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This gene encodes apolipoprotein A-I, which is the major protein component of high density lipoprotein (HDL) in plasma. The protein promotes cholesterol efflux from tissues to the liver for excretion, and it is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. This gene is closely linked with two other apolipoprotein genes on chromosome 11. Defects in this gene are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis. A molecular model was built for the lipid-free apoA-I monomer based on homology with proteins of similar sequence and known three-dimensional structures. ABCA1-independent but apoa1-dependent cholesterol removal pathway may help to prevent early atherosclerosis in Tangier disease. APOA1 has a role in formation of nascent high density lipoprotein particles. APOA1 has a role in regulating ABCA1 expression in macrophages. APOA1 has a varying conformational states as it adjusts from a discoidal to a spherical surface. APOA1 is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. APOA1 to APOB ratio is related to myocardial infarction and stroke. APOAI had distinct inhibitory effects on the lipolysis of large and small emulsions: more effective inhibition for small emulsions. Among these genetic polymorphisms, TaqIB of CETP and MspI of apolipoprotein AI appeared to help significantly to identify diabetic individuals. In particular, the former may have an additional role in the primary prevention of coronary disease. An apoA-I(delta 89-99) deletion mutant generates a phenotype not encountered previously which affects maturation of high-density lipoprotein, inhibits activity of phospholipid transfer protein, and promotes accumulation of abnormal lipoprotein particles. Apo A-I binding to lecithins and small unilamellar vesicles exhibits different helical structures. Apo A-I mutations cannot be firmly establihed in samll number of patients with severe HDL deficiency. Apo AI/ABCA1-dependent and HDL3-mediated lipid efflux. ApoA-1 binds to lipid raft & nonraft domains of the macrophage plasma membrane. Cholesterol exported to apoA-1 from the major slow-efflux pool derives from nonraft regions but the interaction of apoA-1 with lipid rafts is needed to stimulate this efflux. ApoA-I mutants that are poor cholesterol acceptors cross-link poorly to the ATP binding cassette transporter A1 (ATPCA1), affecting cholesterol efflux and inhibiting biogenesis of cholesterol high-density lipoproteins. ApoA-I structure was analyzed to detect the site bound by haptoglobin. Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter. Apolipoprotein A-I alpha -helices 7 and 8 modulate high density lipoprotein subclass distribution. Apolipoprotein A-II inhibits high density lipoprotein remodeling and lipid-poor formation of this protein. Changes in triglycerides were influenced by the apolipoprotein AI XmnI polymorphism (p = 0.04), suggesting a gene-diet interaction (p = 0.03)in hyperuricemia. Data support the hypothesis of increased biliary catabolism of cholesterol in subjects with gallbladder disease characterized by lower Apo B and higher Apo A-I serum concentrations. Degradation of phospholipid transfer protein (PLTP) and PLTP-generated protein by mast cell chymase impairs high affinity efflux of cholesterol from macrophage foam cells. EPR spectroscopy was used to examine the structure of the apoA-I C terminus in lipid-free and lipid-associated states.Spectra of apoA-I in reconstituted HDL revealed a lipid-induced transition of defined beta-strands into alpha-helices. Effects of enrichment of fibroblasts with unesterified cholesterol on the efflux of cellular lipids to apolipoprotein A-I. Expression of Apo A1 is associated with colonic adenocarcinoma progression, and thus Apo A1 is a potential marker of the aggression. FTD patients showed a significantly higher prevalence of low MW apo(a) isoforms than the cognitively healthy controls (P=0.011 and P=0.025, respectively). Our data suggest a role of apo(a) phenotypes of low MW in mediating susceptibility to FTD. G/A polymorphism of the apo A-I promoter region affects not only baseline HDL-C concentrations but also its response to pravastatin treatment. HDL cholesterol levels were 4% (0.06 mmol/l) and 10% (0.15 mmol/l) higher in heterozygotes and mutation homozygotes; the equivalent values for apolipoprotein A1 were 3% and 7% higher. Hepatitis B virus (HBV) reduced steady-state levels of apolipoprotein AI mRNAs in two hepatoma cell lines. Heterozygosity for a novel apoA-I mutation underlies a detrimental lipoprotein profile that is associated with endothelial dysfunction, accelerated carotid arterial wall thickening, and severely enhanced CAD risk. Human apoA-I/C-III/A-IV transgenic rabbits may provide a reliable model for studies of the transcriptional regulation of the cluster, and for evaluating the effects of different agents on the expression of the three genes. In an LDL receptor-deficient mouse model of familial hypercholesterolemia, helper-dependent adenovirus gene transfer of human apoA-I causes long-term overexpression of apoA-I and retards atherosclerosis progression. In chronic hepatitis B, plasma Apo A-I level is not a reliable indicator of fibrosis. In conclusion, 12% of Hypoalphalipoproteinemia subjects were found to carry mutations in apo A-I, LCAT, or GBA genes. In the absence of apoA-1 carboxyl-terminal residues 187-243, removal of residues 1-43 does not induce a major structural reorganization while retaining a protein fold that is consistent with a globular amphipathic alpha-helix bundle. Individuals with this protein are at a higher risk for schizophrenia. Infusion of APOA1 into fasting healthy male subjects activated FVII, increased TAT complex blood levels, and decreased HDL triglyceride blood levels. Mutations may be associated with hypertension. N-terminal deletion mutants of apoA-1, Delta(1-41) and Delta(1-59), show altered lipid-binding ability compared to plasma and wild-type apoA-I, and in double deletion mutants, Delta(1-41, 185-243) and Delta(1-59, 185-243), lipid binding is abolished. NDRG1 interacts with APO A-I and A-II and may have a role in the general mechanisms of HDL-mediated cholesterol transport. Observations of the effects of four mutations in the central region of lipid-free apoA-I (residues 123-165) are consistent with the helical structure of residues 145-164 and the disordered structure of residues 123-142 in lipid-free apoA-I. Patient carrying the apolipoproteins A allele has an increased risk to develop coronary artery disease. Polymorphisms are not associated with severe aortic valve stenosis. Pre-beta apoA-I is formed during cholesteryl ester transfer protein-mediated remodeling of reconstituted HDL, a process in which the phospholipid composition of the particles plays a key role. REVIEW: an update on the experimental studies in which apolipoprotein A-I(Milano), produced as a recombinant protein, has displayed important effects in the treatment of vascular diseases. Results describe a model for a putative hinge domain in the context of recent ""belt"" and ""hairpin"" models of apolipoprotein A-I structure in discoidal high-density lipoprotein particles. Results show that during the early stages, oxidation of HDL gives rise to specifically oxidized forms of apolipoproteins A-I and A-II. Review. the formation, metabolism, and regulation of monomolecular, lipid-free/lipid-poor apoA-I in plasma. Single Nucleotide Polymorphisms in apolipoprotein A-I is associated with variation in plasma triglyceride levels Coronary Arteriosclerosis. The first 44 residues of human apoA-I have a moderate lipid binding affinity and can form both disks in the presence of excess peptide and vesicles of varous sizes over a wide range of excess peptide:lipid ratios. The orphan nuclear receptor liver receptor homolog-1 regulates APOAI transcription and affects cholesterol homeostasis. The protective behavior of apo A-I against vesicle aggregation and cholesterol nucleation in the presence of phospholipase C (PLC) depends on the relative concentrations of lipids (cholesterol and lecithin) and proteins (apo A-I and PLC). The spatial organization of apolipoprotein A-I on the edge of discoidal high density lipoprotein particles: a mass specrometry study. These data provide a novel explanation for the apparent AD-protective effect of inheriting an epsilon2 APOE allele, and suggest that optimizing AT enrichment of CNS lipoproteins or devising APOAI mimetics may augment AT efficacy in treating AD. When LDL apoB-100 pool size is big, there is a higher apoA-I production rate. Slow chylomicron remnant clearance is associated with enhanced apoA-I fractional catabolic rate. Changes in intestinal lipoproteins may be important in determining HDL-C levels. A specific structural element possessing a linear array of acidic residues spanning two apoA-I amphipathic alpha-helices is required to mediate cholesterol efflux and stabilize ABCA1. Additive influence of mutant APOA1 and testosterone on plasma HDL-cholesterol. Alterations in apoA-I conformation can lead to aberrant trafficking and accumulation of apolipoprotein-phospholipid structures, and may underlie the reduced plasma HDL concentrations observed in individuals harboring deletion mutations within helix 6. Alterations in transcriptional control of apo A-I in diabetes (review). Analysis of a novel, ABCA-1-independent, positive feedback pathway for stimulation of potentially anti-atherogenic apoE secretion by alpha-helix-containing molecules including apoA-I and apoE. Analysis of the interfacial properties of ApoA-I at the triolein/water interface. ApoA-I activates PKC alpha by PC-PLC-mediated generation of diacylglycerol initiated by the removal of cellular sphingomyelin and subsequently phosphorylates and stabilizes ABCA1. ApoA-I mobilizes intracellular cholesterol for the ABCA1-mediated release from the compartment that is under the control of ACAT. The cholesterol mobilization process is presumably related to PKC activation by apoA-I. Apolipoprotein A-I has a role in protecting against endotoxin toxicity. Apolipoprotein AI conformation required for systemic amyloidosis is described. Apolipoproteins appear to be a class of mediators that can participate in the regulation of the activity of neutrophils. Association of apolipoprotein A-I with lipids reduces its ability to interact with ATP-binding cassette transporter A1(ABCA1) and the lipid translocase activity of ABCA1 generates alpha-LpA-I-like particles. Comparison of 5 natural point mutations illustrates that a specific sequence between amino acids 110 and 162 is required for LCAT activation. Expression in the heart; detection of apoA-I expression in the hearts of human apoA-I Tg mice indicates that the minimal regulatory elements necessary for cardiac expression of the gene are located near its coding sequence. Individual and combined associations of the apolipoprotein (apo) A-I -75 bp and +83 bp polymorphisms with plasma lipid, lipoprotein and apolipoprotein levels in 734 Caucasian men and women. Inhibition of transforming growth factor-beta activation is required for stimulation of vascular smooth muscle cell proliferation and migration by apolipoprotein(a). Mechanism for the induction of apoA-I might include PPAR-gamma for which oxidized fatty acid is a ligand. Pitavastatin efficiently increases apoA-I in the culture medium of HepG2 cells by promoting apoA-I production through inhibition of HMG-CoA reductase. Prebeta HDL that contains APOa1, but not APOa2, has two metabolic fates in vivo, rapid removal from plasma and catabolism by kidney or remodeling to medium-sized HDL. Results indicate that Tyr(192) is the predominant site of nitration and chlorination when MPO or ONOO(-) oxidizes lipid-free apoA-I but that only chlorination markedly reduces the cholesterol efflux activity of apoA-I. Results suggest that the most efficient reaction between apoA-I and DMPC/DSPC occurs in particular bilayer conditions, probably when small fluid domains are nucleated within a continuous gel phase and interfacial packing defects are maximal. Significance of G--->A polymorphism in gene promoter on serum high density lipoprotein cholesterol levels in Japanese hyperlipidemic subjects. Structure-function studies of variants. Study of apolipoprotein A-I secondary structural and functional properties. Study of structural and functional homology between human apolipoprotein A-I and envelope proteins of human immunodeficiency virus type 1 in CD4 receptor binding. Tested whether rare sequence variants of ABCA1, APOA1, and LCAT collectively contribute to variation in plasma levels of high density lipoprotein cholesterol; nonsynonymous sequence variants were significantly more common in individuals with low HDL-C. The apoCIII enhancer regulates expression of apoAI, apo-CIII, and apoAIV but not apoAV in vivo; the entire cluster has roles in regulating lipid metabolism. The mitogen-activated protein kinase pathway is involved in the regulation of apoA-I gene expression by estrogen. The structural organization of lipid-free apoA-I and the role of different domains in lipid binding, with comparisons to apoE. Translocation of cholesterol and phospholipid into the cytosol is related to the apo A-I-mediated HDL assembly in astrocytes through functional association with caveolin-1 and a cyclosporin A-sensitive cyclophilin protein(s).
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