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 ABC transporter ABCA1 plays a key role in the first steps of the reverse cholesterol transport pathway by mediating lipid efflux from macrophages. Previously, it was demonstrated that human ABCA1 overexpression in vivo in transgenic mice results in a mild elevation of plasma HDL levels and increased efflux of cholesterol from macrophages. In this study, we determined the effect of overexpression of ABCA1 on atherosclerosis development. Human ABCA1 transgenic mice (BAC(+)) were crossed with ApoE(-/-) mice, a strain that spontaneously develop atherosclerotic lesions. BAC(+)ApoE(-/-) mice developed dramatically smaller, less-complex lesions as compared with their ApoE(-/-) counterparts. In addition, there was increased efflux of cholesterol from macrophages isolated from the BAC(+)ApoE(-/-) mice. Although the increase in plasma HDL cholesterol levels was small, HDL particles from BAC(+)ApoE(-/-) mice were significantly better acceptors of cholesterol. Lipid analysis of HDL particles from BAC(+)ApoE(-/-) mice revealed an increase in phospholipid levels, which was correlated significantly with their ability to enhance cholesterol efflux.
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PMID:Increased ABCA1 activity protects against atherosclerosis. 1209 86

Numerous ATP-binding cassette (ABC) transporters are expressed in monocyte-derived macrophages and are subject to sterol-dependent regulation. ABCA1 has been identified as a key regulator of macrophage cholesterol efflux and HDL-mediated reverse cholesterol transport. Although the precise mechanisms of ABCA1 function are not completely understood, recent data suggest that the ABCA1 pathway regulates vesicular traffic, filipodia formation and lipid microdomains, thereby controlling susceptibility to atherosclerosis. Nuclear hormone receptors including LXR/RXR and PPAR/RXR heterodimers are recognized as direct or indirect regulators of ABCA1 expression and are discussed as potential targets for pharmacological intervention in cardiovascular disease. Future studies clarifying the processes involved in the ABCA1 pathway at the cellular level are expected to identify new and possibly more specific pharmaceutical targets.
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PMID:ATP-binding cassette transporters in macrophages: promising drug targets for treatment of cardiovascular disease. 1213 3

The ATP-binding cassette transporter, ABCA1, is a member of the ABC superfamily of proteins involved in the active transport of substrates across cellular membranes. Recent studies have implicated mutations in ABCA1 as the cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). To evaluate the molecular basis of low high density lipoprotein (HDL) in a family with premature coronary artery disease, single strand conformational polymorphism analysis was performed for all coding regions and splice site junctions of ABCA1 with the genomic DNA of the proband. The proband and affected individuals were heterozygotes for C254T with proline converted to leucine (P85L). This mutation was not identified in over 400 chromosomes of healthy subjects. In the FHA kindred, family members heterozygous for the ABCA1 variant also exhibited corresponding low levels of HDL cholesterol. These data confirm recent data that a single defective allele in ABCA1 may be associated with reduced HDL cholesterol and FHA.
Atherosclerosis 2002 Oct
PMID:ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease. 1292 88

In advanced atherosclerosis, macrophage foam cells progressively accumulate large amounts of unesterified or "free" cholesterol (FC), a process that is thought to contribute to foam cell death and lesional necrosis. The cellular consequences of early FC accumulation, including those that lead to further FC accumulation, are poorly understood. In this context, we show that cholesterol and phospholipid efflux mediated by ABCA1, which is initially induced in the cholesterol-loaded macrophage, was inhibited by approximately 80% in pre-toxic FC-loaded macrophages. Cholesterol efflux to HDL(2), which is mediated by a non-ABCA1 pathway, was inhibited by only approximately 20% in FC-loaded macrophages. FC loading led to decreased levels of ABCA1 protein via increased degradation of ABCA1, and not by decreased transcription or translation of AbcA1 mRNA. The decrease in ABCA1 protein occurred relatively early and was not prevented by caspase inhibitors, indicating that it was not a consequence of FC-induced apoptosis. However, inhibition of proteasomal function by lactacystin largely prevented the degradation of ABCA1. Importantly, the FC-induced decrease in ABCA1 function and protein was almost entirely prevented in macrophages that had partial deficiency of npc1 or were exposed to nanomolar concentrations of U18666A, both of which lead to defective cholesterol trafficking to the endoplasmic reticulum, but leave trafficking to the plasma membrane largely intact. Thus, a relatively early event during FC loading of macrophages is increased degradation of ABCA1, which appears to require trafficking of cholesterol to a peripheral cellular site, but not bulk trafficking of excess cholesterol to the plasma membrane. These findings provide new insight into the post-translational regulation of ABCA1 and the pathobiology of the FC-loaded macrophage.
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PMID:ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages. Mechanism involves enhanced ABCA1 degradation in a process requiring full NPC1 activity. 1221 51

Low HDL-cholesterol (HDL-C) concentrations are inversely correlated with cardiovascular disease, and previous studies have demonstrated that variants in the ATP-binding cassette transporter, ABCA1, are responsible for a proportion of HDL-C deficiency states. We identified a novel variant in ABCA1 in a kindred with decreased HDL-C. This variant was not identified in >200 chromosomes of healthy individuals. The proband, a heterozygote for G2265T, developed premature coronary artery disease. In addition to low HDL-C, six biological family members heterozygous for the ABCA1 variant exhibited low HDL-C concentrations compared with unaffected family members (0.83 +/- 0.32 vs 1.33 +/- 0.36 mmol/L; P = 0.009). Despite the decreased HDL-C, carotid artery B-mode ultrasound studies failed to reveal increased intima-media thickening in affected individuals compared with age- and sex-matched controls. Although these data extend previous observations that a single defective ABCA1 allele may lead to decreased HDL-C, associated evidence of early atherosclerosis was not confirmed.
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PMID:Lack of association between increased carotid intima-media thickening and decreased HDL-cholesterol in a family with a novel ABCA1 variant, G2265T. 1240 1

The family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the largest gene family known. While some ABC transporters translocate single substances across membranes with high specificity, others transport a wide variety of different lipophilic compounds. They are responsible for many physiological processes and are also implicated in a number of diseases. The present review focuses on ABC transporter genes which are involved in ageing and age-related diseases. Expression of ABCB1 (MDR1, P-glycoprotein) increases with age in CD4(+) and CD8(+) T-lymphocytes indicating that P-glycoprotein may be involved in the secretion of cytokines, growth factors, and cytotoxic molecules. As T cells in aged individuals are hyporesponsive leading to a reduced immunodefence capability, a role of ABCB1 in age-related immunological processes is presumed. The ABCA1 (ABC1) gene product translocates intracellular cholesterol and phospholipids out of macrophages. Genetic aberrations in ABCA1 cause perturbations in lipoprotein metabolism and contribute to atherosclerosis. ABCA4 (ABCR) represents a retina-specific ABC transporter expressed in rod photoreceptor cells. The ABCA4 gene product translocates retinyl-derivatives. Mutations in the ABCA4 gene contribute to age-related macular degeneration. Polymorphisms in the sulfonylurea receptor gene (ABCC8, SUR1) are associated with non-insulin-dependent diabetes mellitus (NIDDM). Sulfonylureas inhibit potassium conductance and are used to treat NIDDM by stimulation of insulin secretion across ATP-sensitive potassium channels in pancreatic beta-cell membranes. Possible diagnostic and therapeutic implications of ABC transporters for age-related diseases are discussed.
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PMID:Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases. 1243 93

Several ATP-binding cassette (ABC) transporters are critically involved in cholesterol and phospholipid efflux, reverse cholesterol transport, and play an important role in the development of atherosclerosis. Quantification of ABC mRNA is important in studying the regulation of cellular cholesterol homeostasis and mechanisms related to the pathogenesis of atherosclerosis. We have developed a one-step real time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method for measuring mRNA levels of ABCA1, ABCG1, and ABCA2 in murine tissues using the TaqMan(TM) technology. It has significant methodological benefits when compared to classic Northern blotting or semi-quantitative RT-PCR analysis. Using this method, we found high expression levels of ABCA1 in liver and macrophages, and of ABCG1 in the brain and macrophages. The expression of ABCA1 and ABCG1 were further induced in macrophages loaded with acLDL. In contrast, ABCA2 was expressed exclusively in the brain with low expression levels in the macrophages. This method provides a rapid, highly sensitive, specific, and reproducible quantification of ABC mRNA, and can be performed with nanograms of total RNA sample, thus making it a superior method for studying the regulation of ABC transporters in cholesterol efflux and its role in the pathogenesis of atherosclerosis in murine models.
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PMID:Rapid quantification of murine ABC mRNAs by real time reverse transcriptase-polymerase chain reaction. 1245 81

Cholesterol-loaded macrophage foam cells are a central component of atherosclerotic lesions. ABCA1, the defective molecule in Tangier disease, mediates the efflux of phospholipids and cholesterol from cells to apoA-I, reversing foam cell formation. In ABCA1, we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST sequence) that enhances the degradation of ABCA1 by calpain protease and thereby controls the cell surface concentration and cholesterol efflux activity of ABCA1. In an apparent positive feedback loop, apoA-I binds ABCA1, promotes lipid efflux, inhibits calpain degradation, and leads to increased levels of ABCA1. ApoA-I infusion also increases ABCA1 in vivo. These studies reveal a novel mode of regulation of ABCA1 by PEST sequence-mediated calpain proteolysis that appears to be reversed by apolipoprotein-mediated phospholipid efflux. Inhibition of ABCA1 degradation by calpain could represent a novel therapeutic approach to increasing macrophage cholesterol efflux and decreasing atherosclerosis.
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PMID:A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I. 1251 93

Cholesterol efflux from CHOP cells transfected with sterol 27-hydroxylase (CYP27A1) was compared with non-transfected and mock-transfected cells. Transfection caused expression of CYP27A1, formation of 27-hydroxycholesterol, and inhibition of cholesterol biosynthesis. Transfection enhanced cholesterol efflux to apolipoprotein A-I or human plasma by 2-3-fold but did not affect the efflux in the absence of acceptor. The analysis of released sterols revealed that 27-hydroxycholesterol represented only a small proportion of sterols, most of which was non-oxidized cholesterol. Time course and dose dependence studies showed that expression of CYP27A1 in CHOP cells mostly affected the efflux of the "fast" cholesterol pool, and relatively more cholesterol was released with low concentrations of an acceptor. Preincubation of non-transfected cells with exogenous 27-hydroxycholesterol (10(-9) and 10(-7) m) led to the stimulation of cholesterol efflux by 24-60%. Expression of CYP27A1 in CHOP cells did not affect ABCA1 expression and abundance of ABCA1 protein. Thus, introduction of CYP27A1 into cells stimulates cholesterol efflux and therefore may increase protection against atherosclerosis.
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PMID:Expression of sterol 27-hydroxylase (CYP27A1) enhances cholesterol efflux. 1253 3

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor activated by fatty acid derivatives and hypolipidemic drugs of the fibrate class. PPARalpha is expressed in monocytes, macrophages, and foam cells, suggesting a role for this receptor in macrophage lipid homeostasis with consequences for atherosclerosis development. Recently, it was shown that PPARalpha activation promotes cholesterol efflux from macrophages via induction of the ABCA1 pathway. In the present study, the influence of PPARalpha activators on intracellular cholesterol homeostasis was investigated. In human macrophages and foam cells, treatment with fibrates, synthetic PPARalpha activators, led to a decrease in the cholesteryl ester (CE):free cholesterol (FC) ratio. In these cells, PPARalpha activation reduced cholesterol esterification rates and Acyl-CoA:cholesterol acyltransferase-1 (ACAT1) activity. However, PPARalpha activation did not alter ACAT1 gene expression, whereas mRNA levels of carnitine palmitoyltransferase type 1 (CPT-1), a key enzyme in mitochondrial fatty acid catabolism, were induced. Finally, PPARalpha activation blocked CE formation induced by TNF-alpha, possibly due to the inhibition of neutral sphingomyelinase activation by TNF-alpha. In conclusion, our results identify a role for PPARalpha in the control of cholesterol esterification in macrophages, resulting in an enhanced availability of FC for efflux through the ABCA1 pathway.
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PMID:Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages. 1257 49


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