ABCA1

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.{{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 = 150–159 | date = May 1994 | pmid = 8088782 | doi = 10.1006/geno.1994.1237 }} 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 disease by several groups in 1998. Gerd Schmitz's group in Germany{{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 | display-authors = 6 | title = The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 347–351 | date = August 1999 | pmid = 10431237 | doi = 10.1038/11914 | s2cid = 26890624 }} and Michael Hayden's group in British Columbia{{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 | display-authors = 6 | title = Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 336–345 | date = August 1999 | pmid = 10431236 | doi = 10.1038/11905 | s2cid = 1497231 }} 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.{{cite journal | vauthors = Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM, Oram JF | display-authors = 6 | 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–R31 | date = October 1999 | pmid = 10525055 | pmc = 481052 | doi = 10.1172/JCI8119 }} 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.{{cite press release |title=American Heart Association Selects CV Therapeutics' Discovery of Role Of 'Good' Cholesterol-Regulating Gene as Top Ten 1999 Research Advances In Heart Disease |publisher=CV Therapeutics; Incyte Pharmaceuticals |date=January 3, 2000 |url=https://www.prnewswire.com/news-releases/american-heart-association-selects-cv-therapeutics-discovery-of-role-of-good-cholesterol-regulating-gene-as-top-ten-1999-research-advances-in-heart-disease-71912417.html |access-date=May 28, 2018 }} 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.{{cite journal | vauthors = Brunham LR, Singaraja RR, Hayden MR | title = Variations on 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 | year = 2006 | pmid = 16704350 | doi = 10.1146/annurev.nutr.26.061505.111214 }}

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.{{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 }}{{cite journal | vauthors = Schmitz G, Langmann T | title = Structure, function and regulation of the ABC1 gene product | journal = Current Opinion in Lipidology | volume = 12 | issue = 2 | pages = 129–140 | date = April 2001 | pmid = 11264984 | doi = 10.1097/00041433-200104000-00006 | s2cid = 23837673 }}

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.

Physiological role

ABCA1 mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins (apoA1 and apoE) (reverse cholesterol transport), 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.{{cite journal | vauthors = Wagner E, Basso F, Kim CS, Amar MJ | title = ABC lipid transporters | year = 2014 | journal = AccessScience | publisher = McGraw-Hill Education | doi=10.1036/1097-8542.801530 }}

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.{{cite journal | vauthors = Yokoyama S | title = ABCA1 and biogenesis of HDL | journal = Journal of Atherosclerosis and Thrombosis | volume = 13 | issue = 1 | pages = 1–15 | date = February 2006 | pmid = 16505586 | doi = 10.5551/jat.13.1 | doi-access = free }} Adiponectin induces reverse cholesterol transport by an ABCA1-dependent pathway.{{cite journal | vauthors = Hafiane A, Gasbarrino K, Daskalopoulou SS | title = The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism | journal = Metabolism | volume = 100 | pages = 153953 | date = November 2019 | pmid = 31377319 | doi = 10.1016/j.metabol.2019.153953 | s2cid = 203413137 }} Other endogenous metabolites more loosely related to the ABCA1 functions are also reported to influence the expression of this transporter, including glucose and bilirubin.{{cite journal | vauthors = Mauerer R, Ebert S, Langmann T | title = High glucose, unsaturated and saturated fatty acids differentially regulate expression of ATP-binding cassette transporters ABCA1 and ABCG1 in human macrophages | journal = Experimental & Molecular Medicine | volume = 41 | issue = 2 | pages = 126–132 | date = February 2009 | pmid = 19287193 | pmc = 2679329 | doi = 10.3858/emm.2009.41.2.015 }}{{cite journal | vauthors = Wang D, Tosevska A, Heiß EH, Ladurner A, Mölzer C, Wallner M, Bulmer A, Wagner KH, Dirsch VM, Atanasov AG | display-authors = 6 | title = Bilirubin Decreases Macrophage Cholesterol Efflux and ATP-Binding Cassette Transporter A1 Protein Expression | journal = Journal of the American Heart Association | volume = 6 | issue = 5 | pages = e005520 | date = April 2017 | pmid = 28455345 | pmc = 5524097 | doi = 10.1161/JAHA.117.005520 }}

Interactions between members of the apoliprotein family and ABCA1 activate multiple signalling pathways, including the JAK-STAT, PKA, and PKC pathways{{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 | s2cid = 23391447 | doi-access = free }}

Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatory diarylheptanoid antioxidant curcumin.{{cite journal | vauthors = Bachmeier BE, Iancu CM, Killian PH, Kronski E, Mirisola V, Angelini G, Jochum M, Nerlich AG, Pfeffer U | display-authors = 6 | title = Overexpression of the ATP binding cassette gene ABCA1 determines resistance to Curcumin in M14 melanoma cells | journal = Molecular Cancer | volume = 8 | pages = 129 | date = December 2009 | pmid = 20030852 | pmc = 2804606 | doi = 10.1186/1476-4598-8-129 | doi-access = free }}

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"{{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 | display-authors = 6 | title = Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration | journal = Cell Metabolism | volume = 17 | issue = 4 | pages = 549–561 | date = April 2013 | pmid = 23562078 | pmc = 3640261 | doi = 10.1016/j.cmet.2013.03.009 }} 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.http://www.faqs.org/patents/app/20130317090{{full|date=September 2018}}{{Dead link|date=June 2020 |bot=InternetArchiveBot |fix-attempted=yes }}

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.{{cite journal | vauthors = Ordovas JM | title = ABC1: the gene for Tangier disease and beyond | journal = Nutrition Reviews | volume = 58 | issue = 3 Pt 1 | pages = 76–79 | date = March 2000 | pmid = 10812922 | doi = 10.1111/j.1753-4887.2000.tb01843.x | doi-access = free }}{{cite journal | vauthors = Oram JF, Vaughan AM | title = ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins | journal = Current Opinion in Lipidology | volume = 11 | issue = 3 | pages = 253–260 | date = June 2000 | pmid = 10882340 | doi = 10.1097/00041433-200006000-00005 }}

Leukocytes' ABCA1 gene expression is upregulated in postmenopausal women receiving hormone replacement therapy (HRP).{{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 = Gynecological Endocrinology | volume = 27 | issue = 9 | pages = 701–705 | date = September 2011 | pmid = 20807164 | doi = 10.3109/09513590.2010.507826 | s2cid = 203464 }} ABCA1 expression is also upregulated in tumor-associated astroctytes surrounding glioblastoma brain tumors, and is important to the tumor progression. {{cite journal | vauthors = Perelroizen R, Philosof B, Budick-Harmelin N, Chernobylsky T, Ron A, Katzir R, Shimon D, Tessler A, Adir O, Gaoni-Yogev A, Meyer T, Krivitsky A, Shidlovsky N, Madi A, Ruppin E, Mayo L | display-authors = 6 | title = Astrocyte immunometabolic regulation of the tumour microenvironment drives glioblastoma pathogenicity | journal = Brain | pages = 3288–3307 | date = July 2022 | volume = 145 | issue = 9 | pmid = 35899587 | doi = 10.1093/brain/awac222 | pmc = 10233310 | doi-access = free }}{{cite journal | vauthors = Murk K, Hülse R | title = Forced but effective partners in crime: How astrocytes drive the progression of glioblastoma | journal = Brain | pages = 2952–2954 | date = August 2022 | volume = 145 | issue = 9 | pmid = 35978482 | doi = 10.1093/brain/awac302 | doi-access = free }}

Interactive pathway map

Interactions

ABCA1 has been shown to interact with:

APOA1,{{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 = The Journal of Biological Chemistry | volume = 277 | issue = 36 | pages = 33178–33187 | date = September 2002 | pmid = 12084722 | doi = 10.1074/jbc.M204996200 | doi-access = free }}
APOE,
FADD,{{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 = The Journal of Biological Chemistry | volume = 277 | issue = 44 | pages = 41307–41310 | date = November 2002 | pmid = 12235128 | doi = 10.1074/jbc.C200436200 | doi-access = free }}
SNTB2,{{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 = Biochemical and Biophysical Research Communications | volume = 293 | issue = 2 | pages = 759–765 | date = May 2002 | pmid = 12054535 | doi = 10.1016/S0006-291X(02)00303-0 }} and
XPC.{{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 = The EMBO Journal | volume = 22 | issue = 1 | pages = 164–173 | date = January 2003 | pmid = 12505994 | pmc = 140069 | doi = 10.1093/emboj/cdg016 }}

References

External links

{{UCSC genome browser|ABCA1}}
{{UCSC gene details|ABCA1}}

Category:ATP-binding cassette transporters