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)

Atherosclerosis is a disease of blood vessel walls that is thought to be initiated as a reaction of insults to the endothelium. The complex sequence of cellular events that begins with focal inflammation leads to the accumulation of leukocytes in the subendothelial layer and unrestricted uptake of oxidized lipoproteins by macrophages and smooth muscle cells, leading to foam cell formation. Vascular endothelial cells do not undergo the foam cell transformation and do not accumulate cholesterol in atherosclerotic plaques to the same extent as macrophages or smooth muscle cells. However, vascular endothelial cells express receptors for oxidized lipoproteins, and have the biochemical pathways for sterol synthesis and receptor-mediated endocytosis of lipoproteins. Data from the authors' laboratory show that high density lipoproteins but not lipid-free apolipoprotein A-I promote cellular cholesterol efflux in human umbilical vascular endothelial cells and human aortic endothelial cells. Gene expression microarrays were used to examine the differential expression of genes after cholesterol loading. While sterol regulatory element-binding protein-sensitive genes were downregulated, the authors identified a novel transporter, the ATP-binding cassette G1 (ABCG1) to be highly expressed in response to both cellular cholesterol loading and stimulation with the liver X receptor agonist 22-hydroxycholesterol. The ABCA1 gene and protein, the major modulator of cellular cholesterol efflux in macrophages and in peripheral and hepatic tissues, are only weakly expressed in human umbilical vascular endothelial cells and human aortic endothelial cells. These data suggest that endothelial cells maintain cholesterol homeostasis by downregulating cholesterol synthesis and low density lipoprotein receptors and by a cellular cholesterol efflux mechanism onto low-affinity but high-capacity high density lipoproteins. The role of ABC-type transporters, including ABCG1, requires further examination.
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PMID:Cellular cholesterol homeostasis in vascular endothelial cells. 1649 11

Plasma HDL cholesterol levels are inversely related to risk for atherosclerosis. The ATP-binding cassette, subfamily A, member 1 (ABCA1) mediates the rate-controlling step in HDL particle formation, the assembly of free cholesterol and phospholipids with apoA-I. ABCA1 is expressed in many tissues; however, the physiological functions of ABCA1 in specific tissues and organs are still elusive. The liver is known to be the major source of plasma HDL, but it is likely that there are other important sites of HDL biogenesis. To assess the contribution of intestinal ABCA1 to plasma HDL levels in vivo, we generated mice that specifically lack ABCA1 in the intestine. Our results indicate that approximately 30% of the steady-state plasma HDL pool is contributed by intestinal ABCA1 in mice. In addition, our data suggest that HDL derived from intestinal ABCA1 is secreted directly into the circulation and that HDL in lymph is predominantly derived from the plasma compartment. These data establish a critical role for intestinal ABCA1 in plasma HDL biogenesis in vivo.
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PMID:Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. 1654 47

ATP-binding cassette transporters (ABC) G1 and ABCA1 are membrane cholesterol transporters and have been implicated to mediate cholesterol efflux from cells in the presence of high density lipoproteins and its major protein constituent apolipoprotein A-I, respectively. We previously demonstrated that unsaturated fatty acids suppress the stimulatory effects of oxysterols and retinoids on ABCA1 gene transcription. We here demonstrate that unsaturated fatty acids significantly suppress the stimulatory effects of oxysterols and retinoids on the expression of ABCG1 mRNA and protein and the activity of the wild-type human ABCG1 promoter as well as ABCA1. Mutation or deletion of the DR4 element within the ABCG1 or ABCA1 promoters, to which the transcriptional inducers LXR and RXR bind, abolished the suppressive effects of unsaturated fatty acids. Our observations provide the first evidence that unsaturated fatty acids suppress ABCG1 gene expression by a mechanism which involves the binding of LXR/RXR to the promoters. Suppression of both the ABCA1 and ABCG1 genes may indicate that unsaturated fatty acids suppress not only cholesterol efflux to apoA-I and thereby nascent HDL formation but also HDL-dependent cholesterol efflux from vascular cells.
Atherosclerosis 2007 Mar
PMID:Unsaturated fatty acids suppress the expression of the ATP-binding cassette transporter G1 (ABCG1) and ABCA1 genes via an LXR/RXR responsive element. 1673 Jul 33

ATP-binding cassette transporters G5 and G8 are half-transporters expressed on the apical membranes of enterocytes and hepatocytes that limit intestinal uptake and promote secretion of neutral sterols. Genetic defects that inactivate either half-transporter cause accumulation of cholesterol and plant sterols, resulting in premature coronary atherosclerosis. These observations suggest that G5 and G8 promote the translocation of sterols across membranes, but the primary transport substrate of the G5G8 complex has not been directly determined. Here we report the development of a sterol transfer assay using "inside-out" membrane vesicles from Sf9 cells expressing recombinant mouse G5 and G8. Radiolabeled cholesterol or sitosterol was transferred from donor liposomes to G5- and G8-containing membrane vesicles in an ATP-dependent and vanadate-sensitive manner; net transfer of cholesterol was associated with an increase in vesicular cholesterol mass. CTP, GTP, and UTP, as well as ATP, supported transfer but with lesser efficiency (ATP >> CTP > GTP > UTP). Transfer was specific for sterols and was stereoselective; minimal ATP-dependent and vanadate-sensitive transfer of cholesteryl oleate, phosphatidylcholine, or enantiomeric cholesterol was observed. These studies indicate that G5 and G8 are sufficient for reconstitution of sterol transfer activity in vitro and provide the first demonstration that sterols are direct transport substrates of the G5 and G8 heterodimer.
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PMID:Sterol transfer by ABCG5 and ABCG8: in vitro assay and reconstitution. 1686 93

Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 lead to sitosterolemia, a disorder characterized by sterol accumulation and premature atherosclerosis. ABCG5 and ABCG8 are both half-size transporters that have been proposed to function as heterodimers in vivo. We have expressed the recombinant human ABCG5 and ABCG8 genes in the yeast Pichia pastoris and purified the proteins to near homogeneity. Purified ABCG5 and ABCG8 had very low ATPase activities (<5 nmol min(-)(1) mg(-)(1)), suggesting that expression of ABCG5 or ABCG8 alone yielded nonfunctional transporters. Coexpression of the two genes in P. pastoris greatly increased the yield of pure proteins, indicating that the two transporters stabilize each other during expression and purification. Copurified ABCG5/G8 displayed low but significant ATPase activity with a V(max) of approximately 15 nmol min(-)(1) mg(-)(1). The ATPase activity was not stimulated by sterols. The catalytic activity of copurified ABCG5/G8 was characterized in detail, demonstrating low affinity for MgATP, a preference for Mg as a metal cofactor and ATP as a hydrolyzed substrate, and a pH optimum near 8.0. AlFx and BeFx inhibited MgATP hydrolysis by specific trapping of nucleotides in the ABCG5/G8 proteins. Furthermore, ABCG5/G8 eluted as a dimer on gel filtration columns. The data suggest that the hetero-dimer is the catalytically active species, and likely the active species in vivo.
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PMID:Purification and ATP hydrolysis of the putative cholesterol transporters ABCG5 and ABCG8. 1689 93

Macrophages play a central role in the pathogenesis of atherosclerosis by accumulating cholesterol through increased uptake of oxidized low-density lipoproteins by scavenger receptor CD36, leading to foam cell formation. Here we demonstrate the ability of hexarelin, a GH-releasing peptide, to enhance the expression of ATP-binding cassette A1 and G1 transporters and cholesterol efflux in macrophages. These effects were associated with a transcriptional activation of nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma in response to binding of hexarelin to CD36 and GH secretagogue-receptor 1a, the receptor for ghrelin. The hormone binding domain was not required to mediate PPARgamma activation by hexarelin, and phosphorylation of PPARgamma was increased in THP-1 macrophages treated with hexarelin, suggesting that the response to hexarelin may involve PPARgamma activation function-1 activity. However, the activation of PPARgamma by hexarelin did not lead to an increase in CD36 expression, as opposed to liver X receptor (LXR)alpha, suggesting a differential regulation of PPARgamma-targeted genes in response to hexarelin. Chromatin immunoprecipitation assays showed that, in contrast to a PPARgamma agonist, the occupancy of the CD36 promoter by PPARgamma was not increased in THP-1 macrophages treated with hexarelin, whereas the LXRalpha promoter was strongly occupied by PPARgamma in the same conditions. Treatment of apolipoprotein E-null mice maintained on a lipid-rich diet with hexarelin resulted in a significant reduction in atherosclerotic lesions, concomitant with an enhanced expression of PPARgamma and LXRalpha target genes in peritoneal macrophages. The response was strongly impaired in PPARgamma(+/-) macrophages, indicating that PPARgamma was required to mediate the effect of hexarelin. These findings provide a novel mechanism by which the beneficial regulation of PPARgamma and cholesterol metabolism in macrophages could be regulated by CD36 and ghrelin receptor downstream effects.
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PMID:A growth hormone-releasing peptide that binds scavenger receptor CD36 and ghrelin receptor up-regulates sterol transporters and cholesterol efflux in macrophages through a peroxisome proliferator-activated receptor gamma-dependent pathway. 1695 72

ATP-binding cassette (ABC) transporters are a family of proteins that translocate molecules across cellular membranes. Substrates can include lipids, cholesterol and drugs. Mutations in ABC transporter genes can cause human pathologies and drug resistance phenotypes in cancer cells. ABCA2, the second member the A sub-family to be identified, was found at high levels in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine (EM). In vitro models with elevated levels of ABCA2 are resistant to a variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane) (AAPH). ABCA2 is most abundant in the central nervous system (CNS), ovary and macrophages. Enhanced expression of ABCA2 and related proteins, including ABCA1, ABCA4 and ABCA7, is found in human macrophages upon bolus cholesterol treatment. ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and is coordinately expressed with genes involved in cholesterol homeostasis. Additionally, ABCA2 expression has been linked with gene cluster patterns consistent with pathologies including Alzheimer's disease (AD). A single-nucleotide polymorphism (SNP) in exon 14 of the ABCA2 gene was shown to be linked to early onset AD in humans, supporting the observation that ABCA2 expression influences levels of beta-amyloid peptide (Abeta), the primary component of senile plaques. ABCA2 may play a role in cholesterol transport and affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.
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PMID:The ATP-binding cassette transporter ABCA2 as a mediator of intracellular trafficking. 1702 87

A hallmark of atherosclerotic cardiovascular disease (CVD) is the accumulation of cholesterol in arterial macrophages. Factors that modulate circulating and tissue cholesterol levels have major impacts on initiation, progression, and regression of CVD. Four members of the ATP-binding cassette (ABC) transporter family play important roles in this modulation. ABCA1 and ABCG1 export excess cellular cholesterol into the HDL pathway and reduce cholesterol accumulation in macrophages. ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. All 4 transporters are induced by the same sterol-sensing nuclear receptor system. ABCA1 expression and activity are also highly regulated posttranscriptionally by diverse processes. ABCA1 mutations can cause a severe HDL-deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. ABCG5 or ABCG8 mutations can cause sitosterolemia, in which patients accumulate cholesterol and plant sterols in the circulation and develop premature CVD. Disrupting Abca1 or Abcg1 in mice promotes accumulation of excess cholesterol in macrophages, and manipulating mouse macrophage ABCA1 expression affects atherogenesis. Overexpressing ABCG5 and ABCG8 in mice attenuates diet-induced atherosclerosis in association with reduced circulating and liver cholesterol. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and inhibit transcription of all 4 transporters. Thus, impaired ABC cholesterol transporters might contribute to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. Their beneficial effects on cholesterol homeostasis have made these transporters important new therapeutic targets for preventing and reversing CVD.
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PMID:ATP-Binding cassette cholesterol transporters and cardiovascular disease. 1709 32

ATP-binding cassette (ABC) transporters comprise a family of critical membrane bound proteins functioning in the translocation of molecules across cellular membranes. Substrates for transport include lipids, cholesterol and pharmacological agents. Mutations in ABC transporter genes cause a variety of human pathologies and elicit drug resistance phenotypes in cancer cells. ABCA2, the second member the A subfamily to be identified, was highly expressed in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine, and more recently, in human vestibular schwannomas. Cells expressing elevated levels of ABCA2 show resistance to variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane). ABCA2 is expressed in a variety of tissues, with greatest abundance in the central nervous system and macrophages. This transporter, along with other proteins that have a high degree of homology to ABCA2, including ABCA1 and ABCA7, are up-regulated in human macrophages during cholesterol import. Recent studies have shown ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and to be coordinately expressed with sterol-responsive genes. A single nucleotide polymorphism in exon 14 of the ABCA2 gene was shown to be linked to early onset Alzheimer disease (AD) in humans, supporting an earlier study showing ABCA2 expression influences levels of APP and beta-amyloid peptide, the primary component of senile plaques. Studies thus far implicate ABCA2 as a sterol transporter, the deregulation of which may affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.
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PMID:The ABCA2 transporter: intracellular roles in trafficking and metabolism of LDL-derived cholesterol and sterol-related compounds. 1726 23

The ATP-binding cassette transporters, ABCA1 and ABCG1, are LXR-target genes that participate in the removal of cholesterol from lipid-laden macrophages, a crucial anti-atherogenic mechanism. Statins are currently the most efficacious therapy for the treatment of hypercholesterolemia and cardiovascular disease. We and others have shown that statins decrease ABCA1 and ABCG1 expression as well as cholesterol efflux from human macrophages. However, other studies have reported that statins produce no change, or even a modest increase in these variables. In an attempt to reconcile these conflicting reports, we investigated how the effect of statins on transcription of ABCA1 and ABCG1 is modulated by cellular cholesterol status and the extent of macrophage differentiation. We showed that supplementing human macrophages with cholesterol reversed the statin-mediated down-regulation of ABC transporter expression whereas depletion of cellular cholesterol tended to accentuate the statin effect. Down-regulation of ABC transporter expression was more pronounced with increased macrophage differentiation status and already evident at statin concentrations equivalent to those present in plasma. Addition of LXR agonists, which are currently on trial as anti-atherogenic agents, reversed the effects on ABC transporter expression while PPAR alpha and PPAR gamma agonists did not. The significance of these results in light of current and future combination therapies is discussed.
Atherosclerosis 2008 Jan
PMID:The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation. 1746 10


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