Disease relevance of Abca1

• This decrease was associated with a 3- to 4-fold reduction in ATP-binding-cassette transporter 1 (ABC1) mRNA content, the gene responsible for the defect in Tangier disease [1].
• However, the possibly beneficial effects of specific upregulation of macrophage ABCA1 on atherogenesis are still unknown [2].
• Altogether, by pointing out the ABCA1 transporter as a major element controlling cerebral malaria susceptibility, these data provide a novel insight into its pathophysiological mechanisms and are consistent with a pathogenic role of microparticles in this neurological syndrome [3].
• The absence of ABCA1 led to reduced plasma cholesterol levels in both the apoE(-/-) and LDLr(-/-) mice, along with severe skin xanthomatosis characterized by marked foamy macrophages and cholesterol ester accumulation [4].
• ABCA1 defects cause Tangier disease, a disorder characterized by absence of high density lipoprotein and thrombocytopenia [5].

Psychiatry related information on Abca1

• Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease [6].

High impact information on Abca1

• ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease [7].
• Transport of lipids from golgi to plasma membrane is defective in tangier disease patients and Abc1-deficient mice [8].
• ABC1 is expressed on the plasma membrane and the Golgi complex, mediates apo-AI associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux [8].
• Adrenoleukodystrophy (ALD) is caused by mutations in an ATP-binding-cassette transporter located in the peroxisomal membrane, which result in a fatal demyelinating disease in boys and a milder phenotype in men and some heterozygous women [9].
• The two Abelson murine leukemia virus (A-MuLV)-transformed cell lines, BM18-4 and ABC-1, undergo immunoglobulin L-chain gene recombination during passage in tissue culture [10].

Chemical compound and disease context of Abca1

• ATP-binding cassette transporter ABCA1 mediates the transport of cholesterol and phospholipids from cells to HDL apolipoproteins and thus modulates HDL levels and atherogenesis [11].
• Identification of breast cancer resistant protein/mitoxantrone resistance/placenta-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088, topoisomerase I inhibitors with an indolocarbazole structure [12].

Biological context of Abca1

• Abnormal phospholipid composition impairs HDL biogenesis and maturation in mice lacking Abca1 [13].
• These coordinated changes in LXR signaling in mice during progression are consistent with our previous findings that reduction of ABCA1 gene expression stimulates proliferation of LNCaP cells [14].
• Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells [1].
• In summary, selective LXRbeta activation is expected to stimulate ABCA1 gene expression in macrophages, contribute to favorable HDL increases, but circumvent hepatic LXRalpha-dominated lipogenesis [15].
• METHODS AND RESULTS: Chimeras that specifically overexpress ABCA1 in macrophages were generated by transplantation of bone marrow from human ABCA1 bacterial artificial chromosome (BAC) transgenic mice into LDLr-/- mice [2].

Anatomical context of Abca1

• Astrocytes, the primary producer of CNS apoE, were cultured from Abca1+/+, +/-, and -/- mice, and nascent lipoprotein particles were collected [16].
• Herein, we have used Abca1-/- mice to ask whether ABCA1 is involved in lipidation of HDL in the central nervous system (CNS) [16].
• In duodenum, PCN increased Abca1 and Mdr1a mRNA expression in WT mice, but not in PXR-null mice [17].
• METHODS AND RESULTS: We conducted a series of experiments in macrophages isolated from Abca1-deficient and wild-type mice and compared several of their properties that are thought to be related to the development of atherosclerosis [18].
• ABCG1-deficient peritoneal macrophages showed induction of several liver X receptor target genes, such as Abca1 and Srebp1c, and a dramatic increase in apolipoprotein E (apoE) protein both in cell media and lysates, without parallel change in apoE mRNA [19].

Associations of Abca1 with chemical compounds

• Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL [20].
• Most importantly, fecal neutral sterol loss was induced to a similar extent (+300%) by the LXR agonist in DBA/1 wild-type and Abca1(-/-) mice [21].
• Compared to wild-type littermates, Abca1(-/-) HDL had a 4-fold increase in PC, whereas lysophosphatidylcholine (LPC) (125-fold), sphingomyelin (SPH) (49-fold), and phosphatidylethanolamine (PE) (18-fold) showed even higher increases [13].
• As a consequence, the ratios of LPC/PC, SPH/PC, PE/PC, and phosphatidylinositol + phosphatidylserine (PI+PS)/PC were all much higher in HDL from Abca1(-/-), compared to wild-type HDL [13].
• Secretion of triacylglycerol and apoB was decreased following apoA-I incubation with ABCA1-expressing but not abca1(-/-) hepatocytes [22].

Physical interactions of Abca1

• Being associated together with chloride conductance, P2X7 receptors and ABC1 transporters delineate a subtle and complex regulation of IL-1beta production in mammalian Schwann cells [23].

Co-localisations of Abca1

• We also found that 12-month-old PDAPP Abca1-/- mice had a higher percentage of carbonate-insoluble apoE and that apoE deposits co-localize with amyloid plaques, demonstrating that poorly lipidated apoE co-deposits with insoluble Abeta [6].

Regulatory relationships of Abca1

• To test this hypothesis, plasma from Abca1(-/-) mice was incubated with CHO cells that are known to express high levels of ABCA1 with the intent of restoring the flux of phospholipid and cholesterol onto apoAI [13].
• The general ABC transporter inhibitor glibenclamide suppressed both IL-12 p40 and nitric oxide production [24].
• Furthermore, ABC1 transporters could be a target of therapeutic interest for regulating IL-1beta activity in neuroinflammation disorders [23].
• OSBP opposes the activity of LXR by negatively regulating ABCA1 activity in the cytoplasm by sterol-binding domain-dependent protein destabilization [25].

Other interactions of Abca1

• The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein most highly expressed in the central and peripheral nervous system tissues and macrophages [26].
• In peripheral tissues from these LXRalpha-null mice, LXRbeta activation increases ABCA1 and SREBP-1c gene expression in a parallel manner [15].
• Cultured murine hepatocytes were used to examine the role of hepatic ABCA1 in mediating the lipidation of apolipoprotein A-I (apoA-I) for HDL particle formation [22].
• Abca1 knockdown prevented the increase in apoE secretion but had minimal effects on apoE accumulation in cell lysates of Abcg1(-/-) macrophages [19].
• Analysis of hepatic gene expression consistently revealed less activation of ABCA1 and SREBP-1c genes in the liver of LXRalpha null animals than in treated wild-type controls [15].

Analytical, diagnostic and therapeutic context of Abca1

• Immunoprecipitation revealed that alpha1-syntrophin interacted with ABCA1 strongly and that the interaction was via the C-terminal three amino acids SYV of ABCA1 [27].
• The cellular location of another of the differentially expressed ABC transporters, Abcc3, was examined by immunohistochemistry [28].
• The LXR ligand T0901317 elevates ATP binding cassette transporter A1 (ABCA1) and HDL levels in animal models and induces moderate lipogenesis through upregulation of sterol regulatory element binding protein 1c (SREBP1c) [29].
• However, the complete absence of ABCA1 did not affect the development, progression, or composition of atherosclerotic lesions in either the LDLr(-/-) or the apoE(-/-) mice fed a chow or atherogenic diet [4].
• The very low density lipoprotein (VLDL)/LDL size fraction also contained a significant level of cholesterol in ABCA1 deficiency, consistent with the result of immunoprecipitations showing the presence of lipoproteins with both apoA-I and murine apoB [30].

References