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 is_associated_with::protein which in humans is encoded by the ABCA1 is_associated_with::gene. This transporter is a major regulator of cellular is_associated_with::cholesterol and is_associated_with::phospholipid is_associated_with::homeostasis.

Tangier Disease
It was discovered that a mutation in the ABCA1 protein is responsible for causing is_associated_with::Tangier's Disease by several groups in 1998. Gerd Schmitz's group in Germany and Michael Hayden's group in British Columbia 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. 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. 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.

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.

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 is_associated_with::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 is_associated_with::cholesterol and is_associated_with::phospholipids to lipid-poor is_associated_with::apolipoproteins (apo-A1 and apoE), which then form nascent is_associated_with::high-density lipoproteins (HDL). It also mediates the transport of lipids between Golgi and is_associated_with::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.

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

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

Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatory is_associated_with::diarylheptanoid is_associated_with::antioxidant is_associated_with::Curcumin. Downregulation of ABCA1 in senescent macrophages disrupts the cell's ability to remove cholesterol from its cytosoplasm, leading the cells to promote the pathologic is_associated_with::atherogenesis (blood vessel thickening/hardening) which "plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration" 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 is_associated_with::angiogenesis in eye disease. Human data from patients and controls were used to demonstrate the translation of mouse findings in human disease.

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

Interactions
ABCA1 has been shown to interact with:
 * APOA1,
 * APOE,
 * is_associated_with::FADD,
 * is_associated_with::SNTB2, and
 * XPC.