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ABCA1

Official Full Name
ATP-binding cassette, sub-family A (ABC1), member 1
Background
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 (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, 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. In humans, this protein functions as a cholesterol efflux pump in the cellular lipid removal pathway. Mutations in the human gene have been associated with Tangiers disease and familial high-density lipoprotein deficiency.
Synonyms
ABCA1; ATP-binding cassette, sub-family A (ABC1), member 1; ABC1, HDLDT1; ATP-binding cassette sub-family A member 1; Tangier disease; TGD; membrane-bound; ATP-binding cassette transporter 1; ATP-binding cassette transporter A1; cholesterol efflux regulat; cholesterol efflux regulatory protein; ABC1; CERP; ABC-1; HDLDT1

ABCA1 (ATP-binding cassette transporter A1) is a member of the adenosine triphosphate binding cassette protein. The human ABCA1 gene is located in 9q31 and contains 1 453 bp promoter, 14 6581 bp intron and exons. The ABCA1 protein consists of 2261 amino acids and is a membrane transporter with a molecular mass of 254 kb. ABCA1 is symmetric structure with a transmembrane domain (TMD), which is a tandem repeat consisting of 6 transmembrane segments (TMS) and 1 nucleotide binding domain (NBD). NBD is an ATP binding site that provides the energy needed for transmembrane transport of substances. There are various ABCA1 mutations in patients with TD and familial HDL(high-density lipoprotein) deficiency (FHD). These mutations occur mainly in the ABCA1 binding and N-terminal regions. Qiao et al. found that in addition to TMD and NBD, the two extracellular domains of ABCA1 also contain an elongated hydrophobic channel, and the pathogenesis of TD may be related to this.

ABCA1 is distributed in many tissues, with the highest expression of ABCA1 in the pancreas, liver, lungs, adrenal glands, and fetal tissue, and the lowest expression in the kidney, pituitary, breast, and bone marrow. About 30% of ABCA1, which maintains a stable plasma HDL pool in the body, is derived from the intestine, and HDL from the intestine ABCA1 is secreted directly into the blood circulation, whereas HDL in the lymph is derived from plasma.

ABCA1 uses ATP as an energy source to promote the release of free cholesterol and phospholipids from cells. It plays an extremely important regulatory role in the reverse transport of cholesterol, cholesterol metabolism, and HDL metabolism. In addition, ABCA1 also plays a role in regulating apoptosis and inflammatory responses, as well as in regulating the function of ApoAI through endothelial cells. ABCA1 has the title of "gatekeeper" for reverse cholesterol transport and controls the rate-limiting step of HDL formation. The current research on ABCA1 is mainly focused on the promotion of free cholesterol, transport of phospholipids from the intracellular domain to the cell membrane, and then transporting out of the cell via extracellular receptors. Animal experiments show that the lack of ABCA1 can lead to a decrease in HDL and apolipoprotein, and the excessive expression of ABCA1 can increase the HDL. ABCA1 binds to the lipid-laden ApoAI and phospholipid (PL) is first transported to ApoAI under ABCA1 mediation, which then promotes the free cholesterol (FC) flux to form nascent preβ-HDL particles. Then, under the action of lecithin cholesterol thioltransferase (LCAT), FC on the nascent pre-β-HDL is esterified to cholesteryl ester (CE), which finally forms mature α-HDL.

Figure 1. Schematic drawing of HDL formation by ABCA1. (Nagata, et al. 2013).

The Role of ABCA1 in Cells of Various Tissues

The role of ABCA1 in macrophages

ABCA1 plays an important role in the removal of excess free cholesterol in mononuclear macrophages, preventing the formation of foam cells. In tissue cells, macrophages play an important role in the transport of lipids. If a large number of cholesterol lipids and triacylglycerols accumulate in macrophages, they will develop into foam cells. In addition to promoting cholesterol efflux in macrophages, ABCA1 also affects the accumulation of macrophages in surrounding tissues. The function of most macrophages is to eliminate apoptotic cells and necrotic cells (these cells are the main source of cholesterol production). Therefore, ABCA1 dysfunction will lead to macrophage cell membrane cholesterol influx greatly exceeds cholesterol efflux, a large amount of cholesterol deposition and become foam cells. ABCA1 is involved in the reverse transport of cholesterol and translocate intracellular cholesterol to HDL. ABCA1 dysfunction results in the accumulation of large amounts of cholesterol in macrophages to become foam cells, which in turn infiltrate the blood vessel wall and promote the development of AS. In addition, the results of Lu et al. showed that ABCA1 can also increase the risk of blood lipid variability and coronary heart disease.

The role of ABCA1 in hepatocytes

The liver is the main site responsible for HDL production in the body. Xin et al. found that ABCA1 plays an important role in cholesterol efflux and HDL formation in hepatocytes. Expression of ABCA1 in the basolateral membrane of hepatocytes maintains HDL levels in the blood circulation. The expression of ABCA1 in the liver is an important regulator of atherosclerosis susceptibility. Silencing of liver ABCA1 gene can significantly reduce circulating HDL levels and increase atherosclerosis susceptibility.

Regulation of ABCA1 Expression

The ABCA1 protein level and activity can be highly regulated by numerous factors during transcription and post-transcriptional processes. These adjustments include up-regulation, down-regulation, and bi-directional adjustment.

The transcription of the ABCA1 gene induced by excessive loading of cholesterol in cells is mainly dependent on the transcription regulation of the nuclear receptor superfamily, and the liver X receptor/retinoid receptor (LXR/RXR) mediates this induction process. LXR and RXR are intracellular transcription factors. Lin et al. demonstrated that curcumin enhances cholesterol efflux by upregulating ABCA1 expression by activating AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells. The study revealed a possible mechanism for anti-atherosclerosis. LXR binds to RXR after activation with its ligand and forms a heterodimer that binds to the DR4 element and the first intron in the promoter within the ABCA1 gene, then activates the target gene, increases ABCA1, promotes cholesterol efflux outside the cell, and is transported to the liver where it is metabolized.

PPAR can also increase the transcription of ABCA1 gene, and the conformations of its three subtypes after binding to their respective ligands are changed and combined with PPAR response elements in the corresponding target gene promoter, thereby regulating the transcriptional activity of target genes. The LXR and PPAR signaling pathways partially overlap in macrophage cholesterol efflux. The up-regulation of ABCA1 gene transcription by PPARα and PPARγ agonists is likely to be achieved indirectly through activation of LXR/RXR. Evidence suggests that THP-1 macrophage-derived foam cells treated with interferon-gamma (IFN-γ) 100 μg/L show a time-dependent reduction in ABCA1 mRNA and protein levels, indicating that IFN-γ reduces transcription of ABCA1. Platelet-derived growth factor (PDGF) activates the phosphorylation of the kinase AKT downstream of PI3-K, inhibiting ABCA1 promoter activity. HDL, ApoAI also inhibits ABCA1 expression.

In summary, ABCA1 plays an important role in lipid metabolism, inflammatory response, and apoptosis, and is closely related to the development of atherosclerosis, making ABCA1 an important target of treatment for atherosclerotic cardiovascular and cerebrovascular diseases.

Reference:

  1. Qian H, Zhao X, Cao P, et al. Structure of the Human Lipid Exporter ABCA1. Cell, 2017, 169(7):1228.
  2. Xin B, Pashos E E, Cuchel M, et al. ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion. Ebiomedicine, 2017, 18:139-145.
  3. Lu Y, Liu Y, Li Y, et al. Association of ATP-binding cassette transporter A1 gene polymorphisms with plasma lipid variability and coronary heart disease risk. International Journal of Clinical & Experimental Pathology, 2015, 8(10):13441.
  4. Hafiane A, Genest J. ATP binding cassette A1 (ABCA1) mediates microparticle formation during high-density lipoprotein (HDL) biogenesis. Atherosclerosis, 2017, 257:90-99.
  5. XL Lin, MH Liu, HJ Hu, et al. Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells. Dna & Cell Biology, 2015, 34(9):561-572.
  6. Nagata K O, Nakada C, Kasai R S, et al. ABCA1 dimer-monomer interconversion during HDL generation revealed by single-molecule imaging. Pnas, 2013, 110(13):5034.

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