ABCA1

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ABCA1
Identifiers
Aliases ABCA1, ATP-binding cassette, sub-family A (ABC1), member 1, Abca1, ABC-1, Abc1, ABC1, CERP, HDLDT1, TGD, ATP binding cassette subfamily A member 1
External IDs MGI: 99607 HomoloGene: 21130 GeneCards: 19
Genetically Related Diseases
Disease Name References
myopia
metabolic disorder
dyslipidemia
coronary artery disease
RNA expression pattern
PBB GE ABCA1 203504 s at tn.png

PBB GE ABCA1 216066 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005502

NM_013454

RefSeq (protein)

NP_005493.2

NP_038482.3

Location (UCSC) Chr 9: 104.78 – 104.93 Mb Chr 4: 53.03 – 53.16 Mb
PubMed search [5] [6]
Wikidata
View/Edit Human View/Edit Mouse

ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), also known as the cholesterol efflux regulatory protein (CERP) is a protein which in humans is encoded by the ABCA1 gene.[7] This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.

Tangier Disease[edit]

It was discovered that a mutation in the ABCA1 protein is responsible for causing Tangier's Disease by several groups in 1998. Gerd Schmitz's group in Germany[8] and Michael Hayden's group in British Columbia[9] were using standard genetics techniques and DNA from family pedigrees to locate the mutation. Richard Lawn's group at CV Therapeutics in Palo Alto, CA used cDNA microarrays, which were relatively new at the time, to assess gene expression profiles from cell lines created from normal and affected individuals.[10] They showed cell lines from patients with Tangier's disease showed differential regulation of the ABCA1 gene. Subsequent sequencing of the gene identified the mutations. This group received an award from the American Heart Association for their discovery.[11] Tangier disease has been identified in nearly 100 patients worldwide, and patients have a broad range of biochemical and clinical phenotypes as over 100 different mutations have been identified in ABCA1 resulting in the disease.[12]

Function[edit]

The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABCA, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABCA subfamily. Members of the ABCA subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesterol efflux pump in the cellular lipid removal pathway.[13][14]

While the complete 3D-structure of ABCA1 remains relatively unknown, there has been some determination of the c-terminus. The ABCA1 c-terminus contains a PDZ domain, responsible for mediating protein-protein interactions, as well as a VFVNFA motif essential for lipid efflux activity.[12]

Physiological role[edit]

ABCA1 mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins (apo-A1 and apoE), which then form nascent high-density lipoproteins (HDL). It also mediates the transport of lipids between Golgi and cell membrane. Since this protein is needed throughout the body it is expressed ubiquitously as a 220-kDa protein. It is present in higher quantities in tissues that shuttle or are involved in the turnover of lipids such as the liver, the small intestine and adipose tissue.[15]

Factors that act upon the ABCA1 transporter's expression or its posttranslational modification are also molecules that are involved in its subsequent function like fatty acids, cholesterol and also cytokines and cAMP.[16]

Interactions between members of the apoliprotein family and ABCA1 activate multiple signalling pathways, including the JAK-STAT, PKA, and PKC pathways[17]

Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatory diarylheptanoid antioxidant curcumin.[18] Downregulation of ABCA1 in senescent macrophages disrupts the cell's ability to remove cholesterol from its cytosoplasm, leading the cells to promote the pathologic atherogenesis (blood vessel thickening/hardening) which "plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration"[19] Knockout mouse models of AMD treated with agonists that increase ABCA1 in loss of function and gain of function experiments demonstrated the protective role of elevating ABCA1 in regulating angiogenesis in eye disease. Human data from patients and controls were used to demonstrate the translation of mouse findings in human disease.[20]

Clinical significance[edit]

Mutations in this gene have been associated with Tangier disease and familial high-density lipoprotein deficiency. ABCA1 has been shown to be reduced in Tangier disease which features physiological deficiencies of HDL.[21][22] Leukocytes ABCA1 gene expression is upregulated in postmenopausal women receiving hormone replacement therapy (HRP).[23]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin_Pathway_WP430 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article
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  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 

Interactions[edit]

ABCA1 has been shown to interact with:

See also[edit]

References[edit]

  1. ^ "chibi.ubc.ca/Gemma/phenotypes.html?phenotypeUrlId=DOID_11830&geneId=692". 
  2. ^ "chibi.ubc.ca/Gemma/phenotypes.html?phenotypeUrlId=DOID_0014667&geneId=692". 
  3. ^ "chibi.ubc.ca/Gemma/phenotypes.html?phenotypeUrlId=DOID_3146&geneId=692". 
  4. ^ "chibi.ubc.ca/Gemma/phenotypes.html?phenotypeUrlId=DOID_3393&geneId=692". 
  5. ^ "Human PubMed Reference:". 
  6. ^ "Mouse PubMed Reference:". 
  7. ^ Luciani MF, Denizot F, Savary S, Mattei MG, Chimini G (May 1994). "Cloning of two novel ABC transporters mapping on human chromosome 9". Genomics. 21 (1): 150–9. doi:10.1006/geno.1994.1237. PMID 8088782. 
  8. ^ Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, Drobnik W, Barlage S, Büchler C, Porsch-Ozcürümez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G (August 1999). "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease". Nature Genetics. 22 (4): 347–51. doi:10.1038/11914. PMID 10431237. 
  9. ^ Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, Yu L, Brewer C, Collins JA, Molhuizen HO, Loubser O, Ouelette BF, Fichter K, Ashbourne-Excoffon KJ, Sensen CW, Scherer S, Mott S, Denis M, Martindale D, Frohlich J, Morgan K, Koop B, Pimstone S, Kastelein JJ, Genest J, Hayden MR (August 1999). "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency". Nature Genetics. 22 (4): 336–45. doi:10.1038/11905. PMID 10431236. 
  10. ^ Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF (October 1999). "The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway". The Journal of Clinical Investigation. 104 (8): R25–31. doi:10.1172/JCI8119. PMC 481052free to read. PMID 10525055. 
  11. ^ "American Heart Association Selects CV Therapeutics' Discovery of Role Of 'Good' Cholesterol-Regulating Gene as Top Ten 1999 Research Advances In Heart Disease". PR Newswire Association. 2000-01-03. Retrieved 2009-05-08. 
  12. ^ a b Brunham LR, Singaraja RR, Hayden MR (August 2006). "Variations of a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis". Annual Review of Nutrition. 26: 105–129. doi:10.1146/annurev.nutr.26.061505.111214. PMID 16704350. 
  13. ^ "Entrez Gene: ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1". 
  14. ^ Schmitz G, Langmann T (April 2001). "Structure, function and regulation of the ABC1 gene product". Curr. Opin. Lipidol. 12 (2): 129–40. doi:10.1097/00041433-200104000-00006. PMID 11264984. 
  15. ^ E. M. Wagner, F. Basso, C. S. Kim, M. J. A. Amar, "ABC lipid transporters", in AccessScience@McGraw-Hill
  16. ^ Yokoyama S (February 2006). "ABCA1 and biogenesis of HDL". J. Atheroscler. Thromb. 13 (1): 1–15. doi:10.5551/jat.13.1. PMID 16505586. 
  17. ^ Luu W, Sharpe LJ, Gelissen IC, Brown AJ (August 2013). "The role of signalling in cellular cholesterol homeostasis". IUBMB Life. 65 (8): 675–684. doi:10.1002/iub.1182. PMID 23847008. 
  18. ^ Bachmeier BE, Iancu CM, Killian PH, Kronski E, Mirisola V, Angelini G, Jochum M, Nerlich AG, Pfeffer U (2009). "Overexpression of the ATP binding cassette gene ABCA1 determines resistance to Curcumin in M14 melanoma cells". Mol Cancer. 8: 129–141. doi:10.1186/1476-4598-8-129. PMC 2804606free to read. PMID 20030852. 
  19. ^ Sene A, Khan AA, Cox D, Nakamura RE, Santeford A, Kim BM, Sidhu R, Onken MD, Harbour JW, Hagbi-Levi S, Chowers I, Edwards PA, Baldan A, Parks JS, Ory DS, Apte RS (2013). "Impaired Cholesterol Efflux in Senescent Macrophages Promotes Age-Related Macular Degeneration". Cell Metabolism. 17: 549–561. doi:10.1016/j.cmet.2013.03.009. PMID 23562078. 
  20. ^ http://www.faqs.org/patents/app/20130317090
  21. ^ Ordovas JM (March 2000). "ABC1: the gene for Tangier disease and beyond". Nutr. Rev. 58 (3 Pt 1): 76–9. doi:10.1111/j.1753-4887.2000.tb01843.x. PMID 10812922. 
  22. ^ Oram JF, Vaughan AM (June 2000). "ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins". Curr. Opin. Lipidol. 11 (3): 253–60. doi:10.1097/00041433-200006000-00005. PMID 10882340. 
  23. ^ Darabi M, Rabbani M, Ani M, Zarean E, Panjehpour M, Movahedian A (2011). "Increased leukocyte ABCA1 gene expression in post-menopausal women on hormone replacement therapy". Gynecol. Endocrinol. 27 (9): 701–5. doi:10.3109/09513590.2010.507826. PMID 20807164. 
  24. ^ Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW (September 2002). "Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I". J. Biol. Chem. 277 (36): 33178–87. doi:10.1074/jbc.M204996200. PMID 12084722. 
  25. ^ Buechler C, Bared SM, Aslanidis C, Ritter M, Drobnik W, Schmitz G (November 2002). "Molecular and functional interaction of the ATP-binding cassette transporter A1 with Fas-associated death domain protein". J. Biol. Chem. 277 (44): 41307–10. doi:10.1074/jbc.C200436200. PMID 12235128. 
  26. ^ Buechler C, Boettcher A, Bared SM, Probst MC, Schmitz G (May 2002). "The carboxyterminus of the ATP-binding cassette transporter A1 interacts with a beta2-syntrophin/utrophin complex". Biochem. Biophys. Res. Commun. 293 (2): 759–65. doi:10.1016/S0006-291X(02)00303-0. PMID 12054535. 
  27. ^ Shimizu Y, Iwai S, Hanaoka F, Sugasawa K (January 2003). "Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase". EMBO J. 22 (1): 164–73. doi:10.1093/emboj/cdg016. PMC 140069free to read. PMID 12505994. 

Further reading[edit]

External links[edit]