Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.34 (lipoprotein lipase)
 7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacological intervention for altering plasma levels of lipoproteins is usually aimed at reducing atherogenesis and preventing coronary heart disease (CHD). Drug therapy should be attempted only after other nonpharmacological methods (such as elimination of smoking, weight reduction and exercise) have been tried. An overview of the metabolism of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles is the basis of this paper. Various sites suitable for pharmacological intervention are identified. LDL metabolism can be altered at 2 potential sites, with a consequent reduction in the plasma level of this atherogenic lipoprotein. Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (such as lovastatin) and cation-exchange resins (e.g. cholestyramine) reduce LDL levels by stimulating the hepatic synthesis of apolipoprotein (apo) B,E receptors. Very low density lipoprotein (VLDL) secretion is inhibited by nicotinic acid (niacin) and gemfibrozil, leading to a secondary decrease in LDL production from VLDL. Probucol also reduces the LDL concentration and inhibits the oxidative modification of LDL. Gemfibrozil and other fibrates stimulate lipoprotein lipase activity, thereby decreasing VLDL concentration. Reduction of the LDL concentration is effective in reducing CHD incidence, whether this is achieved by stimulation of catabolism or inhibition of production of the lipoprotein. In contrast, the mechanism of raising plasma HDL-cholesterol levels is probably relevant to the potential clinical benefits associated with drug therapy. Gemfibrozil and cholestyramine stimulate synthesis of apoprotein A1, the major protein constituent of HDL particles. Both drugs have been shown to reduce the incidence of CHD in clinical trials, via mechanisms that are related in part to their HDL-raising activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological intervention for altering lipid metabolism. 228 8

Experiments were performed to evaluate the utility of a perfluorochemical emulsion as an artificial blood substitute for studies of lipoprotein metabolism in rats. Perfusing the liver of fed rats with perfluorochemical emulsion FC-34 at the same rate as a 20% red blood cell (RBC) perfusate, there was comparable oxygen uptake; however, there was a greater release of glucose and production of lactate than in RBC perfused livers. Under the stimulation of a low level of free fatty acid, there was less free fatty acid uptake and less triglyceride secretion in emulsion perfused livers. The lipoprotein secreted contained similar apoprotein, but there was a lower triglyceride to cholesterol ratio in the emulsion perfused liver. In addition to these moderate metabolic alterations, the uptake of radiolabeled chylomicron remnants by the perfused liver was almost completely suppressed when the perfluorochemical emulsion was used as an oxygen carrier. In vivo the presence of the perfluorochemical emulsion (5% of blood volume) decreased the rate of clearance of chylomicron remnants, beta-very-low-density lipoprotein (beta-VLDL) and cholesterol-rich high-density lipoprotein (HDLc), but not of low-density lipoprotein (LDL). In the presence of the emulsion, the degradation of 125I remnants, but not of [125I]LDL, by rat hepatoma cells was inhibited. The perfluorochemical emulsion did not inactivate lipoprotein lipase. The perfluorochemical emulsion did not change the triglyceride concentration or apoprotein composition of chylomicron remnants when they were incubated with the perfluorochemical emulsion at 37 degrees C for 1 hour and reisolated. The detergent used to solubilize the fluorocarbon FC-43, Pluronic F-68, did not affect the removal of chylomicron remnants in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of perfluorochemical artificial blood on lipoprotein metabolism in rats. 236 60

Rat VLDL were glycated in vitro in the presence or absence of a reducing agent. Prior to glycation, the VLDL triglyceride was endogenously radiolabelled with [3H]-oleic acid. Post glycation the VLDL B-apoprotein was exogenously radiolabelled with [131]I. The double labelled VLDL was then injected into normal rats and the decline in plasma radioactivity of the two isotopes was used as a measure of triglyceride and particle clearance. VLDL glycated in either the presence or absence of reducing agent exhibited a significantly slower removal of triglyceride and apoprotein B compared to normal VLDL. The ability of glycated VLDL triglyceride to act as substrate for lipoprotein lipase and hepatic lipase was examined. Increasing concentrations of normal and glycated VLDL triglyceride were incubated with post-heparin plasma. The kinetics of triglyceride hydrolysis were determined in a manner analogous to Michaelis-Menten analysis. Glycated VLDL was found to be poorer than normal VLDL as a substrate for lipoprotein lipase. Glycation of VLDL appears to interfere with the lipolysis of its triglyceride. This may explain the delayed clearance of glycated VLDL triglyceride in vivo. Glycation also extended the mean plasma residence time of the VLDL particle. These factors may, in part, contribute to the hypertriglyceridaemia observed in subjects with diabetes mellitus.
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PMID:Glycation of very low density lipoprotein from rat plasma impairs its catabolism. 237 65

Tumor necrosis factor (TNF) has been proposed to mediate the hypertriglyceridemic response to infection by either increasing hepatic lipid synthesis or decreasing clearance of triglyceride-rich particles through inhibition of lipoprotein lipase. We demonstrate that within 90 min of administration of recombinant human TNF alpha to rats there is a rapid increase in plasma levels of very low density lipoproteins (VLDL) of normal ultracentrifugal flotation rate, apoprotein and lipid composition, and particle size, as assessed by nondenaturing gradient gel electrophoresis. Clearance of radioiodinated VLDL 90 min after TNF administration did not differ from that in control animals, consistent with other observations that increases in plasma triglyceride concentrations after TNF precede detectable reductions in tissue lipoprotein lipase activity. Between 90 min and 16 h after TNF, VLDL levels decline, and there are increases in intermediate (IDL) and low (LDL) density lipoproteins consistent with lipolytic processing of VLDL, although the findings are also compatible with direct secretion of IDL and LDL subspecies. By 16 h, there is a 50% increase in protein mass of LDL of normal composition and subspecies distribution, as assessed by nondenaturing gradient gel electrophoresis. These data suggest that the initial locus of TNF's metabolic effects is the liver, and the resulting increases in secretion and metabolic processing of VLDL may represent an early manifestation of the acute phase response.
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PMID:Tumor necrosis factor acutely increases plasma levels of very low density lipoproteins of normal size and composition. 238 45

The levels of plasmatic lipids and the lipo and apoprotein composition of lipoprotein of high density were analysed in 18 patients, diagnosed as having non-insulin dependent diabetes, and compared to a control group of 18 healthy patients. 10 patients showed a moderate hypertriglyceridemia, this sub-group having the main HDL alteration. In this lipoprotein fraction an increase of triglycerides was observed, and a decrease in cholesterol and apoprotein III, probably as result of a lower activity of lipoprotein lipase in plasma.
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PMID:[Modifications in the composition of plasma HDLs in non-insulin-dependent diabetics]. 249 52

To study the role of the two postheparin plasma lipolytic enzymes, lipoprotein lipase (LPL) and hepatic lipase (HL) in high density lipoprotein (HDL) metabolism at a population level, we determined serum lipoproteins, apoproteins A-I, A-II, B, and E, and postheparin plasma LPL and HL activities in 65 subjects with a mean HDL-cholesterol of 34 mg/dl and in 62 subjects with a mean HDL-cholesterol of 87 mg/dl. These two groups represented the highest and lowest 1.4 percentile of a random sample consisting 4,970 subjects. The variation in HDL level was due to a 4.1-fold difference in the HDL2 cholesterol (P less than 0.001) whereas the HDL3 cholesterol level was increased only by 32% (P less than 0.001) in the group with high HDL-cholesterol. Serum apoA-levels were 128 +/- 2.2 mg/dl and 210 +/- 2.8 mg/dl (mean +/- SEM) in hypo- and hyper-HDL cholesterolemia, respectively. Serum apoA-II concentration was elevated by 28% (P less than 0.001) in hyperalphalipoproteinemia. The apoA-I/A-II ratio was elevated only in women with high HDL-cholesterol but not in men, suggesting that elevation of apoA-I is involved in hyperalphalipoproteinemia in females, whereas both apoA proteins are elevated in men with high HDL cholesterol. Serum concentration of apoE and its phenotype distribution were similar in the two groups. The HL activity was reduced in the high HDL-cholesterol group (21.2 +/- 1.5 vs. 38.5 +/- 1.8 mumol/h/ml, P less than 0.001), whereas the LPL activity was elevated in the group with high HDL-cholesterol compared to subjects with low HDL-cholesterol (27.8 +/- 1.3 vs. 19.9 +/- 0.8 mumol/h/ml, P less than 0.001). The HL and LPL activities correlated in opposing ways with the HDL2 cholesterol (r = 0.57, P less than 0.001 and r = 0.51, P less than 0.001, respectively), and this appeared to be independent of the relative ponderosity by multiple correlation analysis. The results demonstrate major influence of both HL and LPL on serum HDL cholesterol concentration at a population level.
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PMID:Postheparin plasma lipoprotein and hepatic lipase are determinants of hypo- and hyperalphalipoproteinemia. 250 59

Following its secretion into the plasma compartment, the high-density lipoprotein (HDL) is presumed to be acted upon by both soluble enzymes, such as lecithin:cholesterol acyltransferase (LCAT), and membrane-associated enzymes, such as lipoprotein lipase and hepatic lipase. Rats were injected intravenously with heparin to release membrane-associated lipolytic activities into the circulation and the collected plasma was incubated overnight at 37 degrees C in the presence or absence of an LCAT inhibitor or an inhibitor of lipoprotein lipase (1 M NaCl). It was observed that lipoprotein lipase accounted for most of the triglyceride hydrolase activity in the heparin-treated plasma, and that the heparin-releasable activities caused an increase in HDL density but no measurable change in particle size when LCAT was inhibited. Heparin treatment caused about a 60% decrease in plasma triacylglycerol during the interval between injection of heparin and blood collection. Although this caused marked compositional changes in the d less than 1.063 g/ml lipoproteins, no changes were observed in the lipid composition or apoprotein distribution in the HDL. Subsequent incubation for 18 h at 37 degrees C produced marked increases in the apoE content of HDL from heparin-treated plasma even when LCAT was inhibited. Time-course studies showed that in the presence of an LCAT inhibitor there was considerable conversion of phosphatidylcholine to lysophosphatidylcholine in heparin-treated plasma, and that this activity was diminished by 1 M NaCl, but that no phospholipolysis was observed in control plasma. By contrast, both heparin-treated and control plasma possessed substantial triglyceride hydrolase activity. The concurrent action of lipases and LCAT was observed to reduce the maximum level of cholesterol esterification which could be achieved in the absence of lipase activity. It is concluded that changes in HDL particle size are mainly attributable to LCAT, but that lipase activities, which are either free in rat plasma or releasable by heparin, play a role in restructuring the phospholipid moiety and altering the protein composition of the HDL, especially with respect to apoE, a potential ligand to cellular receptors.
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PMID:Effects of heparin-induced lipolytic activity on the structure of rat high-density lipoprotein. 271 84

Degradation of phosphatidylcholine to lysophosphatidylcholine occurs during oxidative modification of low density lipoproteins (LDL). In this study, we have shown that this phospholipid hydrolysis is brought about by an LDL-associated phospholipase A2 that can hydrolyze oxidized but not intact LDL phosphatidylcholine. The chemical nature of the oxidized phospholipids that can act as substrates for this enzyme was not fully characterized, but we hypothesized that the specificity of the enzyme for oxidized LDL phosphatidylcholine might be explained by fragmentation of polyunsaturated sn-2 fatty acyl groups in LDL phosphatidylcholine during oxidation. To facilitate characterization of this enzyme, we therefore selected a fluorescent phosphatidylcholine substrate that had a short-chain, polar residue in the sn-2 position: 1-palmitoyl 2-(6-[7-nitrobenzoxadiazolyl]amino) caproyl phosphatidylcholine, (C6NBD PC). This substrate was efficiently hydrolyzed by LDL, but the dodecanoyl analogue of C6NBD PC, which differed only in that a 12-carbon rather than a 6-carbon acyl derivative was present in the sn-2 position, was not hydrolyzed. The phospholipase activity was heat-stable, calcium-independent, and was inhibited by the serine esterase inhibitors phenylmethylsulfonyl-fluoride and diisopropylfluorophosphate, but was resistant to p-bromophenacylbromide and dithiobisnitrobenzoic acid. The phospholipid hydrolysis could not be attributed to the action of lecithin:cholesterol acyltransferase or lipoprotein lipase. Nearly all of the activity in EDTA-anticoagulated normal plasma was physically associated with apoB-containing lipoproteins, but this apoprotein was not essential as enzyme activity was present in plasma from abetalipoproteinemic patients. These properties are very similar to those recently reported for human plasma platelet-activating factor (PAF) acetylhydrolase. In the present study, we found that acylhydrolase activity against C6NBD PC, PAF, and oxidized phosphatidylcholine copurfied through gel filtration and ion-exchange chromatography. Substrate competition was demonstrated between C6NBD PC, PAF, and oxidized 2-arachidonyl phosphatidylcholine, suggesting that a single enzyme was active against all three substrates. The enzyme had an apparent molecular weight of 40,000-45,000 by high pressure gel exclusion chromatography. Inhibition of this activity with disopropyfluorophosphate prior to oxidative modification of LDL prevented phospholipid hydrolysis but did not affect the production of thiobarbituric acid reactive compounds or the change in electrophoretic mobility. In addition, this inhibition of phospholipase did not prevent the rapid degradati
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PMID:Hydrolysis of phosphatidylcholine during LDL oxidation is mediated by platelet-activating factor acetylhydrolase. 272 38

A lower accessibility to water-soluble quenchers of tryptophanyls of VLDL apolipoproteins B, E, C as compared to LDL apoB chromophores has been detected by a fluorescence quenching technique. The dynamic behaviour of the tryptophanyls of VLDL amphipathic apolipoproteins E and C did not change in the presence of a detergent, Tween-20, at sub-lytic concentrations. However, a reversible structural transition registered by the 'red' shift of the emission spectrum maximum and the changes in the quenching pattern by I- occurred under these conditions. The increase in the VLDL tryptophanyl accessibility to acrylamide and the decrease in the quenching constant were observed at partial and complete solubilization of the VLDL particles by the detergent. Dissociation of apolipoproteins from VLDL occurred after their treatment with Tween-20 or lipoprotein lipase isolated from bovine milk, and the tryptophanyl population not participating in fluorescence energy transfer on lipid phase-localized fluorescent probe pyrene appeared. In the presence of Tween-20, the relative affinity of apoE for the lipid matrix of VLDL was lower than that of apoC. Besides, the uncompetitive mode of inhibition of the LPL activity by apoC-III has been demonstrated. It is suggested that: (1) the amphipathic apolipoproteins E and C are organized as clusters on the VLDL surface and/or partially shielded by apolipoprotein B: (2) self-regulation of lypolysis may exist involving detergent-like reaction product accumulation and changes in relative apolipoprotein contents.
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PMID:Topo-dynamic characteristics of human plasma VLDL apolipoproteins and efficiency of triacylglycerol hydrolysis by lipoprotein lipase. 277 63

The role of lipoprotein lipase in the pathophysiology of lipid changes during alpha-receptor or beta-receptor blockade was evaluated in this clinical trial. Thirty hypertensive patients were given 2 mg of prazosin twice daily or 100 mg of metoprolol twice daily for 10 weeks, according to an open, randomized protocol. Both drugs were effective in reducing arterial blood pressure (from 153 +/- 16/102 +/- 6 mm Hg to 146 +/- 12/92 +/- 8 mm Hg with prazosin and from 158 +/- 17/103 +/- 8 to 144 +/- 14/94 +/- 10 mm Hg with metoprolol). Prazosin significantly reduced total plasma cholesterol from 202 +/- 39 to 188 +/- 36 mg/dl and increased high-density lipoprotein cholesterol from 36 +/- 8 to 40.5 +/- 11 mg/dl. Prazosin did not affect plasma triglycerides levels, whereas patients taking metoprolol had a slight rise in these levels, from 122 +/- 42 to 142 +/- 57 mg/dl, along with a decrease in high-density lipoprotein cholesterol from 37 +/- 10 to 31 +/- 8 mg/dl. The concentration of apoprotein B did not change significantly with either treatment. Lipoprotein lipase activity increased in the prazosin group from 28.4 +/- 16 to 37.7 +/- 14 mumol/liter per minute (p less than 0.01), but did not change significantly (29.9 +/- 12 versus 32.8 +/- 8 mumol/liter per minute) in patients treated with the beta blocker. These data, which confirm previous reports of serum lipid changes during antihypertensive therapy, suggest that alpha1 blockers may interfere with lipoprotein lipase, possibly by reducing its catecholamine-mediated inactivation.
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PMID:Effects of alpha-adrenergic and beta-adrenergic receptor blockade on lipid metabolism. 286 56


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