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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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 55:1016–1122
Fredrickson DS (1964) The inheritance of high density lipoprotein deficiency (Tangier disease). J Clin Invest 43:228–243
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 51:2505–2514
Ferrans VJ, Fredrickson DS (1975) The pathology of Tangier disease. A light and electron microscopic study. Am J Pathol 78:101–158
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 75:521–526
Chu FC, Kuwabara T, Cogan PG, Schaefer EJ, Brewer HB Jr (1979) Ocular manifestations of familial high density lipoprotein deficiency (Tangier disease). Arch Opthalmol 97:1926–1928
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 17:1–10
Kocen RS, Lloyd JK, Lascelles PT, Fosbrooke AS, Williams D (1967) Familial alpha lipoprotein deficiency (Tangier disease) with neurologic abnormalities. Lancet 1:1341–1344
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 93:261–266
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 107:85–98
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 156:217–225
Assmann G, Herbert PN, Fredrickson DS, Forte T (1977) Isolation and characterization of an abnormal high density lipoprotein in Tangier disease. J Clin Invest 60:242–251
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 299:905–910
Assmann G, Smootz E (1978) High density lipoprotein infusion and partial plasma exchange in Tangier disease. Eur J Clin Invest 8:131–140
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 22:217–226
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 159:231–236
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 30:805–809
Schaefer EJ (1984) The clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 4:303–322
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 35:871–882
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 72:1611–1621
Luciani MF, Denizot F, Savary S, Mattei MG, Chimini G (1994) Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics 21:150–159
Francis GA, Knopp RH, Oram JF (1995) Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease. J Clin Invest 96:78–87
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 15:683–689
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 20:96–98
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 257:29–33
Brooks-Wilson A, Marcil M, Clee SM et al (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22:336–346
Bodzioch M, Orso E, Klucken J et al (1999) The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Gen 22:347–351
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 22:352–355
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 96:12685–126890
Lawn RM, Wade DP, Garvin J (1999) The Tangier disease gene product ABC1 controls the cellular apolipoprotein mediated lipid removal pathway. J Clin Invest 104:25–31
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 41:433–441
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 41:1125–1135
Young SJ (1999) Fielding CJ The ABCs of cholesterol efflux. Nat Genet 22:316–318
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 154:607–611
Probst MC, Thumann H, Aslanidas C et al (2004) Screening for functional sequence variants and mutations in ABCA1. Atherosclerosis 175:269–279
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 46:1516–1520
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 48:1409–1416
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 16:1412–1422
Iatan I, Alrasadi K, Ruel I et al (2008) Effects of ABCA1 mutations on risk of myocardial infarction. Curr Atheroscler Rep 10:413–426
Vaisman BL, Lambert G, Amar MJ et al (2001) ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion. J Clin Invest 108:303–309
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 99:407–412
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 44:829–836
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 279:15571–15578
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 15:1555–1561
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 7:53–58
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 24:1755–1760
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 28:1672–1678
Lamon-Fava S, Asztalos BF, Schaefer EJ (unpublished observations)
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Schaefer, E.J., Brewer, H.B. (2010). ATP Binding Cassette A1 Transporter Function and Tangier Disease. In: Schaefer, E. (eds) High Density Lipoproteins, Dyslipidemia, and Coronary Heart Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1059-2_8
Download citation
DOI: https://doi.org/10.1007/978-1-4419-1059-2_8
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-1058-5
Online ISBN: 978-1-4419-1059-2
eBook Packages: MedicineMedicine (R0)