Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Accumulating in vitro and in vivo studies have proposed a role for mast cells in the pathogenesis of atherosclerosis. Here, we studied the role of mast cells in lipoprotein metabolism, a key element in the atherosclerotic disease. Male mice deficient in low-density lipoprotein receptors and mast cells on a Western diet for 26 weeks had significantly less atherosclerotic changes both in aortic sinus (55%, P = 0.0009) and in aorta (31%, P = 0.049), as compared to mast cell-competent littermates. Mast cell-deficient female mice had significantly less atherosclerotic changes in aortic sinus (43%, P = 0.011). Furthermore, we found a significant positive correlation between the extent of atherosclerosis and the number of adventitial/perivascular mast cells in aortic sinus of mast cell-competent mice (r = 0.615, P = 0.015). Serum cholesterol and triglyceride levels were significantly lower in both male (63%, P = 0.0005 and 57%, P = 0.004) and female (73%, P = 0.00009 and 54%, P = 0.007) mast cell-deficient mice, with a concomitant decrease in atherogenic apoB-containing particles and serum prebeta-high-density lipoprotein and phospholipid transfer protein activity in both male (69% and 24%) and female (74% and 54%) mast cell-deficient mice. Serum soluble intercellular adhesion molecule was decreased in both male (32%, P = 0.004) and female (28%, P = 0.003) mast cell-deficient mice, whereas serum amyloid A was similar between mast cell-deficient and competent mice. In conclusion, mast cells participate in the pathogenesis of atherosclerosis in ldlr(-/-) mice by inducing both an atherogenic lipid profile and vascular inflammation.
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PMID:Mast cells promote atherosclerosis by inducing both an atherogenic lipid profile and vascular inflammation. 2002 59

Plasma phospholipid transfer protein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Animal studies have shown that it is closely related to the development of atherosclerosis. Although many studies have indicated that PLTP activity is increased in diabetes mellitus, the role of PLTP in diabetes is still unclear. To evaluate the influence of a high-fat meal on PLTP activity, 50 nondiabetic patients with coronary heart disease (CHD), 50 insulin-treated Type 2 diabetics, and 50 healthy controls were included. We determined PLTP activity before and 4 and 8 h after a high-fat meal. As expected, serum PLTP activity was significantly higher in CHD patients than in healthy controls (71.0 +/- 46.2 vs. 54.0 +/- 33.8 pmol/microl/h, P = 0.032) at baseline. More importantly, we found that serum PLTP activity increased to its maximum 4 h after fat loading and then decreased to nearly basal levels after 8 h both in controls and CHD patients. In contrast, PLTP activity continuously increased during this time period in the diabetic patients. With regards to the data from this study we hypothesize that serum PLTP is involved in the clearance of postprandial lipoproteins and this process is attenuated in diabetes. Since postprandial lipoproteins are atherogenic, the delay in clearance of these particles could play an important role in the development of atherosclerosis in patients with diabetes mellitus.
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PMID:Serum phospholipid transfer protein activity after a high fat meal in patients with insulin-treated type 2 diabetes. 2010 50

A high saturated fat diet induces free cholesterol and phospholipid accumulation in the plasma of phospholipid transfer protein (Pltp)-deficient mice. In this study, we examined the atherogenic consequence of this phenomenon and investigated the possible mechanism(s). Pltp KO/Apoe KO mice that were fed a coconut oil-enriched high-fat diet (COD) for 7 weeks had higher plasma free cholesterol (149%), phospholipids (15%), and sphingomyelin (54%) than Apoe KO controls. In contrast to chow-fed animals, COD-fed Pltp KO/Apoe KO mice had the same atherosclerotic lesion size as that of Apoe KO mice. Similar to Pltp KO mice, plasma from COD-fed Pltp KO/Apoe KO mice contained VLDL/LDL-sized lamellar particles. Bile measurement indicated that COD-fed Pltp KO mice have 33% less hepatic cholesterol output than controls. In conclusion, COD-fed, Pltp-deficient mice are no longer protected from atherosclerosis and have impaired biliary lipid secretion, which is associated with free cholesterol and phospholipid accumulation.
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PMID:Diet-induced lipid accumulation in phospholipid transfer protein-deficient mice: its atherogenicity and potential mechanism. 2054 42

Reverse cholesterol transport (RCT) describes the process whereby cholesterol in peripheral tissues is transported to the liver where it is ultimately excreted in the form of bile. Given the atherogenic role of cholesterol accumulation within the vessel intima, removal of cholesterol through RCT is considered an anti-atherogenic process. The major constituents of RCT include cell membrane- bound lipid transporters, plasma lipid acceptors, plasma proteins and enzymes, and lipid receptors of liver cell membrane. One major cholesterol acceptor in RCT is high-density lipoprotein (HDL). Both the characteristics and level of HDL are critical determinants for RCT. It is known that phospholipid transfer protein (PLTP) impacts both HDL cholesterol level and biological quality of the HDL molecule. Recent data suggest that PLTP has a site-specific variation in its function. Moreover, the RCT pathway also has multiple steps both in the peripheral tissues and circulation. Therefore, PLTP may influence the RCT pathway at multiple levels. In this review, we focus on the potential role of PLTP in RCT through its impact on HDL homeostasis. The relationship between PLTP and RCT is expected to be an important area in finding novel therapies for atherosclerosis.
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PMID:Role of phospholipid transfer protein in high-density lipoprotein- mediated reverse cholesterol transport. 2136 62

It has been reported that phospholipid transfer protein (PLTP) is an independent risk factor for human coronary artery disease. In mouse models, it has been demonstrated that PLTP overexpression induces atherosclerosis, while its deficiency reduces it. PLTP is considered a promising target for pharmacological intervention to treat atherosclerosis. However, we must still answer a number of questions before its pharmaceutical potential can be fully explored. In this review, we summarized the recent progresses made in the PLTP research field and focused on its effect on apoB-containing- triglyceride-rich particle and HDL metabolism.
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PMID:The impact of phospholipid transfer protein (PLTP) on lipoprotein metabolism. 2289 26

Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.
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PMID:Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. 2342 79

Knockout technology has established the functions of many genes affecting plasma lipid and lipoprotein levels and the development of atherosclerosis. However, many genes remain to be characterized. The ability to produce mice lacking whole-body expression of a given gene is still one of the most powerful techniques available for determining gene function. A complementary approach, underutilized yet vitally important to understanding lipoprotein metabolism, is the ability to create mice with gene deficiency only in a specific tissue. Liver, intestine, and macrophages are the major tissues and cells involved in lipoprotein metabolism and atherosclerosis, and additional tissues such as adipose tissue and brain are also of interest. Thus, feasible approaches to prepare general and tissue-specific gene knockout mouse models are necessary. Here, we describe our general procedure for generating whole-body knockout mice, using as an example the preparation of general (whole-body) phospholipid transfer protein (PLTP) gene knockout mice. We also describe several approaches to generating liver, intestine, and myeloid cell-specific tissue-specific knockout mice, using as an example the preparation of tissue-specific knockout mice for the subunit 2 of serine palmitoyltransferase (SPT), a key enzyme for sphingomyelin de novo synthesis. Bone marrow transplantation is an alternative means of creating myeloid cell-specific knockout mice. The general principles and techniques described here apply to the establishment of other gene knockout mouse models as well. The ability to manipulate gene expression in specific tissues as well as throughout the entire body of the mouse is anticipated to yield novel insights into lipid and lipoprotein metabolism and the development of atherosclerosis.
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PMID:Generation of general and tissue-specific gene knockout mouse models. 2391 91

Regardless of its effect on the concentrations of serum cholesterol, statins exert pleiotropic effects, including the regulation of endothelial function, reduced oxidative stress and inflammation, as well as a slight improvement in the concentrations of high density lipoprotein (HDL). However, its role on the composition of HDL is not yet established. The aim of this study was to evaluate the composition of HDL subfractions, HDLsub>2 and HDL3, after 14 days of placebo and atorvastatin (10 mg/day) use in 30 asymptomatic volunteers. The serum parameters and the HDL subfractions compositions were determined using radiometric, nephelometric and biochemical enzymatic methods. We observed significant reductions of total cholesterol, low density lipoprotein (LDL) and apolipoprotein B-100 by 28%, 40% and 38%, respectively. The analyses of chemical composition of the subfractions revealed a lower lipid protein ratio in HDL2, suggesting enrichment in proteins, and also lower in HDL3, probably by an increase in the number of particles. Several mechanisms can be suggested for the effects observed after the use of atorvastatin, such as a possible action on the reverse cholesterol transport (decreased activity of hepatic lipase and increased phospholipid transfer protein, PLTP), which would explain the enrichment of HDL. The results suggest that statin use may be relevant in the primary prevention of atherosclerosis not only by its lowering effect on LDLcholesterol and its anti-inflammatory effect but also by beneficial changes in HDL subfractions.
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PMID:Chemical modification of high density lipoprotein subfractions - HDL2 and HDL3 - after use of atorvastatin. 2454 77

High-density lipoprotein (HDL) intravascular metabolism is complex, and the major HDL functions are esterification of cholesterol and reverse cholesterol transport, in which cholesterol from cells is excreted in bile. HDL has also several other antiatherogenic functions: antioxidative, vasodilatatory, anti-inflammatory, antiapoptotic, anti thrombotic, and anti infectious. Low HDL cholesterol is a major risk factor for cardiovas cular disease (CVD) and high HDL cholesterol may favor the many protective abilities of HDL. However, aspects of HDL function can be independent of HDL cholesterol levels, including the efflux of cholesterol from cells to HDL. Some populations show low incidence of CVD despite their low HDL cholesterol. Lipid exchange between HDL and other lipoproteins and cells is fundamental in HDL metabolism and reverse cholesterol transport. By determining HDL composition, lipid transfers can also affect HDL functions that depend on proteins that anchor on HDL particle surface. Cholesteryl ester protein (CETP) and phospholipid transfer protein facilitate lipid transfers among lipoprotein classes, but the role of the lipid transfers and transfer proteins in atherosclerosis and other diseases is not well established. CETP has become a therapeutic target because CETP inhibitors increase HDL cholesterol, but to date the clinical trials failed to show benefits for the patients. Recently, we introduced a practical in vitro assay to evaluate the simultaneous transfer from a donor nanoemulsion to HDL of unesterified and esterified cho lesterol, phospholipids, and triglycerides. Groups of subjects at different clinical, nutritional, and training conditions were tested, and among other findings, lower transfer ratios of unesterified cholesterol to HDL were predictors of the presence of CVD.
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PMID:HDL metabolism and atheroprotection: predictive value of lipid transfers. 2523 9

High-density lipoprotein (HDL) is considered to be an anti-atherogenic lipoprotein moiety. Generation of genetically modified (total body and tissue-specific knockout) mouse models has significantly contributed to our understanding of HDL function. Here we will review data from knockout mouse studies on the importance of HDL's major alipoprotein apoA-I, the ABC transporters A1 and G1, lecithin:cholesterol acyltransferase, phospholipid transfer protein, and scavenger receptor BI for HDL's metabolism and its protection against atherosclerosis in mice. The initial generation and maturation of HDL particles as well as the selective delivery of its cholesterol to the liver are essential parameters in the life cycle of HDL. Detrimental atherosclerosis effects observed in response to HDL deficiency in mice cannot be solely attributed to the low HDL levels per se, as the low HDL levels are in most models paralleled by changes in non-HDL-cholesterol levels. However, the cholesterol efflux function of HDL is of critical importance to overcome foam cell formation and the development of atherosclerotic lesions in mice. Although HDL is predominantly studied for its atheroprotective action, the mouse data also suggest an essential role for HDL as cholesterol donor for steroidogenic tissues, including the adrenals and ovaries. Furthermore, it appears that a relevant interaction exists between HDL-mediated cellular cholesterol efflux and the susceptibility to inflammation, which (1) provides strong support for the novel concept that inflammation and metabolism are intertwining biological processes and (2) identifies the efflux function of HDL as putative therapeutic target also in other inflammatory diseases than atherosclerosis.
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PMID:Mouse models of disturbed HDL metabolism. 2552 93


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