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ABCA7

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ABCA7
Identifiers
AliasesABCA7, ABCA-SSN, ABCX, AD9, ATP binding cassette subfamily A member 7
External IDsOMIM: 605414; MGI: 1351646; HomoloGene: 22783; GeneCards: ABCA7; OMA:ABCA7 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10347

27403

Ensembl

ENSG00000064687

ENSMUSG00000035722

UniProt

Q8IZY2

Q91V24

RefSeq (mRNA)

NM_019112
NM_033308

NM_013850
NM_001347081

RefSeq (protein)

NP_061985

NP_001334010
NP_038878

Location (UCSC)Chr 19: 1.04 – 1.07 MbChr 10: 79.83 – 79.85 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ATP-binding cassette sub-family A member 7 is a protein that in humans is encoded by the ABCA7 gene.[5]

Function

The 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 intra-cellular membranes. ABC genes are divided into seven distinct subfamilies: ABC1, MDR/TAP, CFTR/MRP, ALD (adrenoleukodystrophy), OABP, GCN20, and White. This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This full transporter has been detected predominantly in myelo-lymphatic tissues with the highest expression in peripheral leukocytes, thymus, spleen, and bone marrow. The function of this protein is not yet known; however, the expression pattern suggests a role in lipid homeostasis in cells of the immune system. Alternative splicing of this gene results in two transcript variants.[5]

Lack of ABCA7 gene exhibits phenotypes in mice, such as moderate decrease in plasma HDL and adipose tissues only in female, while release of cellular cholesterol and phospholipid is not impaired. [6] Accordingly, decrease in plasma lectin level was also reported. [7] Reduction of CD3 or CD1d may lead to dysfunction of T cells by deletion of ABCA7. [8] [9]

On the other hand, transfected and expressed ABCA7, but not endogenous ABCA7, mediates release of cell phospholipid and cholesterol to generate HDL-like particles but contain less cholesterol than those generated by ABCA1. [10] [11] ABCA7-generated HDL is smaller and appears as a single peak in a molecular sieve HPLC analysis in comparison to HDL generated by ABCA1 that shows twin peaks of small and poor in cholesterol and large and rich in cholesterol. [12] [13] ABCA7 mRNA generates full length cDNA and a spliced form of cDNA, and only the former is capable of generating HDL when transfected. [14]

ABCA7 was shown associated with cellular phagocytotic activity [15] [16]. The promoter of ABCA7 contains sterol regulatory element (SRE) so that ABCA7 is down-regulated by cell cholesterol through sterol regulatory element binding protein (SREBP) 2 [15]. Therefore, ABCA7 expression and phagocytosis are up-regulated by use of HMG-reductase inhibitors (statins) [17]. In addition, ABCA7 is stabilized like ABCA1 by helical apolipoproteins such as apoA-I,[18] [19][20]and phagocytosis is accordingly increased in such a condition.[20]

In summary, ABCA7 is a substantially related protein to ABCA1 but it does not mediate cell cholesterol release by generation of HDL unless it is externally transfected and expressed in vitro. ABCA7 is shown associated with cellular phagocytotic function in vivo and in vitro, and expression of the ABCA7 gene is regulated by cell cholesterol mainly through the SRE/SREBP system in a negative feed-back fashion in contrast to positive feedback by the LXR/RXR system for ABCA1.[21] ABCA7 thus links cholesterol metabolism to host defense system.

Clinical significance

In 2011, two genome-wide association studies (GWAS) identified ABCA7 as a new susceptibility locus for late-onset Alzheimer’s disease. [22] [23] The finding was also confirmed by other meta-analysis investigations later. [24][25] Such association of ABCA7 variants was reported on more specific findings of the disease such as memory decline and incident mild cognitive impairment [26] or cortical and hippocampal atrophy.[27][28]

Protein-disrupting variants in ABCA7 have been shown to predispose to Alzheimer's disease.[29] The Icelandic database of Decode Genetics has shown a doubled probability of developing Alzheimer's disease when inactive variants of the ABCA7 gene are present.[30]


By using the knock-out mice, ABCA7 was indicated involved in generation and processing of amyloid β (Aβ) peptides. In the brain of the amyloid precursor protein transgenic mice, deletion of ABCA7 resulted in accumulation of Aβ40 and Aβ42 in the early stage [31] apparently by accelerating Aβ production. [31][32] More rapid endocytosis of amyloid precursor protein was observed in primary microglia from ABCA7 deficient mice. [31] Roles of ABCA7 are also implicated for microglial phagocytotic function [33] and immune responses. [34][35] Although the direct target of ABCA7 function is unclear, the findings are so far mechanistically consistent with the increased Aβ production.


See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000064687 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035722 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: ABCA7 ATP-binding cassette, sub-family A (ABC1), member 7".
  6. ^ Kim WS, Fitzgerald ML, Kang K, Okuhira K, Bell SA, Manning JJ, Koehn SL, Lu N, Moore KJ, Freeman MW. Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels. J Biol Chem. 2005 Feb 4;280(5):3989-95. doi: 10.1074/jbc.M412602200. Epub 2004 Nov 17. PMID: 15550377.
  7. ^ Bhatia S, Fu Y, Hsiao JT, Halliday GM, Kim WS. Deletion of Alzheimer's Disease Risk Gene ABCA7 Alters White Adipose Tissue Development and Leptin Levels. J Alzheimers Dis Rep. 2017 Dec 16;1(1):237-247. doi: 10.3233/ADR-170029. PMID: 30480241; PMCID: PMC6159609.
  8. ^ Meurs I, Calpe-Berdiel L, Habets KL, Zhao Y, Korporaal SJ, Mommaas AM, Josselin E, Hildebrand RB, Ye D, Out R, Kuiper J, Van Berkel TJ, Chimini G, Van Eck M. Effects of deletion of macrophage ABCA7 on lipid metabolism and the development of atherosclerosis in the presence and absence of ABCA1. PLoS One. 2012;7(3):e30984. doi: 10.1371/journal.pone.0030984. Epub 2012 Mar 5. Erratum in: PLoS One. 2012;7(5). doi:10.1371/annotation/577d9009-baf4-46ea-b44e-eda094b604db. PMID: 22403608; PMCID: PMC3293875.
  9. ^ Nowyhed HN, Chandra S, Kiosses W, Marcovecchio P, Andary F, Zhao M, Fitzgerald ML, Kronenberg M, Hedrick CC. ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content. Sci Rep. 2017 Jan 16;7:40273. doi: 10.1038/srep40273. PMID: 28091533; PMCID: PMC5238393.
  10. ^ Wang N, Lan D, Gerbod-Giannone M, Linsel-Nitschke P, Jehle AW, Chen W, Martinez LO, Tall AR (Oct 2003). "ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux". The Journal of Biological Chemistry. 278 (44): 42906–12. doi:10.1074/jbc.M307831200. PMID 12917409.
  11. ^ Abe-Dohmae S, Ikeda Y, Matsuo M, Hayashi M, Okuhira K, Ueda K, Yokoyama S (Jan 2004). "Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate high density lipoprotein". The Journal of Biological Chemistry. 279 (1): 604–11. doi:10.1074/jbc.M309888200. PMID 14570867.
  12. ^ Hayashi M, Abe-Dohmae S, Okazaki M, Ueda K, Yokoyama S (Aug 2005). "Heterogeneity of high density lipoprotein generated by ABCA1 and ABCA7". Journal of Lipid Research. 46 (8): 1703–11. doi:10.1194/jlr.M500092-JLR200. PMID 15930518.
  13. ^ Abe-Dohmae S, Kato KH, Kumon Y, Hu W, Ishigami H, Iwamoto N, Okazaki M, Wu CA, Tsujita M, Ueda K, Yokoyama S. Serum amyloid A generates high density lipoprotein with cellular lipid in an ABCA1- or ABCA7-dependent manner. J Lipid Res. 2006 Jul;47(7):1542-50. doi: 10.1194/jlr.M600145-JLR200. Epub 2006 Apr 10. PMID: 16607034.
  14. ^ Ikeda Y, Abe-Dohmae S, Munehira Y, Aoki R, Kawamoto S, Furuya A, Shitara K, Amachi T, Kioka N, Matsuo M, Yokoyama S, Ueda K (Nov 2003). "Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release". Biochemical and Biophysical Research Communications. 311 (2): 313–8. doi:10.1016/j.bbrc.2003.10.002. PMID 14592415.
  15. ^ a b Iwamoto, Noriyuki; Abe-Dohmae, Sumiko; Sato, Ryuichiro; Yokoyama, Shinji (September 2006). "ABCA7 expression is regulated by cellular cholesterol through the SREBP2 pathway and associated with phagocytosis". Journal of Lipid Research. 47 (9): 1915–1927. doi:10.1194/jlr.M600127-JLR200. ISSN 0022-2275. PMID 16788211.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Jehle, Andreas W.; Gardai, Shyra J.; Li, Suzhao; Linsel-Nitschke, Patrick; Morimoto, Konosuke; Janssen, William J.; Vandivier, R. William; Wang, Nan; Greenberg, Steven; Dale, Benjamin M.; Qin, Chunbo (2006-08-14). "ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages". The Journal of Cell Biology. 174 (4): 547–556. doi:10.1083/jcb.200601030. ISSN 0021-9525. PMC 2064260. PMID 16908670.
  17. ^ Tanaka, Nobukiyo; Abe-Dohmae, Sumiko; Iwamoto, Noriyuki; Fitzgerald, Michael L.; Yokoyama, Shinji (August 2011). "HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7". Atherosclerosis. 217 (2): 407–414. doi:10.1016/j.atherosclerosis.2011.06.031. ISSN 1879-1484. PMC 3150192. PMID 21762915.
  18. ^ Arakawa, Reijiro; Yokoyama, Shinji (2002-06-21). "Helical apolipoproteins stabilize ATP-binding cassette transporter A1 by protecting it from thiol protease-mediated degradation". The Journal of Biological Chemistry. 277 (25): 22426–22429. doi:10.1074/jbc.M202996200. ISSN 0021-9258. PMID 11950847.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Lu, Rui; Arakawa, Reijiro; Ito-Osumi, Chisato; Iwamoto, Noriyuki; Yokoyama, Shinji (October 2008). "ApoA-I facilitates ABCA1 recycle/accumulation to cell surface by inhibiting its intracellular degradation and increases HDL generation". Arteriosclerosis, Thrombosis, and Vascular Biology. 28 (10): 1820–1824. doi:10.1161/ATVBAHA.108.169482. ISSN 1524-4636. PMID 18617649.
  20. ^ a b Tanaka, Nobukiyo; Abe-Dohmae, Sumiko; Iwamoto, Noriyuki; Fitzgerald, Michael L.; Yokoyama, Shinji (September 2010). "Helical apolipoproteins of high-density lipoprotein enhance phagocytosis by stabilizing ATP-binding cassette transporter A7". Journal of Lipid Research. 51 (9): 2591–2599. doi:10.1194/jlr.M006049. ISSN 1539-7262. PMC 2918442. PMID 20495215.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Costet, P.; Luo, Y.; Wang, N.; Tall, A. R. (2000-09-08). "Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor". The Journal of Biological Chemistry. 275 (36): 28240–28245. doi:10.1074/jbc.M003337200. ISSN 0021-9258. PMID 10858438.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  22. ^ Hollingworth, Paul; Harold, Denise; Sims, Rebecca; Gerrish, Amy; Lambert, Jean-Charles; Carrasquillo, Minerva M.; Abraham, Richard; Hamshere, Marian L.; Pahwa, Jaspreet Singh; Moskvina, Valentina; Dowzell, Kimberley (May 2011). "Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease". Nature Genetics. 43 (5): 429–435. doi:10.1038/ng.803. ISSN 1546-1718. PMC 3084173. PMID 21460840.
  23. ^ Naj, Adam C.; Jun, Gyungah; Beecham, Gary W.; Wang, Li-San; Vardarajan, Badri Narayan; Buros, Jacqueline; Gallins, Paul J.; Buxbaum, Joseph D.; Jarvik, Gail P.; Crane, Paul K.; Larson, Eric B. (May 2011). "Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease". Nature Genetics. 43 (5): 436–441. doi:10.1038/ng.801. ISSN 1546-1718. PMC 3090745. PMID 21460841.
  24. ^ Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis (2013-04-10). "Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans". JAMA. 309 (14): 1483–1492. doi:10.1001/jama.2013.2973. ISSN 1538-3598. PMC 3667653. PMID 23571587.
  25. ^ Lambert, J. C.; Ibrahim-Verbaas, C. A.; Harold, D.; Naj, A. C.; Sims, R.; Bellenguez, C.; DeStafano, A. L.; Bis, J. C.; Beecham, G. W.; Grenier-Boley, B.; Russo, G. (December 2013). "Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease". Nature Genetics. 45 (12): 1452–1458. doi:10.1038/ng.2802. ISSN 1546-1718. PMC 3896259. PMID 24162737.
  26. ^ Carrasquillo, Minerva M.; Crook, Julia E.; Pedraza, Otto; Thomas, Colleen S.; Pankratz, V. Shane; Allen, Mariet; Nguyen, Thuy; Malphrus, Kimberly G.; Ma, Li; Bisceglio, Gina D.; Roberts, Rosebud O. (January 2015). "Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease". Neurobiology of Aging. 36 (1): 60–67. doi:10.1016/j.neurobiolaging.2014.07.042. ISSN 1558-1497. PMC 4268433. PMID 25189118.
  27. ^ Ramirez, Leslie M.; Goukasian, Naira; Porat, Shai; Hwang, Kristy S.; Eastman, Jennifer A.; Hurtz, Sona; Wang, Benjamin; Vang, Nouchee; Sears, Renee; Klein, Eric; Coppola, Giovanni (March 2016). "Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy". Neurobiology of Aging. 39: 82–89. doi:10.1016/j.neurobiolaging.2015.10.037. ISSN 1558-1497. PMID 26923404.
  28. ^ Schott, Jonathan M.; Crutch, Sebastian J.; Carrasquillo, Minerva M.; Uphill, James; Shakespeare, Tim J.; Ryan, Natalie S.; Yong, Keir X.; Lehmann, Manja; Ertekin-Taner, Nilufer; Graff-Radford, Neill R.; Boeve, Bradley F. (August 2016). "Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease". Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 12 (8): 862–871. doi:10.1016/j.jalz.2016.01.010. ISSN 1552-5279. PMC 4982482. PMID 26993346.
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  30. ^ Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, et al. (May 2015). "Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease". Nature Genetics. 47 (5): 445–7. doi:10.1038/ng.3246. hdl:11250/296499. PMID 25807283. S2CID 205349727. {{cite journal}}: Unknown parameter |lay-url= ignored (help); Unknown parameter |laysource= ignored (help)
  31. ^ a b c Satoh, Kanayo; Abe-Dohmae, Sumiko; Yokoyama, Shinji; St George-Hyslop, Peter; Fraser, Paul E. (2015-10-02). "ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing". The Journal of Biological Chemistry. 290 (40): 24152–24165. doi:10.1074/jbc.M115.655076. ISSN 1083-351X. PMC 4591804. PMID 26260791.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  32. ^ Sakae, Nobutaka; Liu, Chia-Chen; Shinohara, Mitsuru; Frisch-Daiello, Jessica; Ma, Li; Yamazaki, Yu; Tachibana, Masaya; Younkin, Linda; Kurti, Aishe; Carrasquillo, Minerva M.; Zou, Fanggeng (2016-03-30). "ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology". The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 36 (13): 3848–3859. doi:10.1523/JNEUROSCI.3757-15.2016. ISSN 1529-2401. PMC 4812140. PMID 27030769.
  33. ^ Fu, YuHong; Hsiao, Jen-Hsiang T.; Paxinos, George; Halliday, Glenda M.; Kim, Woojin Scott (September 2016). "ABCA7 Mediates Phagocytic Clearance of Amyloid-β in the Brain". Journal of Alzheimer's disease: JAD. 54 (2): 569–584. doi:10.3233/JAD-160456. ISSN 1875-8908. PMID 27472885.
  34. ^ Aikawa, Tomonori; Ren, Yingxue; Yamazaki, Yu; Tachibana, Masaya; Johnson, Madeleine R.; Anderson, Casey T.; Martens, Yuka A.; Holm, Marie-Louise; Asmann, Yan W.; Saito, Takashi; Saido, Takaomi C. (November 2019). "ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain". Proceedings of the National Academy of Sciences of the United States of America. 116 (47): 23790–23796. doi:10.1073/pnas.1908529116. ISSN 1091-6490. PMC 6876254. PMID 31690660.
  35. ^ Nowyhed, Heba N.; Chandra, Shilpi; Kiosses, William; Marcovecchio, Paola; Andary, Farah; Zhao, Meng; Fitzgerald, Michael L.; Kronenberg, Mitchell; Hedrick, Catherine C. (January 2017). "ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content". Scientific Reports. 7: 40273. doi:10.1038/srep40273. ISSN 2045-2322. PMC 5238393. PMID 28091533.

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