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)

Plasma high density lipoprotein (HDL)-cholesterol levels are negatively correlated with the incidence of coronary artery disease. HDL plays an important role in protecting against atherosclerosis by removing cholesterol from atheroma and transporting it back to the liver. The ATP-binding cassette transporters (ABCA1 and ABCG1) and scavenger receptor BI (SR-BI) are thought to be one of the rate-limiting factors to generate HDL in the liver. Adiponectin (APN) secreted from adipocytes is also one of the important molecules to inhibit the development of atherosclerosis. Recently, it has been reported that plasma HDL-cholesterol levels are positively correlated with plasma APN concentrations in humans. Therefore, we investigated the association of APN with HDL assembly in the liver. Human hepatoma cell line, HepG2 cells, were incubated for 24h in the culture medium with the indicated concentrations of recombinant APN. APN enhanced the mRNA level of apolipoprotein A-I (apoA-I) in HepG2 cells and increased the secretion of apoA-I from the cells to the medium. Furthermore, APN increased both mRNA and protein levels of ABCA1, but not ABCG1 and SR-BI, in HepG2 cells. Taken together, the current study demonstrates that APN might protect against atherosclerosis by increasing HDL assembly through enhancing ABCA1 pathway and apoA-1 synthesis in the liver.
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PMID:Adiponectin accelerates reverse cholesterol transport by increasing high density lipoprotein assembly in the liver. 1752 14

The controlled uptake and release of lipid compounds is a hallmark feature of living cells. Numerous factors have been implicated in these complex transmembrane transport processes. The recent discovery of a novel class of transporter molecules, the group of A-subclass ATP-binding cassette (ABC) transporters, has brought new insights into the molecular basis of cellular lipid transport. Available evidence indicates that individual ABC A-subclass transporters function as key components of highly specialized cellular lipid export machineries in major physiological systems and, when defective, cause hereditary diseases in the cardiovascular, respiratory, visual and integumentary systems, respectively. Intriguingly, a steadily growing body of evidence suggests that ABC A lipid transporters play important roles in the pathogenesis of complex disorders with high incidence including atherosclerosis, Alzheimer's disease and age-related macula degeneration. The present article reviews the biology of this emerging group of proteins and their implication in human pathologies.
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PMID:[ABC A-subclass transporters--key regulators of molecular lipid transport]. 1763 70

In the early 1960s liver cytochrome P450 (P450) was known as an enzyme in drug metabolism. By the late 1970s, P450 induction was associated with elevation of plasma high-density lipoprotein cholesterol and apolipoprotein AI indicating a reduced risk of atherosclerotic disease. Later on, 57 human P450 genes have been identified. One P450 enzyme participates in cholesterol synthesis, and several others catabolize it to oxysterols and other metabolites. Oxysterols are physiological ligands specific for liver X receptors (LXRs) in the activation of ATP-binding cassette (ABC) transporter and other cholesterol-lowering genes. Elevation of cholesterol leads to an endogenous induction of P450 and consequently to enhanced generation of oxysterols and activation of genes coding proteins which efflux cholesterol out of cells, transport it to the liver, catabolize and excrete cholesterol into bile, and prevent absorption of cholesterol in the intestine in the processes that maintain cellular cholesterol homeostasis and protect arteries from atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) co-operate with LXRs and ABC transporters in cholesterol regulation. Secretion of oxysterol is a direct pathway for cellular cholesterol elimination. Several compounds induce P450 and other genes regulating cholesterol balance and prevent or regress atherosclerosis, whereas inhibition of P450 blocks oxidative reactions, promotes cholesterol accumulation, and enhances the atherosclerotic vascular process.
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PMID:Cytochrome P450--physiological key factor against cholesterol accumulation and the atherosclerotic vascular process. 1770 78

The NAD(+)-dependent deacetylase Sir2 regulates life span in lower eukaryotes. The mammalian ortholog SIRT1 regulates physiological processes including apoptosis, fat metabolism, glucose homeostasis, and neurodegeneration. Here we show that SIRT1 is a positive regulator of liver X receptor (LXR) proteins, nuclear receptors that function as cholesterol sensors and regulate whole-body cholesterol and lipid homeostasis. LXR acetylation is evident at a single conserved lysine (K432 in LXRalpha and K433 in LXRbeta) adjacent to the ligand-regulated activation domain AF2. SIRT1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRalpha by this sirtuin. Loss of SIRT1 in vivo reduces expression of a variety of LXR targets involved in lipid metabolism, including ABCA1, an ATP-binding cassette (ABC) transporter that mediates an early step of HDL biogenesis. Our findings suggest that deacetylation of LXRs by SIRT1 may be a mechanism that affects atherosclerosis and other aging-associated diseases.
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PMID:SIRT1 deacetylates and positively regulates the nuclear receptor LXR. 1798 78

HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediated sterol efflux in this disease process, we transplanted BM from Abca1(-/-)Abcg1(-/-) mice into LDL receptor-deficient mice and administered a high-cholesterol diet. Compared with control and single-KO BM recipients, Abca1(-/-)Abcg1(-/-) BM recipients showed accelerated atherosclerosis and extensive infiltration of the myocardium and spleen with macrophage foam cells. In experiments with isolated macrophages, combined ABCA1 and ABCG1 deficiency resulted in impaired cholesterol efflux to HDL or apoA-1, profoundly decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines. In addition, these cells showed increased apoptosis when challenged with free cholesterol or oxidized LDL loading. These results suggest that the combined effects of ABCA1 and ABCG1 in mediating macrophage sterol efflux are central to the antiatherogenic properties of HDL.
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PMID:Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice. 1799 62

Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acyl-CoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets.
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PMID:Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. 1800 Sep 63

The human breast cancer resistance protein is an ATP-binding cassette (ABC) multidrug transporter that affects the bioavailability of chemotherapeutic drugs and can confer drug resistance on cancer cells. It is the second member of the ABCG subfamily, other members of which are associated with human steroid disorders such as hypercholesterolemia, sitosterolemia, and atherosclerosis. The molecular bases of protein-steroid interactions in ABC transporters are unknown. Here, we identify a steroid-binding element in the membrane domain of ABCG2 with a similarity to steroid hormone/nuclear receptors. The element facilitates steroid hormone binding and mediates modulation of ABCG2 activity. The identification of this element might provide an opportunity for the development of new therapeutic ligands for ABCG2.
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PMID:A functional steroid-binding element in an ATP-binding cassette multidrug transporter. 1809 74

High-density lipoprotein (HDL) has been identified as a potential target in the treatment of atherosclerotic vascular disease. The failure of torcetrapib, an inhibitor of cholesteryl ester transfer protein (CETP) that markedly increased HDL levels in a clinical trial, has called into doubt the efficacy of HDL elevation. Recent analysis suggests that failure may have been caused by off-target toxicity and that HDL is functional and promotes regression of atherosclerosis. New studies highlight the central importance of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in reducing macrophage foam cell formation, inflammation, and atherosclerosis. A variety of approaches to increasing HDL may eventually be successful in treating atherosclerosis.
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PMID:HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. 1846 Mar 28

Plant sterols and stanols (phytosterols/phytostanols) are known to reduce serum low-density lipoprotein (LDL)-cholesterol level, and food products containing these plant compounds are widely used as a therapeutic dietary option to reduce plasma cholesterol and atherosclerotic risk. The cholesterol-lowering action of phytosterols/phytostanols is thought to occur, at least in part, through competition with dietary and biliary cholesterol for intestinal absorption in mixed micelles. However, recent evidence suggests that phytosterols/phytostanols may regulate proteins implicated in cholesterol metabolism both in enterocytes and hepatocytes. Important advances in the understanding of intestinal sterol absorption have provided potential molecular targets of phytosterols. An increased activity of ATP-binding cassette transporter A1 (ABCA1) and ABCG5/G8 heterodimer has been proposed as a mechanism underlying the hypocholesterolaemic effect of phytosterols. Conclusive studies using ABCA1 and ABCG5/G8-deficient mice have demonstrated that the phytosterol-mediated inhibition of intestinal cholesterol absorption is independent of these ATP-binding cassette (ABC) transporters. Other reports have proposed a phytosterol/phytostanol action on cholesterol esterification and lipoprotein assembly, cholesterol synthesis and apolipoprotein (apo) B100-containing lipoprotein removal. The accumulation of phytosterols in ABCG5/G8-deficient mice, which develop features of human sitosterolaemia, disrupts cholesterol homeostasis by affecting sterol regulatory element-binding protein (SREBP)-2 processing and liver X receptor (LXR) regulatory pathways. This article reviews the progress to date in studying these effects of phytosterols/phytostanols and the molecular mechanisms involved.
Atherosclerosis 2009 Mar
PMID:New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism. 1869 49

Plasma high density lipoprotein (HDL)-cholesterol levels are inversely correlated to the risk of atherosclerotic cardiovascular diseases. Reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis, in which HDL particles play a crucial role to carry cholesterol derived from peripheral tissues to the liver. Recently, ATP-binding cassette transporters (ABCA1, ABCG1) and scavenger receptor (SR-BI) have been identified as important membrane receptors to generate HDL by removing cholesterol from foam cells. Adiponectin (APN) secreted from adipocytes is one of the important molecules to inhibit the development of atherosclerosis. Epidemiological studies have revealed a positive correlation between plasma HDL-cholesterol and APN concentrations in humans, although its mechanism has not been clarified. Therefore, in the present study, we investigated the role of APN on RCT, in particular, cellular cholesterol efflux from human monocyte-derived and APN-knockout (APN-KO) mice macrophages. APN up-regulated the expression of ABCA1 in human macrophages, respectively. ApoA-1-mediated cholesterol efflux from macrophages was also increased by APN treatment. Furthermore, the mRNA expression of LXRalpha and PPARgamma was increased by APN. In APN-KO mice, the expression of ABCA1, LXRalpha, PPARgamma, and apoA-I-mediated cholesterol efflux was decreased compared with wild-type mice. In summary, APN might protect against atherosclerosis by increasing apoA-I-mediated cholesterol efflux from macrophages through ABCA1-dependent pathway by the activation of LXRalpha and PPARgamma.
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PMID:Adiponectin prevents atherosclerosis by increasing cholesterol efflux from macrophages. 1870 20


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