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. [5] This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis.
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 [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 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. [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 a PDZ domain, responsible for mediating protein-protein interactions, as well as a VFVNFA motif essential for lipid efflux activity. [10]
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. [13]
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. [14] Adiponectin induces reverse cholesterol transport by an ABCA1-dependent pathway. [15] Other endogenous metabolites more loosely related to the ABCA1 functions are also reported to influence the expression of this transporter, including glucose and bilirubin. [16] [17]
Interactions between members of the apoliprotein family and ABCA1 activate multiple signalling pathways, including the JAK-STAT, PKA, and PKC pathways [18]
Overexpression of ABCA1 has been reported to induce resistance to the anti-inflammatory diarylheptanoid antioxidant curcumin. [19] 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" [20] 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. [21]
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. [22] [23] Leukocytes ABCA1 gene expression is upregulated in postmenopausal women receiving hormone replacement therapy (HRP). [24] ABCA1 expression is also upregulated in tumor-associated astroctytes surrounding glioblastoma brain tumors, and is important to the tumor progression. [25] [26]
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
ABCA1 has been shown to interact with:
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle and transporting up to hundreds of fat molecules per particle.
The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density (VLDL) or Chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.
ATP-binding cassette sub-family A member 12 also known as ATP-binding cassette transporter 12 is a protein that in humans is encoded by the ABCA12 gene.
Tangier disease or hypoalphalipoproteinemia is an extremely rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein (HDL), often referred to as "good cholesterol", in the bloodstream. Worldwide, approximately 100 cases have even been identified.
The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Healthy persons absorb only about 5% of dietary plant sterols, but sitosterolemia patients absorb 15% to 60% of ingested sitosterol without excreting much into the bile. The phytosterol campesterol is more readily absorbed than sitosterol.
Apolipoprotein AI(ApoA-I) is a protein that in humans is encoded by the APOA1 gene. As the major component of HDL particles, it has a specific role in lipid metabolism.
The ATP-binding cassette 4 gene encodes the Multidrug resistance protein 3. ABCB4 is associated with progressive familial intrahepatic cholestasis type 3 and intrahepatic cholestasis of pregnancy.
ATP-binding cassette, sub-family A (ABC1), member 4, also known as ABCA4 or ABCR, is a protein which in humans is encoded by the ABCA4 gene.
Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ABCC2 gene.
ATP-binding cassette sub-family G member 1 is a protein that in humans is encoded by the ABCG1 gene. It is a homolog of the well-known Drosophila gene white.
ATP-binding cassette sub-family G member 5 is a protein that in humans is encoded by the ABCG5 gene.
ATP-binding cassette sub-family G member 8 is a protein that in humans is encoded by the ABCG8 gene.
ATP-binding cassette sub-family A member 2 is a protein that in humans is encoded by the ABCA2 gene.
ATP-binding cassette sub-family A member 7 is a protein that in humans is encoded by the ABCA7 gene.
ATP-binding cassette sub-family A member 3 is a protein that in humans is encoded by the ABCA3 gene.
Zinc finger protein 202 is a transcription factor first associated with breast cancer. It is a protein that, in humans, is encoded by the ZNF202 gene.
ATP-binding cassette sub-family G member 4 is a protein that in humans is encoded by the ABCG4 gene.
ATP-binding cassette, sub-family A (ABC1), member 5 is a protein that in humans is encoded by the ABCA5 gene.
