Disease relevance of ABCA1

• ApoE secretion from HMDM of ABCA1-deficient patients with Tangier disease was also decreased [1].
• Recombinant expression of a dominant negative form of FADD or the C terminus of ABCA1 in the human hepatoma cell line HepG2 markedly reduced the transfer of phospholipids to apoA-I [2].
• Recently, a haplotype in ABCA1 gene was associated with increased risk of type II diabetes mellitus (DM) [3].
• Importantly, immunoblotting of ABCA-1 showed a dramatic decrease of ABCA1 protein, the key molecule of cholesterol efflux, in atheroma compared with MIT [4].
• A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia [5].
• CsA also inhibited secretion from primary human Tangier disease macrophages and from mouse macrophages deficient in ABCA1, indicating that the effect is independent of the known inhibition of ABCA1 by CsA [6].

Psychiatry related information on ABCA1

• Recent epidemiological, biological and genetic data indicate a relationship between cholesterol and Alzheimer's disease (AD) including the association of polymorphisms of ABCA1 (a gene that is known to participate in cholesterol and phospholipid transport) with AD prevalence [7].
• Moderate alcohol consumption increases cholesterol efflux mediated by ABCA1 [8].
• In addition, during fetal epidermal development, ABCA1 expression decreases at days 18-22 of gestation (term = 22 days), leaving more cholesterol available during the critical period of barrier formation [9].
• These data strongly suggest that M.grisea requires the up-regulation of specific ABC transporters for pathogenesis; most likely to protect itself against plant defense mechanisms [10].

High impact information on ABCA1

• Although it is clear that mammalian peroxisomes under in vivo conditions are closed structures, which require the active presence of metabolite transporter proteins, much remains to be learned about the permeability properties of mammalian peroxisomes and the role of the four half ATP-binding cassette (ABC) transporters therein [11].
• ATP-binding cassette (ABC) transporters couple ATP hydrolysis to the uptake and efflux of solutes across the cell membrane in bacteria and eukaryotic cells [12].
• In humans, many diseases, such as cystic fibrosis, hyperinsulinemia, and macular dystrophy, are traced to defects in ABC transporters [12].
• Major physiological functions of ABC transporters include the transport of lipids, bile salts, toxic compounds, and peptides for antigen presentation or other purposes [13].
• The available outline of the human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease [13].

Chemical compound and disease context of ABCA1

• These mutants, unlike wild type ABCA1, produced little or no apoA-I-stimulated cholesterol efflux when transfected into 293 cells, establishing their causality in Tangier disease [14].
• Mutations in ABCA1 cause Tangier disease, a severe HDL deficiency syndrome characterized by a rapid turnover of plasma apolipoprotein A-I, accumulation of sterol in tissue macrophages, and prevalent atherosclerosis [15].
• ApoA-I-induced signaling was abrogated by glyburide, an inhibitor of the ABC transporter family, and in fibroblasts from patients with Tangier disease, which do not express ABCA1 [16].
• Unlike apoA-I, L-37pA and D-37pA were also capable, although at a reduced rate, of causing lipid efflux independent of ABCA1 from control cells, Tangier disease cells, and paraformaldehyde fixed ABCA1 cells [17].
• In Fu5AH hepatoma cells that contain scavenger receptor class B, type I, but not functional ABCA1, we observed no effect of probucol on cholesterol efflux [18].

Biological context of ABCA1

• Overexpression of ZNF202m1 in RAW264.7 macrophages prevented the induction of ABCA1 gene expression by 20(S)OH-cholesterol and 9-cis-retinoic acid, further substantiating the interference of ZNF202 in critical elements of transcriptional activation [19].
• This study reveals a novel defect in cellular cholesterol homeostasis induced by GSL storage and identifies PDMP as a new agent for enhancing cholesterol efflux via the ABCA1/apoA-I pathway [20].
• We show here that phosphorylation of ABCA1 in HEK293 cells was reduced by 63 +/- 2.4% after removal of the PEST sequence (ABCA1delPEST) or by incubation of cells with apoAI (58 +/- 3.3%) [21].
• LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 (formerly known as ABC1) [22].
• We demonstrate here that the full-length ZNF202m1 isoform binds to GnT repeats within the promotors of ABCA1 (-229/-210) and ABCG1 (-572/-552) [19].

Anatomical context of ABCA1

• During incubations of up to 6 h, apoE secretion from both THP1 macrophages and HMDM was stimulated by 8-Br-cAMP, which activates ABCA1 expression [1].
• Inhibition of ABCA1 in HMDM prevented the occurrence of anti-apoE-immunoreactive granular structures in the plasma membrane [1].
• The dynamics of ABCA1-mediated apoA-I lipidation were investigated in intact human fibroblasts induced with 22(R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells) [23].
• Trypsin limited-digestion of purified ABCA1 in the detergent-soluble form suggested that it retained conformation similar to ABCA1 expressed in the membranes of human fibroblast WI-38 cells [24].
• The expression of syntaxins and ABCA1 in cultured human monocytes during M-CSF differentiation and cholesterol loading was investigated and syntaxins 3, 6, and 13 were found induced in foam cells together with ABCA1 [25].

Associations of ABCA1 with chemical compounds

• The ATP-binding cassette transporter A1 (ABCA1) mediates efflux of cellular cholesterol to lipid-poor apolipoproteins but not to HDL particles that constitute the bulk of plasma HDL [26].
• The putative ABCA1 inhibitor glyburide and antisense oligonucleotides directed against ABCA1 mRNA significantly reduced apoE secretion from THP1 macrophages and HMDM [1].
• Here we investigated the contribution of the adenosine triphosphate binding cassette transporters ABCA1 and ABC8 to the secretion of apoE from either primary human monocyte-derived macrophages (HMDM) or human THP1 macrophages [1].
• This implies that lipidation of apolipoprotein A-I by the ABCA1 pathway is required for generating HDL particles and clearing sterol from macrophages [15].
• Treatment of intact cells with either phosphatidylcholine-specific phospholipase C or sphingomyelinase affected neither (125)I-apoA-I binding nor (125)I-apoA-I/ABCA1 cross-linking [23].
• Functional analyses of the coding polymorphisms showed an effect of the V825I substitution on ABCA1 function, with the 825I variant having higher activity in mediating cholesterol efflux than the wild-type (825V) [27].
• We describe a novel bihelical peptide with asymmetry in the lipid affinity of its helices and properties similar to apoA-I in terms of specificity for cholesterol efflux by the ABCA1 transporter and low cytotoxicity [28].

Physical interactions of ABCA1

• Apolipoprotein A-I (apoA-I)-mediated cholesterol efflux involves the binding of apoA-I to the plasma membrane via its C terminus and requires cellular ATP-binding cassette transporter (ABCA1) activity [29].
• Fas-associated death domain protein (FADD) was identified to bind to ABCA1, and this interaction was confirmed by pull-down assays and co-immunoprecipitations [2].
• Mutant cells lacking JAK2 had a severely impaired apoA-I-mediated cholesterol and phospholipid efflux and apoA-I binding despite normal ABCA1 protein levels and near normal cholesterol translocase activity [30].
• It is concluded that ABCA1 forms a complex with syntaxin 13 and flotillin-1, residing at the plasma membrane and in phagosomes that are partially located in raft microdomains [25].
• ApoE isoforms showed similar binding for ABCA1 and exhibited identical kinetics in their abilities to induce ABCA1-dependent cholesterol efflux [31].

Enzymatic interactions of ABCA1

• Apolipoprotein A-I activates protein kinase C alpha signaling to phosphorylate and stabilize ATP binding cassette transporter A1 for the high density lipoprotein assembly [32].
• The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport [33].

Regulatory relationships of ABCA1

• These results suggest that the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells [30].
• ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation [34].
• Downregulated CD36 and oxLDL uptake and stimulated ABCA1/G1 and cholesterol efflux as anti-atherosclerotic mechanisms of interleukin-10 [35].
• We conclude that ABCA1 transduces signals from apoA-I by complexing and activating Cdc42 and downstream kinases and, therefore, acts as a full apoA-I receptor [16].
• Genes of cholesterol metabolism in human atheroma: overexpression of perilipin and genes promoting cholesterol storage and repression of ABCA1 expression [4].

Other interactions of ABCA1

• ATP-binding cassette transporter A1 contains a novel C-terminal VFVNFA motif that is required for its cholesterol efflux and ApoA-I binding activities [36].
• We show here that treatment of human NPC1(-/-) fibroblasts with the liver X receptor (LXR) agonist TO-901317 increases ABCA1 expression and activity in human NPC1(-/-) fibroblasts, as indicated by near normalization of efflux of radiolabeled phosphatidylcholine and a marked increase in efflux of cholesterol mass to apoA-I [37].
• The association of FADD with ABCA1 provides an unexpected link between high density lipoprotein metabolism and an adaptor molecule mainly described in death receptor signal transduction [2].
• This transcriptional effect required the presence of the SCAN domain in ZNF202 and the functional integrity of a TATA box at position -24 of ABCA1, whereas the presence of GnT binding motifs was nonessential [19].
• ABC2, therefore, is a glycosylated ABC transporter protein, and may play an especially important role in the brain [38].

Analytical, diagnostic and therapeutic context of ABCA1

• Through site-directed mutagenesis studies of consensus PKA phosphorylation sites and in vitro PKA kinase assays, we show that Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA [39].
• The colocalization of ABCA1 and syntaxin 13 was also shown by immunofluorescence microscopy [25].
• The cell surface biotinylation experiment followed by Western blot analyses demonstrated a markedly dominant expression of ABCA1 on the basolateral surface, which was clearly confirmed by the confocal laser scanning microscopy [40].
• Sequence analysis identified 14 polymorphisms in the promoter region of ABCA1 [41].
• In order to know if the presence of the R219K variant in the ABCA1 gene could be a protective factor for premature CHD in FH, we have determined the presence of this genetic variant by amplification by PCR and restriction analysis in a group of 374 FH subjects, with and without premature CHD [5].

References