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)

Plasma phospholipid binding to cell-derived cholesterol is important in reverse cholesterol transport, a key step in the regression of atherosclerosis. However, the mechanism by which phospholipids are transferred from cells to plasma remains unclear. [3H]Choline-labeled phospholipid efflux from fibroblasts has been studied using plasma and its components as acceptors. The kinetics were resolved into a fast component (k1 = 0.119 +/- 0.23 min-1) that corresponded to high-affinity binding of high-density lipoproteins (HDL) to the cell surface and a slow component (k2 = 0.0047 +/- 0.0009 min-1) due to protein-mediated desorption (n = 3). Altering the donor charge with heparinase or the acceptor charge by acetylation abolished the fast component, while the slow phase was unchanged. Only HDL displayed biexponential kinetics, comparable to whole plasma. Half-lives for low-density lipoprotein and very-low-density lipoprotein were t1/2 = 278 +/- 22 min and t1/2 = 1003 +/- 147 min, respectively. In the absence of transfer factor, HDL alone significantly reduced phospholipid efflux (t1/2 = 663 min). Phospholipid transfer protein restored biexponential kinetics. We conclude that cell membranes are a potentially important source of plasma phospholipids and that protein-mediated transfer to HDL is the major route for cell-to-plasma transfer. This step represents a locus for anti-atherosclerotic intervention.
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PMID:Mechanism of cellular phospholipid efflux. 823 Nov 74

Lecithin:cholesteryl acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of cholesterol and the subsequent transfer of cholesteryl ester from high density lipoproteins (HDL) towards very low and low density lipoproteins (VLDL + LDL). Phospholipid transfer protein (PLTP), lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in plasma phospholipid and triglyceride metabolism and also affect HDL. Equivocal changes in plasma cholesteryl ester transfer have been reported in non-insulin-dependent diabetes mellitus (NIDDM). In 16 NIDDM men with plasma triglycerides < or = 4.5 mmol/l and cholesterol < or = 8.0 mmol/l. plasma cholesteryl ester transfer (CET), cholesterol esterification rate, LCAT and PLTP activity levels were higher (P < 0.05 to P < 0.02) in conjunction with higher plasma triglycerides (P < 0.01) and lower HDL cholesterol and cholesteryl ester levels (P < 0.05) compared to 16 matched healthy men. Multiple stepwise regression analysis demonstrated that CET was positively related to VLDL + LDL cholesterol (P < 0.001), triglycerides (P = 0.001), PLTP activity (P = 0.007) and CETP activity (P = 0.008, multiple r = 0.94). NIDDM had no effect on CET, independently from these parameters. HDL cholesteryl ester was negatively related to CET (P= 0.017), HL activity (P = 0.033) and NIDDM (P = 0.047) and positively to LCAT activity levels (P = 0.034, multiple r = 0.68). It is concluded that the elevated CET in plasma from NIDDM patients is associated with higher plasma triglycerides and PLTP activity levels. Furthermore, our data suggest that in normo- and moderately dyslipidaemic subjects PLTP and CETP activity levels per se may influence the rate of cholesteryl ester transfer in plasma. Plasma cholesteryl ester transfer appears to be a determinant of HDL cholesteryl ester, but other factors are likely to contribute to lower HDL cholesteryl ester levels in NIDDM.
Atherosclerosis 1998 Sep
PMID:Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein. 973 17

High-density lipoproteins (HDL) play a major protective role against the development of coronary artery disease. Phospholipid transfer protein (PLTP) is a main factor regulating the size and composition of HDL in the circulation and plays an important role in controlling plasma HDL levels. This is achieved via both the phospholipid transfer activity of PLTP and its capability to cause HDL conversion. The present review focuses on the impact of PLTP on HDL metabolism. The basic characteristics and structure of the PLTP protein are described. The two main functions of PLTP, PLTP-mediated phospholipid transfer and HDL conversion are reviewed, and the mechanisms and control, as well as the physiological significance of these processes are discussed. The relationship between PLTP and the related cholesteryl ester transfer protein (CETP) is reviewed. Thereafter other functions of PLTP are recapitulated: the ability of PLTP to transfer cholesterol, alpha-tocopherol and lipopolysaccharide (LPS), and the suggested involvement of PLTP in cellular cholesterol traffic. The discussion on PLTP activity and mass in (patho)physiological settings includes new data on the presence of two forms of PLTP in the circulation, one catalytically active and the other inactive. Finally, future directions for PLTP research are outlined.
Atherosclerosis 2001 Apr
PMID:The impact of phospholipid transfer protein (PLTP) on HDL metabolism. 1125 96

Phospholipid transfer protein (PLTP) is a member of the lipid transfer/lipopolysaccharide binding protein gene family. Recently, the crystal structure of one of the members of the gene family, bactericidal permeability increasing protein, was solved, providing potential insights into the mechanisms of action of PLTP. These molecules contain intrinsic lipid binding sites and appear to act as carrier proteins that shuttle between lipoproteins to redistribute lipids. The phenotype of PLTP transgenic and gene knock out mice indicates that PLTP plays a major role in the metabolism of high-density lipoprotein (HDL) and apoB-containing lipoproteins and thereby influences the concentration, apolipoprotein content, and size of lipoprotein particles in plasma. Recent data indicate that PLTP deficiency in mice is associated with a decrease of atherosclerosis, despite decreased HDL levels. At lease two underlined mechanisms are involved in the reduction of atherosclerosis in PLTP deficient status, 1) reduction of apoB-containing lipoprotein production and levels; and 2) increase of anti-oxidation potential. Human studies indicated that PLTP activity positively correlated with aging, obesity, diabetes and coronary artery disease. A challenge for the future will be the inhibition of PLTP for therapeutic benefit.
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PMID:The effect of phospholipid transfer protein on lipoprotein metabolism and atherosclerosis. 1208 20

Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling. Lipoprotein lipase hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. Hepatic lipase reduces HDL particle size by hydrolysing its triglycerides and phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low HDL2 cholesterol in insulin resistance. The esterification of free cholesterol by LCAT increases HDL particle size. Plasma cholesterol esterification is unaltered or increased in type 2 diabetes mellitus, probably depending on the extent of triglyceride elevation. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins, and is involved in decreasing HDL size. An increased plasma cholesteryl ester transfer is frequently observed in insulin-resistant conditions, and is considered to be a determinant of low HDL cholesterol. Phospholipid transfer protein generates small pre beta-HDL particles that are initial acceptors of cell-derived cholesterol. Its activity in plasma is elevated in insulin resistance and type 2 diabetes mellitus in association with high plasma triglycerides and obesity. In insulin resistance, the ability of plasma to promote cellular cholesterol efflux may be maintained consequent to increases in PLTP activity and pre beta-HDL. However, cellular cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of ATP binding cassette transporter 1 and scavenger receptor class B type I are likely to result in diminished cellular cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived cholesterol and subsequent hepatobiliary transport is altered in insulin resistance and type 2 diabetes mellitus is unknown. Specific CETP inhibitors have been developed that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animals. As an increased CETP-mediated cholesteryl ester transfer represents a plausible metabolic intermediate between high triglycerides and low HDL cholesterol, studies are warranted to evaluate the effects of these agents in insulin resistance- and diabetes-associated dyslipidaemia.
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PMID:Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. 1463 88

This review deals with four lipid transfer proteins (LTP): three are involved in cholesteryl ester (CE) synthesis or transport, the fourth deals with plasma phospholipid (PL) transfer. Experimental models of atherosclerosis, clinical and epidemiological studies provided information as to the relationship of these LTP(s) to atherosclerosis, which is the main focus of this review. Thus, inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) 1 and 2 decreases cholesterol absorption, plasma cholesterol and aortic cholesterol esterification in the aorta. The discovery that tamoxifen is a potent ACAT inhibitor explained the plasma cholesterol lowering of the drug. The use of ACAT inhibition in humans is under current investigation. As low cholesteryl ester transfer protein (CETP) activity is connected with high HDL-C, several CETP inhibitors were tried in rabbits, with variable results. A new CETP inhibitor, Torcetrapib, was tested in humans and there was a 50-100% increase in HDL-C. Lecithin cholesterol acyl-transferase (LCAT) influences oxidative stress, which can be lowered by transient LCAT gene transfer in LCAT-/- mice. Phospholipid transfer protein (PLTP) deficiency reduced apo B production in apo E-/- mice, as well as oxidative stress in four models of mouse atherosclerosis. In conclusion, the ability to increase HDL-C so markedly by inhibitors of CETP introduces us into a new era in prevention and treatment of coronary heart disease (CHD).
Atherosclerosis 2005 Feb
PMID:Lipid transfer proteins (LTP) and atherosclerosis. 1569 28

Phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins, and plays an essential role in HDL metabolism. The regulation of PLTP is poorly understood and recent evidence suggests that PLTP activity increases during acute-phase response. Since type 2 diabetes is associated with chronic subclinical inflammation, the objective is to determine whether inflammation modulates PLTP in diabetes. Plasma PLTP activity was assayed by measuring the transfer of radiolabeled phosphatidylcholine from liposomes to HDL and high-sensitivity C-reactive protein (CRP) by immunoturbidimetric assay in 280 type 2 diabetic patients and 105 controls. Plasma PLTP activity (2364+/-651 nmol/ml/h versus 1880+/-586 nmol/ml/h in control, mean +/- S.D., P <0.01) and CRP (1.64(0.89-3.23)mg/l versus 0.99(0.53-2.23 mg/l, median (interquartile range), P<0.01) were increased in diabetic subjects. PLTP activity correlated significantly with age, BMI, HbA1c, log(CRP) and apolipoprotein AI and B in diabetic subjects. General linear model analysis showed that only apolipoprotein AI, age, BMI, and log(CRP) were independent determinants of PLTP activity. In conclusion, PLTP activity is increased in diabetes and apolipoprotein AI is a major determinant of PLTP activity. There is also an independent association between CRP and PLTP activity, suggesting that subclinical inflammation may influence PLTP activity in diabetes.
Atherosclerosis 2005 Feb
PMID:Plasma phospholipid transfer protein activity and subclinical inflammation in type 2 diabetes mellitus. 1575 64

Reverse cholesterol transport (RCT) is the pathway, by which the excess of cholesterol is removed from peripheral cells to the liver. An early step of RCT is the efflux of free cholesterol from cell membranes that is mediated by high-density lipoproteins (HDL). Phospholipid transfer protein (PLTP) transfers phospholipids between apolipoprotein-B-containing lipoproteins (i.e., chylomicrons and very low-density lipoproteins) and HDL. PLTP contributes to the HDL maturation and increases the ability of HDL to extract the cellular cholesterol. It is known that RCT is impaired in type 2 diabetic patients, especially when cardiovascular complication is associated with. In this study, we measured the serum capacity that promotes cellular cholesterol efflux and the plasma PLTP activity in type 2 diabetic patients with coronary artery disease (CAD) (n = 35), those without CAD (n = 24), and 35 healthy subjects as a sex- and age-matched control. In patients with CAD, plasma triglyceride level was higher compared to controls (p < 0.01) and HDL-cholesterol was lower (p < 0.01 vs control and the patients without CAD). In diabetic patients with or without CAD, PLTP activity was consistently increased, compared to controls, while cellular cholesterol efflux activity was decreased by 20% (p < 0.001) or 13.5% (p < 0.01), respectively. In conclusion, plasma PLTP activity was increased in type 2 diabetic patients with or without CAD, which could impair cellular cholesterol removal and might accelerate atherosclerosis in diabetic patients.
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PMID:Increased phospholipid transfer protein activity associated with the impaired cellular cholesterol efflux in type 2 diabetic subjects with coronary artery disease. 1791 6

Phospholipid transfer protein (PLTP) is a multifunctional protein synthesized by various cell types and secreted into the plasma. Plasma PLTP is able to transfer phospholipids between lipoproteins and modulate HDL particles. Mice with overexpression of human PLTP have an increased ability to generate pre beta-HDL, reduced total HDL levels and an increased susceptibility to atherosclerosis. As the macrophage is a key component of the atherosclerotic lesion and an important site of PLTP expression, we investigated the role of systemic and peripheral PLTP in macrophage cholesterol efflux and reverse cholesterol transport (RCT) in vivo. We used an assay in which (3)H-labelled cholesterol-loaded macrophages were injected intraperitoneally into recipient mice, and radioactivity was quantified in plasma, liver and faeces. Firstly, wild type macrophages were injected into wild type, PLTP transgenic (PLTPtg) and apoAI transgenic (apoAItg) mice. While plasma (3)H-tracer levels in apoAItg mice were increased compared with wild type mice, they were reduced in PLTPtg mice. Moreover, overexpression of PLTP significantly decreased faecal (3)H-tracer levels compared with wild type and apoAItg mice. Secondly, wild type mice were injected with peritoneal macrophages derived from PLTPtg or wild type mice. No significant difference in the amount of (3)H-tracer in plasma, liver or faeces was found between the two groups of mice. Our findings demonstrate that macrophage cholesterol efflux and RCT to faeces is impaired in PLTP transgenic mice, and that elevation of macrophage-PLTP does not affect RCT, indicating that higher systemic PLTP levels may promote atherosclerosis development by decreasing the rate of macrophage RCT.
Atherosclerosis 2009 Jun
PMID:Elevation of systemic PLTP, but not macrophage-PLTP, impairs macrophage reverse cholesterol transport in transgenic mice. 1910 May 48

Phospholipid transfer protein (PLTP) is an important modulator of phospholipid transfer and exchange among proteins. It also plays a role in inflammation and oxidative stress. Accordingly, PLTP has been implicated in the development of atherosclerosis. Left ventricular (LV) systolic dysfunction is common in patients with atherosclerosis, and both inflammation and oxidative stress have also been implicated in its development and progression. The goal of the present study was to examine the relation between plasma PLTP activity and LV systolic function. Baseline plasma PLTP activity was measured in 389 male patients referred for coronary angiography for a variety of indications. Detailed clinical, angiographic and laboratory characteristics were available for the patients. Compared to those patients with normal LV function (defined as an ejection fraction of >or=55% on ventriculography), patients with any degree of LV dysfunction had elevated PLTP activity (median PLTP 17.8 pmol/microl/h versus 15.9 pmol/microl/h, p=0.0038). Using multivariate analysis, and adjusting for a variety of confounding variables known to affect both LV function and PLTP activity, PLTP activity was an independent predictor of the presence of any left ventricular systolic dysfunction in the entire population (OR 1.47, 95% CI 1.12-1.93, p=0.0052). Furthermore, PLTP activity was an independent predictor of the presence of LV dysfunction in both patients with and without myocardial infarction on presentation (OR 2.39, 95% CI 1.18-4.86, p=0.0161 and OR 1.41, 95% CI 1.05-1.89, p=0.0206, respectively). In conclusion, PLTP activity may represent a novel marker of LV systolic dysfunction in patients with known or suspected coronary artery disease.
Atherosclerosis 2009 Nov
PMID:Relation of baseline plasma phospholipid transfer protein (PLTP) activity to left ventricular systolic dysfunction in patients referred for coronary angiography. 1944 93


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