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{{Infobox_gene}}
{{CMG}}


{{SK}} CERP; cholesterol efflux regulatory protein
'''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]].<ref name="pmid8088782">{{cite journal | vauthors = Luciani MF, Denizot F, Savary S, Mattei MG, Chimini G | title = Cloning of two novel ABC transporters mapping on human chromosome 9 | journal = Genomics | volume = 21 | issue = 1 | pages = 150–9 | date = May 1994 | pmid = 8088782 | doi = 10.1006/geno.1994.1237 }}</ref> This transporter is a major regulator of cellular [[cholesterol]] and [[phospholipid]] [[homeostasis]].
{{PBB_Controls
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = no
| update_citations = yes
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{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = ATP-binding cassette, sub-family A (ABC1), member 1
| HGNCid = 29
| Symbol = ABCA1
| AltSymbols =; ABC-1; ABC1; CERP; FLJ14958; HDLDT1; TGD
| OMIM = 600046
| ECnumber = 
| Homologene = 21130
| MGIid = 99607
| GeneAtlas_image1 = PBB_GE_ABCA1_203504_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_ABCA1_216066_at_tn.png
| Function = {{GNF_GO|id=GO:0000166 |text = nucleotide binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0008509 |text = anion transmembrane transporter activity}} {{GNF_GO|id=GO:0015248 |text = sterol transporter activity}} {{GNF_GO|id=GO:0016887 |text = ATPase activity}}
| Component = {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005794 |text = Golgi apparatus}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006810 |text = transport}} {{GNF_GO|id=GO:0006911 |text = phagocytosis, engulfment}} {{GNF_GO|id=GO:0008202 |text = steroid metabolic process}} {{GNF_GO|id=GO:0008203 |text = cholesterol metabolic process}} {{GNF_GO|id=GO:0030301 |text = cholesterol transport}} {{GNF_GO|id=GO:0042158 |text = lipoprotein biosynthetic process}} {{GNF_GO|id=GO:0045332 |text = phospholipid translocation}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 19
    | Hs_Ensembl = ENSG00000165029
    | Hs_RefseqProtein = NP_005493
    | Hs_RefseqmRNA = NM_005502
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 9
    | Hs_GenLoc_start = 106583104
    | Hs_GenLoc_end = 106730339
    | Hs_Uniprot = O95477
    | Mm_EntrezGene = 11303
    | Mm_Ensembl = ENSMUSG00000015243
    | Mm_RefseqmRNA = NM_013454
    | Mm_RefseqProtein = NP_038482
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 4
    | Mm_GenLoc_start = 53051888
    | Mm_GenLoc_end = 53180992
    | Mm_Uniprot = Q8BPY1
  }}
}}


==Overview==
== Tangier Disease ==
'''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]].<ref name="pmid8088782">{{cite journal | author = Luciani MF, Denizot F, Savary S, Mattei MG, Chimini G | title = Cloning of two novel ABC transporters mapping on human chromosome 9 | journal = Genomics | volume = 21 | issue = 1 | pages = 150–9 | year = 1994 | month = May | pmid = 8088782 | doi = 10.1006/geno.1994.1237 | url =  }}</ref> This transporter is a major regulator of cellular [[cholesterol]] and [[phospholipid]] [[homeostasis]]. The membrane-associated protein encoded by this gene is a member of the superfamily of [[ATP-binding cassette transporter|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.  Mutations in this gene have been associated with [[Tangier disease]] and familial [[high-density lipoprotein]] deficiency.<ref>{{cite web | title = Entrez Gene: ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=19| accessdate =}}</ref>
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<ref name="pmid10431237">{{cite journal | vauthors = 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 | title = The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 347–51 | date = August 1999 | pmid = 10431237 | doi = 10.1038/11914 }}</ref> and Michael Hayden's group in British Columbia<ref name="pmid10431236">{{cite journal | vauthors = 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 | title = Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 336–45 | date = August 1999 | pmid = 10431236 | doi = 10.1038/11905 }}</ref> 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.<ref name="pmid10525055">{{cite journal | vauthors = Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF | title = The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway | journal = The Journal of Clinical Investigation | volume = 104 | issue = 8 | pages = R25–31 | date = October 1999 | pmid = 10525055 | pmc = 481052 | doi = 10.1172/JCI8119 }}</ref> 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.<ref name="urlAmerican Heart Association ">{{cite web | url = http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/01-03-2000/0001106348&EDATE= | title = American Heart Association Selects CV Therapeutics' Discovery of Role Of 'Good' Cholesterol-Regulating Gene as Top Ten 1999 Research Advances In Heart Disease | author = | authorlink = | date = 2000-01-03 | format = | work = | publisher = PR Newswire Association | pages = | archiveurl = | archivedate = | quote = | accessdate = 2009-05-08}}</ref> 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.<ref name="pmid16704350">{{cite journal | vauthors = Brunham LR, Singaraja RR, Hayden MR | title = Variations of a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis | journal = Annual Review of Nutrition | volume = 26 | pages = 105–129 | date = August 2006 | pmid = 16704350 | pmc =  | doi = 10.1146/annurev.nutr.26.061505.111214 }}</ref>
{{See also|ATP-binding cassette transporter}}


==Tangier Disease==
== Function ==
ABCA1 was discovered as the mutation causing [[Tangier Disease]] by several groups in 1998.  Gerd Schmitz's group in Germany<ref name="pmid10431237">{{cite journal | author = 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 | title = The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 347–51 | year = 1999 | month = August | pmid = 10431237 | doi = 10.1038/11914 | url =  }}</ref> and Michael Hayden's group in British Columbia<ref name="pmid10431236">{{cite journal | author = 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 | title = Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 336–45 | year = 1999 | month = August | pmid = 10431236 | doi = 10.1038/11905 | url = }}</ref> 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 effected individuals.<ref name="pmid10525055">{{cite journal | author = Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF | title = The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway | journal = The Journal of Clinical Investigation | volume = 104 | issue = 8 | pages = R25–31 | year = 1999 | month = October | pmid = 10525055 | pmc = 481052 | doi = 10.1172/JCI8119 | url =  }}</ref>  They showed cell lines from patients with Tangier 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.<ref name="urlAmerican Heart Association ">{{cite web | url = http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/01-03-2000/0001106348&EDATE= | title = American Heart Association Selects CV Therapeutics' Discovery of Role Of 'Good' Cholesterol-Regulating Gene as Top Ten 1999 Research Advances In Heart Disease | author = | authorlink = | coauthors = | date = 2000-01-03 | format = | work = | publisher = PR Newswire Association | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2009-05-08}}</ref>
The membrane-associated protein encoded by this gene is a member of the superfamily of [[ATP-binding cassette transporter|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 (microbiology)|efflux]] pump in the cellular lipid removal pathway.<ref>{{cite web | title = Entrez Gene: ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=19| accessdate = }}</ref><ref name="pmid11264984">{{cite journal | vauthors = Schmitz G, Langmann T | title = Structure, function and regulation of the ABC1 gene product | journal = Curr. Opin. Lipidol. | volume = 12 | issue = 2 | pages = 129–40 | date = April 2001 | pmid = 11264984 | doi = 10.1097/00041433-200104000-00006 }}</ref>


==Function==
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.<ref name="pmid16704350" />
The membrane-associated protein encoded by this gene is a member of the superfamily of [[ATP-binding cassette transporter|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 (microbiology)|efflux]] pump in the cellular lipid removal pathway.<ref>{{cite web | title = Entrez Gene: ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=19| accessdate = }}</ref><ref name="pmid11264984">{{cite journal | author = Schmitz G, Langmann T | title = Structure, function and regulation of the ABC1 gene product | journal = Curr. Opin. Lipidol. | volume = 12 | issue = 2 | pages = 129–40 | year = 2001 | month = April | pmid = 11264984 | doi = 10.1097/00041433-200104000-00006| url = }}</ref>


==Physiological role==
== Physiological role ==
ABCA1 mediates the efflux of [[cholesterol]] and [[phospholipid]]s to lipid-poor [[apolipoprotein]]s (apo-A1 and apoE), which then form nascent [[high-density lipoprotein]]s (HDL). It also mediates the transport of lipids between Golgi and [[cell membrane]]. Since this protein is needed throughout the body it is [[Biosynthesis|expressed]] ubiquitously as a 220-[[Dalton (unit)|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.<ref>E. M. Wagner, F. Basso, C. S. Kim, M. J. A. Amar, "ABC lipid transporters", in AccessScience@McGraw-Hill</ref>  
ABCA1 mediates the efflux of [[cholesterol]] and [[phospholipid]]s to lipid-poor [[apolipoprotein]]s (apo-A1 and apoE), which then form nascent [[high-density lipoprotein]]s (HDL). It also mediates the transport of lipids between Golgi and [[cell membrane]]. Since this protein is needed throughout the body it is [[Biosynthesis|expressed]] ubiquitously as a 220-[[Dalton (unit)|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.<ref>E. M. Wagner, F. Basso, C. S. Kim, M. J. A. Amar, "ABC lipid transporters", in AccessScience@McGraw-Hill</ref>


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 acid]]s, cholesterol and also [[cytokine]]s and [[cyclic adenosine monophosphate]].<ref name="pmid16505586">{{cite journal | author = Yokoyama S | title = ABCA1 and biogenesis of HDL | journal = J. Atheroscler. Thromb. | volume = 13 | issue = 1 | pages = 1–15 | year = 2006 | month = February | pmid = 16505586 | doi = 10.5551/jat.13.1| url = http://www.jstage.jst.go.jp/article/jat/13/1/13_1/_article }}</ref>
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 acid]]s, cholesterol and also [[cytokine]]s and [[cyclic adenosine monophosphate|cAMP]].<ref name="pmid16505586">{{cite journal | vauthors = Yokoyama S | title = ABCA1 and biogenesis of HDL | journal = J. Atheroscler. Thromb. | volume = 13 | issue = 1 | pages = 1–15 | date = February 2006 | pmid = 16505586 | doi = 10.5551/jat.13.1 | url = http://www.jstage.jst.go.jp/article/jat/13/1/13_1/_article }}</ref> Other endogenous [[metabolite]]s more loosely related to the ABCA1 functions are also reported to influence the expression of this transporter, including [[glucose]] and [[bilirubin]].<ref>Mauerer R, Ebert S, Langmann T. [https://www.ncbi.nlm.nih.gov/pubmed/19287193 High glucose, unsaturated and saturated fatty acids differentially regulate expression of ATP-binding cassette transporters ABCA1 and ABCG1 in human macrophages]. Exp Mol Med. 2009 Feb 28;41(2):126-32. [http://www.nature.com/emm/journal/v41/n2/full/emm200916a.html PubMed PMID 19287193].</ref><ref>Wang D, Tosevska A, Heiß EH, Ladurner A, Mölzer C, Wallner M, Bulmer A, Wagner KH, Dirsch VM, Atanasov AG. [https://www.ncbi.nlm.nih.gov/pubmed/28455345 Bilirubin Decreases Macrophage Cholesterol Efflux and ATP-Binding Cassette Transporter A1 Protein Expression]. J Am Heart Assoc. 2017 Apr 28;6(5). pii: e005520. [http://jaha.ahajournals.org/content/6/5/e005520.long doi: 10.1161/JAHA.117.005520].</ref>


Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatory, dietary [[polyphenolic antioxidant]] [[Curcumin]]<ref>{{cite journal | author = Bachmeier BE, Iancu CM, Killian PH, Kronski E, Mirisola V, Angelini G, Jochum M, Nerlich AG,Pfeffer U.| year = 2009 | title = Overexpression of the ATP binding cassette gene ABCA1 determines resistance to Curcumin in M14 melanoma cells | journal = Mol Cancer| volume = 8 | pages = 129–141 | pmid = 20030852 | doi=10.1186/1476-4598-8-129 | pmc=2804606}}</ref>
Interactions between members of the apoliprotein family and ABCA1 activate multiple signalling pathways, including the [[JAK-STAT signaling pathway|JAK-STAT]], [[Protein Kinase A|PKA]], and [[Protein Kinase C|PKC]] pathways<ref name="pmid23847008 ">{{cite journal | vauthors = Luu W, Sharpe LJ, Gelissen IC, Brown AJ | title = The role of signalling in cellular cholesterol homeostasis | journal = IUBMB Life | volume = 65 | issue = 8 | pages = 675–684 | date = August 2013 | pmid = 23847008 | doi = 10.1002/iub.1182 | url = http://onlinelibrary.wiley.com/doi/10.1002/iub.1182/abstract;jsessionid=6413E9E73AC4A13EC015AFCE2D5D0F80.d01t01 }}</ref>
Downregulation of ABCA1 in senescent macrophages disrupts the cell's ability to remove cholesterol from it's cytosoplasm, leading the cells to promote the pathologic angiogenesis that "plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration" <ref>{{cite journal | author = Sene A, Khan AA,, et al| year = 2013 | title = Impaired Cholesterol Efflux in Senescent Macrophages Promotes Age-Related Macular Degeneration | journal = Cell Metabolism| volume = 17 | pages = 549–561 }}</ref>


==Clinical significance==
Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatory [[diarylheptanoid]] [[antioxidant]] [[curcumin]].<ref>{{cite journal | vauthors = Bachmeier BE, Iancu CM, Killian PH, Kronski E, Mirisola V, Angelini G, Jochum M, Nerlich AG, Pfeffer U | title = Overexpression of the ATP binding cassette gene ABCA1 determines resistance to Curcumin in M14 melanoma cells | journal = Mol Cancer | volume = 8 | pages = 129–141 | year = 2009 | pmid = 20030852 | pmc = 2804606 | doi = 10.1186/1476-4598-8-129 }}</ref>
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.<ref name="pmid10812922">{{cite journal | author = Ordovas JM | title = ABC1: the gene for Tangier disease and beyond | journal = Nutr. Rev. | volume = 58 | issue = 3 Pt 1 | pages = 76–9 | year = 2000 | month = March | pmid = 10812922 | doi = 10.1111/j.1753-4887.2000.tb01843.x| url =  }}</ref><ref name="pmid10882340">{{cite journal | author = Oram JF, Vaughan AM | title = ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins | journal = Curr. Opin. Lipidol. | volume = 11 | issue = 3 | pages = 253–60 | year = 2000 | month = June | pmid = 10882340 | doi = 10.1097/00041433-200006000-00005| url = }}</ref>
Downregulation of ABCA1 in senescent macrophages disrupts the cell's ability to remove cholesterol from its cytoplasm, leading the cells to promote pathologic [[atherogenesis]] (blood vessel thickening/hardening) which "plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration"<ref>{{cite journal | vauthors = 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 | title = Impaired Cholesterol Efflux in Senescent Macrophages Promotes Age-Related Macular Degeneration | journal = Cell Metabolism | volume = 17 | pages = 549–561 | year = 2013 | pmid = 23562078 | doi = 10.1016/j.cmet.2013.03.009 | pmc=3640261}}</ref> Knockout mouse models of [[Age-related macular degeneration|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.<ref>http://www.faqs.org/patents/app/20130317090</ref>


==Interactions==
== Clinical significance ==
ABCA1 has been shown to [[Protein-protein interaction|interact]] with [[Apolipoprotein A1]],<ref name=pmid12084722>{{cite journal |last=Fitzgerald |first=Michael L |authorlink= |coauthors=Morris Andrea L, Rhee Jeongmi S, Andersson Lorna P, Mendez Armando J, Freeman Mason W |year=2002|month=September  |title=Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I |journal=J. Biol. Chem. |volume=277 |issue=36 |pages=33178–87 |publisher= |location = United States| issn = 0021-9258| pmid = 12084722 |doi = 10.1074/jbc.M204996200 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[FADD]],<ref name=pmid12235128>{{cite journal |last=Buechler |first=Christa |authorlink= |coauthors=Bared Salim Maa, Aslanidis Charalampos, Ritter Mirko, Drobnik Wolfgang, Schmitz Gerd |year=2002|month=November  |title=Molecular and functional interaction of the ATP-binding cassette transporter A1 with Fas-associated death domain protein |journal=J. Biol. Chem. |volume=277 |issue=44 |pages=41307–10 |publisher= |location = United States| issn = 0021-9258| pmid = 12235128 |doi = 10.1074/jbc.C200436200 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref> [[XPC (gene)|XPC]]<ref name=pmid12505994>{{cite journal |last=Shimizu |first=Yuichiro |authorlink= |coauthors=Iwai Shigenori, Hanaoka Fumio, Sugasawa Kaoru |year=2003|month=January  |title=Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase |journal=EMBO J. |volume=22 |issue=1 |pages=164–73 |publisher= |location = England| issn = 0261-4189| pmid = 12505994 |doi = 10.1093/emboj/cdg016 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |pmc=140069 }}</ref> and [[SNTB2]].<ref name=pmid12054535>{{cite journal |last=Buechler |first=Christa |authorlink= |coauthors=Boettcher Alfred, Bared Salim Maa, Probst Mario C O, Schmitz Gerd |year=2002|month=May. |title=The carboxyterminus of the ATP-binding cassette transporter A1 interacts with a beta2-syntrophin/utrophin complex |journal=Biochem. Biophys. Res. Commun. |volume=293 |issue=2 |pages=759–65 |publisher= |location = United States| issn = 0006-291X| pmid = 12054535 |doi = 10.1016/S0006-291X(02)00303-0 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref>
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.<ref name="pmid10812922">{{cite journal | vauthors = Ordovas JM | title = ABC1: the gene for Tangier disease and beyond | journal = Nutr. Rev. | volume = 58 | issue = 3 Pt 1 | pages = 76–9 | date = March 2000 | pmid = 10812922 | doi = 10.1111/j.1753-4887.2000.tb01843.x }}</ref><ref name="pmid10882340">{{cite journal | vauthors = Oram JF, Vaughan AM | title = ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins | journal = Curr. Opin. Lipidol. | volume = 11 | issue = 3 | pages = 253–60 | date = June 2000 | pmid = 10882340 | doi = 10.1097/00041433-200006000-00005 }}</ref>
Leukocytes ABCA1 gene expression is upregulated in postmenopausal women receiving [[Hormone replacement therapy (menopause)|hormone replacement therapy (HRP)]].<ref name="pmid20807164">{{cite journal | vauthors = Darabi M, Rabbani M, Ani M, Zarean E, Panjehpour M, Movahedian A | title = Increased leukocyte ABCA1 gene expression in post-menopausal women on hormone replacement therapy | journal = Gynecol. Endocrinol. | volume = 27 | issue = 9 | pages = 701–5 | year = 2011 | pmid = 20807164 | doi = 10.3109/09513590.2010.507826 }}</ref>


==References==
== Interactive pathway map ==
{{StatinPathway_WP430|highlight=ABCA1}}
 
== Interactions ==
ABCA1 has been shown to [[Protein-protein interaction|interact]] with:
* [[Apolipoprotein A1|APOA1]],<ref name = pmid12084722>{{cite journal | vauthors = Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ, Freeman MW | title = Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I | journal = J. Biol. Chem. | volume = 277 | issue = 36 | pages = 33178–87 | date = September 2002 | pmid = 12084722 | doi = 10.1074/jbc.M204996200 }}</ref>
* [[Apolipoprotein E|APOE]],
* [[FADD]],<ref name = pmid12235128>{{cite journal | vauthors = Buechler C, Bared SM, Aslanidis C, Ritter M, Drobnik W, Schmitz G | title = Molecular and functional interaction of the ATP-binding cassette transporter A1 with Fas-associated death domain protein | journal = J. Biol. Chem. | volume = 277 | issue = 44 | pages = 41307–10 | date = November 2002 | pmid = 12235128 | doi = 10.1074/jbc.C200436200 }}</ref>
* [[SNTB2]],<ref name = pmid12054535>{{cite journal | vauthors = Buechler C, Boettcher A, Bared SM, Probst MC, Schmitz G | title = The carboxyterminus of the ATP-binding cassette transporter A1 interacts with a beta2-syntrophin/utrophin complex | journal = Biochem. Biophys. Res. Commun. | volume = 293 | issue = 2 | pages = 759–65 | date = May 2002 | pmid = 12054535 | doi = 10.1016/S0006-291X(02)00303-0 }}</ref> and
* [[XPC (gene)|XPC]].<ref name = pmid12505994>{{cite journal | vauthors = Shimizu Y, Iwai S, Hanaoka F, Sugasawa K | title = Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase | journal = EMBO J. | volume = 22 | issue = 1 | pages = 164–73 | date = January 2003 | pmid = 12505994 | pmc = 140069 | doi = 10.1093/emboj/cdg016 }}</ref>
 
== See also ==
* [[ATP-binding cassette transporter]]
 
== References ==
{{Reflist|2}}
{{Reflist|2}}


[[Category:ABC transporters]]
== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Tam SP, Mok L, Chimini G, Vasa M, Deeley RG | title = ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of oxysterol by intact cells | journal = Am J Physiol Cell Physiol | volume = 291 | issue = 3 | pages = C490–502 | year = 2006 | pmid = 16611739 | doi = 10.1152/ajpcell.00055.2006 }}
* {{cite journal | vauthors = Oram JF | title = ATP-binding cassette transporter A1 and cholesterol trafficking | journal = Curr. Opin. Lipidol. | volume = 13 | issue = 4 | pages = 373–81 | year = 2003 | pmid = 12151852 | doi = 10.1097/00041433-200208000-00004 }}
* {{cite journal | vauthors = Hong SH, Rhyne J, Zeller K, Miller M | title = ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease | journal = Atherosclerosis | volume = 164 | issue = 2 | pages = 245–50 | year = 2003 | pmid = 12204794 | doi = 10.1016/S0021-9150(02)00106-5 }}
* {{cite journal | vauthors = Kozak M | title = Emerging links between initiation of translation and human diseases | journal = Mamm. Genome | volume = 13 | issue = 8 | pages = 401–10 | year = 2003 | pmid = 12226704 | doi = 10.1007/s00335-002-4002-5 }}
* {{cite journal | vauthors = Joyce C, Freeman L, Brewer HB, Santamarina-Fojo S | title = Study of ABCA1 function in transgenic mice | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 23 | issue = 6 | pages = 965–71 | year = 2004 | pmid = 12615681 | doi = 10.1161/01.ATV.0000055194.85073.FF }}
* {{cite journal | vauthors = Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR | title = Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene | journal = Arterioscler. Thromb. Vasc. Biol. | volume = 23 | issue = 8 | pages = 1322–32 | year = 2004 | pmid = 12763760 | doi = 10.1161/01.ATV.0000078520.89539.77 }}
* {{cite journal | vauthors = Nofer JR, Remaley AT | title = Tangier disease: still more questions than answers | journal = Cell. Mol. Life Sci. | volume = 62 | issue = 19–20 | pages = 2150–60 | year = 2005 | pmid = 16235041 | doi = 10.1007/s00018-005-5125-0 }}
* {{cite journal | vauthors = Yokoyama S | title = ABCA1 and biogenesis of HDL | journal = J. Atheroscler. Thromb. | volume = 13 | issue = 1 | pages = 1–15 | year = 2006 | pmid = 16505586 | doi = 10.5551/jat.13.1 }}
* {{cite journal | vauthors = Schmitz G, Schambeck CM | title = Molecular defects in the ABCA1 pathway affect platelet function | journal = Pathophysiol. Haemost. Thromb. | volume = 35 | issue = 1–2 | pages = 166–74 | year = 2006 | pmid = 16855366 | doi = 10.1159/000093563 }}
{{refend}}
 
== External links ==
* {{UCSC genome browser|ABCA1}}
* {{UCSC gene details|ABCA1}}


{{ABC transporters}}
{{Lipoproteins}}
{{Lipoproteins}}
{{Membrane transport proteins}}
 
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[[Category:ABC transporters]]

Revision as of 02:06, 9 November 2017

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View/Edit Human

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.[1] This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.

Tangier Disease

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[2] and Michael Hayden's group in British Columbia[3] 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.[4] 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.[5] 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.[6]

Function

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.[7][8]

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.[6]

Physiological role

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.[9]

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.[10] Other endogenous metabolites more loosely related to the ABCA1 functions are also reported to influence the expression of this transporter, including glucose and bilirubin.[11][12]

Interactions between members of the apoliprotein family and ABCA1 activate multiple signalling pathways, including the JAK-STAT, PKA, and PKC pathways[13]

Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatory diarylheptanoid antioxidant curcumin.[14] Downregulation of ABCA1 in senescent macrophages disrupts the cell's ability to remove cholesterol from its cytoplasm, leading the cells to promote pathologic atherogenesis (blood vessel thickening/hardening) which "plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration"[15] 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.[16]

Clinical significance

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.[17][18] Leukocytes ABCA1 gene expression is upregulated in postmenopausal women receiving hormone replacement therapy (HRP).[19]

Interactive pathway map

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

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Statin Pathway edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Interactions

ABCA1 has been shown to interact with:

See also

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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 481052. PMID 10525055.
  5. ↑ "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.
  6. ↑ 6.0 6.1 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.
  7. ↑ "Entrez Gene: ABCA1 ATP-binding cassette, sub-family A (ABC1), member 1".
  8. ↑ 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.
  9. ↑ E. M. Wagner, F. Basso, C. S. Kim, M. J. A. Amar, "ABC lipid transporters", in AccessScience@McGraw-Hill
  10. ↑ Yokoyama S (February 2006). "ABCA1 and biogenesis of HDL". J. Atheroscler. Thromb. 13 (1): 1–15. doi:10.5551/jat.13.1. PMID 16505586.
  11. ↑ Mauerer R, Ebert S, Langmann T. High glucose, unsaturated and saturated fatty acids differentially regulate expression of ATP-binding cassette transporters ABCA1 and ABCG1 in human macrophages. Exp Mol Med. 2009 Feb 28;41(2):126-32. PubMed PMID 19287193.
  12. ↑ Wang D, Tosevska A, Heiß EH, Ladurner A, Mölzer C, Wallner M, Bulmer A, Wagner KH, Dirsch VM, Atanasov AG. Bilirubin Decreases Macrophage Cholesterol Efflux and ATP-Binding Cassette Transporter A1 Protein Expression. J Am Heart Assoc. 2017 Apr 28;6(5). pii: e005520. doi: 10.1161/JAHA.117.005520.
  13. ↑ 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.
  14. ↑ 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 2804606. PMID 20030852.
  15. ↑ 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. PMC 3640261. PMID 23562078.
  16. ↑ http://www.faqs.org/patents/app/20130317090
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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 140069. PMID 12505994.

Further reading

External links

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