
  26. 26.
    Brooks-Wilson A, Marcil M, Clee SM et al (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336–346CrossRefPubMedGoogle Scholar
  27. 27.
    Bodzioch M, Orso E, Klucken J et al (1999) The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Gen 22:347–351CrossRefGoogle Scholar
  28. 28.
    Rust S, Rosier M, Funke H et al (1999) Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352–355CrossRefPubMedGoogle Scholar
  29. 29.
    Remaley AT, Rust S, Rosier M et al (1999) 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 96:12685–126890CrossRefPubMedGoogle Scholar
  30. 30.
    Lawn RM, Wade DP, Garvin J (1999) The Tangier disease gene product ABC1 controls the cellular apolipoprotein mediated lipid removal pathway. J Clin Invest 104:25–31CrossRefGoogle Scholar
  31. 31.
    Brousseau ME, Schaefer EJ, Dupuis J et al (2000) Novel mutations in the gene encoding ATP-binding cassette 1 in four Tangier disease kindreds. J Lipid Res 41:433–441PubMedGoogle Scholar
  32. 32.
    Brousseau ME, Eberhart GP, Dupuis J et al (2000) Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size. J Lipid Res 41:1125–1135PubMedGoogle Scholar
  33. 33.
    Young SJ (1999) Fielding CJ The ABCs of cholesterol efflux. Nat Genet 22:316–318CrossRefPubMedGoogle Scholar
  34. 34.
    Brousseau ME, Bodzioch M, Schaefer EJ et al (2001) Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease. Atherosclerosis 154:607–611CrossRefPubMedGoogle Scholar
  35. 35.
    Probst MC, Thumann H, Aslanidas C et al (2004) Screening for functional sequence variants and mutations in ABCA1. Atherosclerosis 175:269–279CrossRefPubMedGoogle Scholar
  36. 36.
    Frikke-Schmidt R, Nordestgaard BG, Schnohr P et al (2005) Mutations in ABCA1 predict risk of ischemic heart disease in the Copenhagen City Heart Study population. J Am Coll Cardiol 46:1516–1520CrossRefPubMedGoogle Scholar
  37. 37.
    Soro-Paavonen A, Naukkarinen J, Lee-Ruechert M et al (2007) Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with low HDL. J Lipid Res 48:1409–1416CrossRefPubMedGoogle Scholar
  38. 38.
    Kyriakou T, Rontrefrant DE, Viturro E et al (2007) Functional polymorphisms in ABCA1 influence age of onset in coronary artery disease patients. Hum Mol Genet 16:1412–1422CrossRefPubMedGoogle Scholar
  39. 39.
    Iatan I, Alrasadi K, Ruel I et al (2008) Effects of ABCA1 mutations on risk of myocardial infarction. Curr Atheroscler Rep 10:413–426CrossRefPubMedGoogle Scholar
  40. 40.
    Vaisman BL, Lambert G, Amar MJ et al (2001) ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion. J Clin Invest 108:303–309PubMedGoogle Scholar
  41. 41.
    Joyce CV, Amar MJ, Lambert G et al (2002) The ATP binding cassette transporter A1 (ABCA1) modulates the development of atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci USA 99:407–412CrossRefPubMedGoogle Scholar
  42. 42.
    Remaley AT, Thomas F, Stonik J et al (2003) Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1 dependent and an ABCA1 independent pathway. J Lipid Res 44:829–836CrossRefGoogle Scholar
  43. 43.
    Neufeld EB, Stonik JA, Demosky SJ Jr et al (2004) The ABCA1 transporter mediates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease. J Biol Chem 279:15571–15578CrossRefPubMedGoogle Scholar
  44. 44.
    Eckardstein A, Langer C, Engel T et al (2001) ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocyte derived macrophages. FASEB J 15:1555–1561CrossRefGoogle Scholar
  45. 45.
    Chinetti G, Lestavel S, Bocher V et al (2001) Peroxisomal proliferation activator receptor alpha and peroxisomal proliferation activator receptor gamma activation includes cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 transporter. Nat Med 7:53–58CrossRefPubMedGoogle Scholar
  46. 46.
    Brewer HB Jr, Remaley AT, Neufeld EB et al (2004) Regulation of plasma HDL levels by the ABCA1 transporter and the emerging role of HDL in the treatment of cardiovascular disease. Arterioscler Thromb Vasc Biol 24:1755–1760CrossRefPubMedGoogle Scholar
  47. 47.
    Lamon-Fava S, Diffenderfer MR, Barrett PHR, Buchsbaum A, Nyaku M, Horvath K, Asztalos BF, Otokozawa S, Ai M, Matthan NR, Lichtenstein AH, Dolnikowski GG, Schaefer EJ (2008) Extended-release niacin alters the metabolism of plasma apolipoprotein (apo) A-I and apoB-containing lipoproteins. Arterioscler Thromb Vasc Biol 28:1672–1678CrossRefPubMedGoogle Scholar
  48. 48.
    Lamon-Fava S, Asztalos BF, Schaefer EJ (unpublished observations)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Tufts UniversityBostonUSA

Personalised recommendations