Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ATP-binding cassette transporter A1 (ABCA1) encodes a membrane protein that promotes cholesterol and phospholipid efflux from cells. Mutations in ABCA1 lead to HDL deficiency and tissue accumulation of macrophages in patients with homozygous Tangier disease. In this study, we examined whether the complete absence of ABCA1 or selected inactivation in macrophages is accompanied by an increase in atherosclerotic lesion progression in hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) mice and LDLR receptor-deficient (LDLr(-/-)) mice. 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. 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. In contrast, bone marrow transplantation studies demonstrated that the selective inactivation of ABCA1 in macrophages markedly increased atherosclerosis and foam cell accumulation in apoE(-/-). Taken together, these findings demonstrate that the complete absence of ABCA1 has a major impact on plasma lipoprotein homeostasis, and the proposed antiatherogenic effect resulting from ABCA1 deficiency is compensated by a less atherogenic profile. ABCA1 deficiency in macrophages, however, demonstrates the antiatherogenic properties of ABCA1 independent of plasma lipids and HDL levels.
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PMID:Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. 1195 Jul 2

The 2 principal approaches to management of dyslipidemias are lifestyle intervention and lipid-modifying drug therapy. Recent revisions to the American Heart Association's dietary guidelines for reducing cardiovascular disease emphasize an overall healthy eating pattern and maintenance of appropriate body weight, together with achieving a desirable blood pressure and a desirable lipoprotein profile. New National Cholesterol Education Program treatment guidelines include a scoring system for calculating coronary heart disease (CHD) risk that is adapted from the Framingham Heart Study, as well as a category of CHD risk equivalents (e.g., diabetes) that will encourage more aggressive therapeutic intervention for individuals at high short-term risk for CHD, even in the absence of clinically evident coronary disease. Classes of lipid-modifying drugs include bile acid sequestrants (resins), fibrates, and statins, with each class exerting different effects on the lipid profile. Nicotinic acid (niacin) is also an approved lipid-modifying agent. The armamentarium for treating lipid disorders and atherosclerosis now includes statins that can decrease low-density lipoprotein (LDL) cholesterol levels by up to 55%, as well as a resin with improved tolerability. In patients with high levels of LDL cholesterol and triglycerides, together with low concentrations of high-density lipoprotein cholesterol, combination therapy may be effective. Moreover, researchers are currently investigating the development of drugs directed at molecular targets, including cholesterol esterification and accumulation in macrophage foam cells (e.g., inhibiting acyl-coenzyme A : cholesterol acyltransferase), degradation of atherosclerotic plaque (e.g., decreasing the expression of matrix metalloproteinases), and reverse cholesterol transport (e.g., stimulating ATP-binding cassette transporter A1).
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PMID:Management of dyslipidemia. 1204 90

ATP-binding cassette transporter A1 (ABCA1) was recently recognized as the mutant molecule responsible for Tangier disease with low HDL levels, accumulation of cholesteryl esters in tissues, and increased risk of cardiovascular disease. Extensive studies for the past 2 years have recognized the critical role of ABCA1 in cholesterol and phospholipid trafficking. Since the removal of cholesterol from tissues is a key step in the prevention of atherosclerosis, significant attention has been focused on this molecule. Natural ABCA1 mutations in Tangier disease (TD) patients and WHAM chickens together with induced mutation in ABCA1 knock-out mice unequivocally established the important role of ABCA1 in maintaining circulating HDL levels and promoting cholesterol efflux from the arterial wall. Mice lacking ABCA1 showed similar phenotypes observed in Tangier disease patients with low levels of HDL. Further understanding of the roles of ABCA1 in lipid transport and atherosclerosis became clear from studies with ABCA1 transgenic mice. These mice showed enhanced cholesterol efflux from macrophages and reduced atherosclerotic lesion formation. The promoter of the ABCA1 gene has been mapped to a large extent, with the exception of cAMP response element. The present review summarizes recent developments on the role of ABCA1 in cholesterol efflux and prevention of atherosclerosis. Given the antiatherogenic properties of ABCA1, this molecule can serve as an appropriate target for developing drugs to treat individuals with low levels of HDL.
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PMID:ATP binding cassette transporter A1--key roles in cellular lipid transport and atherosclerosis. 1223 82

HDL metabolism is crucial in maintaining cellular cholesterol and phospholipid homeostasis and prevention of atherosclerosis progression. Recent work identified the ATP-binding cassette transporter A1 (ABCA1) as the major regulator of plasma high density lipoprotein (HDL) cholesterol responsible for the removal of excess cholesterol from peripheral cells and tissues. Here we discuss some novel aspects of the ABCA1 network: 1) the cellular pathways involved in cholesterol and phospholipid efflux, 2) regulation of ABCA1, 3) sulfonylurea receptor 1 (SUR1)- or cystic fibrosis transmembrane conductance regulator (CFTR)-like function of ABCA1, 4) interaction of the ABCA1 C-terminus with beta2-syntrophin, 5) ABCA1 modulation of the Rho GTPase Cdc42, 6) localization of ABCA1 in plasma membrane microdomains and intracellular sites, 7) differential effects of prebeta-HDL precursors on ABCA1 mediated alpha-HDL particle formation and 8) ABCA1 in platelets and its relation to phosphatidylserine-flippase activity. A complex regulatory network and additional antiatherogenic features that may depend on the composition of prebeta-HDL precursor particles are believed to coordinate ABCA1 function in reverse cholesterol and phospholipid transport. Distinct prebeta-HDL ligand-specific receptor-clusters are involved that may modulate specific signaling pathways with varying outcomes related to prebeta-HDL particle composition, the cell-type and the cellular response status.
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PMID:ABCA1: regulation, trafficking and association with heteromeric proteins. 1245 78

ATP-binding cassette transporter A1 (ABCA1) transports cellular cholesterol to lipid-poor apolipoproteins. Mutations in the ABCA1 gene are linked to rare phenotypes, familial hypoalphalipoproteinemia (FHA) and Tangier disease (TD), characterized by markedly decreased plasma high-density lipoprotein cholesterol (HDL-C) levels. The aim was to test if the ABCA1 locus is a major locus regulating HDL-C levels in the homogenous Finnish population with a high prevalence of coronary heart disease (CHD). Firstly, the ABCA1 locus was tested for linkage to HDL-C levels in 35 families with premature CHD and low HDL-C levels. Secondly, 62 men with low HDL-C levels and CHD were screened for the five mutations known to cause FHA. Thirdly, polymorphisms of the ABCA1 gene were tested for an association with HDL-C levels in a population sample of 515 subjects. The ABCA1 locus was not linked to HDL-C levels in the CHD families, and no carriers of the FHA mutations were found. The AA596 genotype was associated with higher HDL-C levels compared with the GG and GA genotypes in the women, but not in the men. The G596A genotypes explained 4% and the A2589G genotypes 3% of the variation in plasma HDL-C levels in women. The data suggest that the ABCA1 locus is of minor importance in the regulation of HDL-C in Finns.
Atherosclerosis 2003 Feb
PMID:ATP-binding cassette transporter A1 locus is not a major determinant of HDL-C levels in a population at high risk for coronary heart disease. 1461 18

The ATP-binding cassette transporter A1 (ABCA1), identified in 1999 as the gene defective in Tangier disease, promotes efflux of cellular cholesterol from macrophages and other peripheral tissues to apolipoprotein acceptors. These ABCA1-mediated processes are anticipated to have antiatherogenic properties, prompting the development of pharmacological agents that increase ABCA1 gene expression as well as the establishment of ABCA1-transgenic mouse lines. Preliminary studies of ABCA1-Tg mice seem to validate the selection of this transporter as a therapeutic target for the treatment of low HDL syndromes and cardiovascular disease but have also raised new questions regarding the function of ABCA1. In particular, the relative contribution of hepatic and peripheral ABCA1 to plasma HDL levels and to reverse cholesterol transport, as well as the potential role of ABCA1 in modulating the plasma concentrations of the apolipoprotein B-containing lipoproteins and protecting against atherosclerosis, seem to be promising areas of investigation. The present review summarizes the most recent studies and discusses insights provided by these transgenic mouse models.
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PMID:Study of ABCA1 function in transgenic mice. 1261 81

Recently, variants in ATP-binding cassette transporter A1 (ABCA1) were demonstrated to be associated with increased level of high density lipoprotein cholesterol (HDL-C) and decreased risk of coronary artery disease (CAD) in Caucasians. However, this is not universally applicable due to the ethnic or environmental differences. In this context, to clarify the effect of ABCA1 in Japanese, we evaluated the phenotypic effects of I/M 823 and R/K 219 variants on the plasma level of HDL-C in 410 patients recruited in our hospital. Subjects with M 823 allele had significantly higher level of HDL-C than those without M823 allele (49.0+/-15.1 vs. 44.9+/-11.5 mg/dl, respectively, P<0.05). This statistical significance did not change even after multiple regression analysis. In contrast, there was no difference in HDL-C level among the genotypes in R/K 219 polymorphism. Further, in our study population an inverse relationship was shown to exist between HDL-C level and incidence of CAD. However, no positive association was observed between those variants and susceptibility to CAD. In this study, we provide evidence that I/M 823 variant, not R/K 219 variant, in ABCA1 is one of the determinants of HDL-C level, suggesting the importance of this gene on lipid metabolism in Japanese.
Atherosclerosis 2003 Jul
PMID:A common Ile 823 Met variant of ATP-binding cassette transporter A1 gene (ABCA1) alters high density lipoprotein cholesterol level in Japanese population. 1286 Feb 56

Low levels of transgenic mouse apolipoprotein E (apoE) suppress atherosclerosis in apoE knockout (apoE-/-) mice without normalizing plasma cholesterol. To test whether this is due to facilitation of cholesterol efflux from the vessel wall, we produced apoA-I-/-/apoE-/- mice with or without the transgene. Even without apoA-I and HDL, apoA-I-/-/apoE-/- mice had the same amount of aorta cholesteryl ester as apoE-/- mice. Low apoE in the apoA-I-/-/apoE-/- transgenic mice reduced aortic lesions by 70% versus their apoA-I-/-/apoE-/- siblings. To define the free cholesterol (FC) efflux capacity of lipoproteins from the various genotypes, sera were assayed on macrophages expressing ATP-binding cassette transporter A1 (ABCA1). Surprisingly, ABCA1 FC efflux was twice as high to sera from the apoA-I-/-/apoE-/- or apoE-/- mice compared with wild-type mice, and this activity correlated with serum apoA-IV. Immunodepletion of apoA-IV from apoA-I-/-/apoE-/- serum abolished ABCA1 FC efflux, indicating that apoAI-V serves as a potent acceptor for FC efflux via ABCA1. With increasing apoE expression, apoA-IV and FC acceptor capacity decreased, indicating a reciprocal relationship between plasma apoE and apoA-IV. Low plasma apoE (1-3 x 10(-8) M) suppresses atherosclerosis by as yet undefined mechanisms, not dependent on the presence of apoA-I or HDL or an increased capacity of serum acceptors for FC efflux.
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PMID:Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression. 1295 61

Cholesterol efflux, an important mechanism by which high density lipoproteins (HDL) protect against atherosclerosis, is initiated by docking of apolipoprotein A-I (apoA-I), a major HDL protein, to specific binding sites followed by activation of ATP-binding cassette transporter A1 (ABCA1) and translocation of cholesterol from intracellular compartments to the exofacial monolayer of the plasma membrane where it is accessible to HDL. In this report, we investigated potential signal transduction pathways that may link apoA-I binding to cholesterol translocation to the plasma membrane and cholesterol efflux. By using pull-down assays we found that apoA-I substantially increased the amount of activated Cdc42, Rac1, and Rho in human fibroblasts. Moreover, apoA-I induced actin polymerization, which is known to be controlled by Rho family G proteins. Inhibition of Cdc42 and Rac1 with Clostridium difficile toxin B inhibited apoA-I-induced cholesterol efflux, whereas inhibition of Rho with Clostridium botulinum C3-exoenzyme exerted opposite effects. Adenoviral expression of a Cdc42(T17N) dominant negative mutant substantially reduced apoA-I-induced cholesterol efflux, whereas dominant negative Rac1(T17N) had no effect. We further found that two downstream effectors of Cdc42/Rac1 signaling, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), are activated by apoA-I. Pharmacological inhibition of JNK but not p38 MAPK decreased apoA-I-induced cholesterol efflux, whereas anisomycin and hydrogen peroxide, two direct JNK activators, could partially substitute for apoA-I in its ability to induce cholesterol efflux. These results for the first time demonstrate activation of Rho family G proteins and stress kinases by apoA-I and implicate the involvement of Cdc42 and JNK in the apoA-I-induced cholesterol efflux.
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PMID:Involvement of Cdc42 signaling in apoA-I-induced cholesterol efflux. 1456 54

ATP-binding cassette transporter A1 (ABCA1) mediates transport of cellular cholesterol and phospholipids to high density lipoprotein (HDL) apolipoproteins, such as apoA-I. ABCA1 mutations can cause a severe HDL deficiency and atherosclerosis. Here we show that the protein-tyrosine kinase (TK) Janus kinase 2 (JAK2) modulates the apolipoprotein interactions with ABCA1 required for removing cellular lipids. The protein kinase A (PKA) inhibitor H89, the TK inhibitor genistein, and the JAK2 inhibitor AG490 suppressed apoA-I-mediated cholesterol and phospholipid efflux from ABCA1-expressing cells without altering the membrane ABCA1 content. Whereas PKA inhibition had no effect on apoA-I binding to cells or to ABCA1, TK and JAK2 inhibition greatly reduced these activities. Conversely, PKA but not JAK2 inhibition significantly reduced the intrinsic cholesterol translocase activity of ABCA1. 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. Thus, although PKA modulates ABCA1 lipid transport activity, JAK2 appears to selectively modulate apolipoprotein interactions with ABCA1. TK-mediated phosphorylation of ABCA1 was undetectable, implicating the involvement of another JAK2-targeted protein. Acute incubation of ABCA1-expressing cells with apoA-I had no effect on ABCA1 phosphorylation but stimulated JAK2 autophosphorylation. 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.
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PMID:Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol. 1466 33


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