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, HDLCQTL13, HPALP1
ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), also known as thecholesterol efflux regulatory protein (CERP) is aprotein which in humans is encoded by theABCA1gene.[5] This transporter is a major regulator of cellularcholesterol andphospholipidhomeostasis.
It was discovered that a mutation in the ABCA1 protein is responsible for causingTangier disease by several groups in 1998. Gerd Schmitz's group in Germany[6] and Michael Hayden's group in British Columbia[7] 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.[8] 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.[9] 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.[10]
The membrane-associated protein encoded by this gene is a member of the superfamily ofATP-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 cholesterolefflux pump in the cellular lipid removal pathway.[11][12]
While the complete 3D-structure of ABCA1 remains relatively unknown, there has been some determination of the c-terminus. The ABCA1 c-terminus contains aPDZ domain, responsible for mediating protein-protein interactions, as well as a VFVNFA motif essential for lipid efflux activity.[10]
ABCA1 mediates the efflux ofcholesterol andphospholipids to lipid-poorapolipoproteins (apoA1 and apoE) (reverse cholesterol transport), which then form nascenthigh-density lipoproteins (HDL). It also mediates the transport of lipids between Golgi andcell membrane. Since this protein is needed throughout the body it isexpressed ubiquitously as a 220kDa 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.[13]
Factors that act upon the ABCA1 transporter's expression or itsposttranslational modification are also molecules that are involved in its subsequent function likefatty acids, cholesterol and alsocytokines andcAMP.[14]Adiponectin induces reverse cholesterol transport by an ABCA1-dependent pathway.[15] Other endogenousmetabolites more loosely related to the ABCA1 functions are also reported to influence the expression of this transporter, includingglucose andbilirubin.[16][17]
Interactions between members of the apoliprotein family and ABCA1 activate multiple signalling pathways, including theJAK-STAT,PKA, andPKC pathways[18]
Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatorydiarylheptanoidantioxidantcurcumin.[19]Downregulation of ABCA1 in senescent macrophages disrupts the cell's ability to remove cholesterol from its cytoplasm, leading the cells to promote pathologicatherogenesis (blood vessel thickening/hardening) which "plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration"[20] Knockout mouse models ofAMD treated with agonists that increase ABCA1 in loss of function and gain of function experiments demonstrated the protective role of elevating ABCA1 in regulatingangiogenesis in eye disease. Human data from patients and controls were used to demonstrate the translation of mouse findings in human disease.[21]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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):150–159.doi:10.1006/geno.1994.1237.PMID8088782.
^Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, et al. (August 1999). "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease".Nature Genetics.22 (4):347–351.doi:10.1038/11914.PMID10431237.S2CID26890624.
^Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, et al. (August 1999). "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency".Nature Genetics.22 (4):336–345.doi:10.1038/11905.PMID10431236.S2CID1497231.
^abBrunham LR, Singaraja RR, Hayden MR (2006). "Variations on 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.PMID16704350.
^Oram JF, Vaughan AM (June 2000). "ABCA1-mediated transport of cellular cholesterol and phospholipids to HDL apolipoproteins".Current Opinion in Lipidology.11 (3):253–260.doi:10.1097/00041433-200006000-00005.PMID10882340.
^Darabi M, Rabbani M, Ani M, Zarean E, Panjehpour M, Movahedian A (September 2011). "Increased leukocyte ABCA1 gene expression in post-menopausal women on hormone replacement therapy".Gynecological Endocrinology.27 (9):701–705.doi:10.3109/09513590.2010.507826.PMID20807164.S2CID203464.
^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".Biochemical and Biophysical Research Communications.293 (2):759–765.doi:10.1016/S0006-291X(02)00303-0.PMID12054535.
Tam SP, Mok L, Chimini G, Vasa M, Deeley RG (September 2006). "ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of oxysterol by intact cells".American Journal of Physiology. Cell Physiology.291 (3):C490 –C502.doi:10.1152/ajpcell.00055.2006.PMID16611739.S2CID24019526.
Hong SH, Rhyne J, Zeller K, Miller M (October 2002). "ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease".Atherosclerosis.164 (2):245–250.doi:10.1016/S0021-9150(02)00106-5.PMID12204794.
Schmitz G, Schambeck CM (2006). "Molecular defects in the ABCA1 pathway affect platelet function".Pathophysiology of Haemostasis and Thrombosis.35 (1–2):166–174.doi:10.1159/000093563.PMID16855366.S2CID71978568.
