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: EC:3.1.1.34 (lipoprotein lipase)
7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoprotein lipase is bound to heparin-like molecules at the surface of capillary endothelial cells. For maximal activity, the enzyme requires apolipoprotein C-II, a protein constituent of triacylglycerol-rich lipoproteins. In this report, the interactions of apolipoprotein C-II, heparin and sonicated vesicles of dipalmitoylphosphatidylcholine with purified bovine milk lipoprotein lipase were studied by gel filtration on Bio-Gel A5m. In the presence of vesicles of dipalmitoylphosphatidylcholine (1 mg), lipoprotein lipase (25 micrograms) associated with phospholipids even in the absence of apolipoprotein C-II. With limited phospholipid (40 micrograms), the amount of enzyme which associated with lipid decreased in the presence of apolipoprotein C-II (20 micrograms). Human plasma apolipoprotein C-III, another protein constituent of triacylglycerol-rich lipoproteins, also caused a decrease in the amount of enzyme associated with phospholipid. These results suggest that apolipoprotein C-II does not increase the activity of the enzyme by facilitating its interaction with a lipid interface. In the absence of lipid, lipoprotein lipase and apolipoprotein C-II (molar ratio, 1 : 1) eluted from Bio-Gel A5m as two separate components. The interaction of heparin with lipoprotein lipase was studied using a specific [3H]heparin, which was isolated by affinity chromatography on immobilized lipoprotein lipase; the [3H]heparin eluted with 0.6 M NaCl. Specific [3H]heparin coeluted with lipoprotein lipase when the enzyme was associated with phospholipid; the [3H]heparin was released from the enzyme by 0.75 M NaCl.
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PMID:Interaction of lipoprotein lipase with phospholipid vesicles. Role of apolipoprotein C-II and heparin. 689 27

The composition of apolipoprotein C of the very low density lipoproteins (VLDL) was examined in 23 treated Type 2 (non-insulin-dependent) diabetic patients, who had elevated VLDL concentrations. Apolipoprotein C was separated by isoelectric focussing into apolipoprotein C-II which is known as the specific activator of lipoprotein lipase, and three apolipoprotein C-III fragments. A regulatory role has been ascribed to the ratio of apolipoprotein C-II to apolipoprotein C-III in the removal of plasma triglycerides. In our diabetic group, the composition of apolipoprotein C of the VLDL particles was not different from that of a healthy control group. In particular, the above apolipoprotein ratio and the relative amounts of apolipoprotein C-III fragments were normal. Hypertriglyceridaemia in these diabetic subjects does not seem to be related to alterations in the apolipoprotein C composition.
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PMID:Apolipoprotein C in type 2 (non-insulin-dependent) diabetic patients with hypertriglyceridaemia. 710 45

A specific, accurate, and sensitive double antibody radioimmunoassay for measuring human apolipoprotein (apo) C-III has been developed. Anti-apoC-III(1) developed in rabbits cross-reacted completely with apoC-III subspecies. Analytical isoelectric focusing of delipidated triglyceride-rich lipoproteins (TRL) was done to assess the percentage of total apoC-III mass comprised by apoC-III(0), C-III(1), and C-III(2), and the data were used to compute the absolute plasma TRL apoC-III subspecie concentration. Total plasma apoC-III was 11.1 +/- 0.9 mg/dl (mean +/- SEM) in 29 normolipidemic healthy subjects; 21.3 +/- 4.9, 27.5 +/- 2.2, and 53.6 +/- 7 mg/dl in 3, 16, and 13 patients with primary types III, IV, and V hyperlipoproteinemia, respectively, and significantly (P < 0.01) higher than normal. Total plasma triglycerides (TG) correlated positively with total plasma apoC-III (r = 0.88; P = 0.0001) and TRL apoc-III (r = 0.88; P = 0.0001). Progressive hypertriglyceridemia was associated with a rise in the percent of total apoC-III in TRL isolated at d < 1.006 g/ml (r = 0.78; P < 0.0001; n = 43) and a reciprocal decline in the TRL-free plasma fraction (d > 1.006 g/ml). ApoC-III comprised significantly more of HDL(2) than HDL(3) protein (7.3 +/- 0.2 versus 1.6 +/- 0.2%, respectively, P < 0.01). HDL(2) and HDL(3) isolated from patients with type IV hyperlipoproteinemia had subnormal apoC-III as percent of total protein (2.4 +/- 0.5 and 0.6 +/- 0.1, respectively). Total plasma TG correlated negatively with i) apoC-III as percent of total HDL protein (r = -0.67; P = 0.002, n = 20); ii) apoC-III as percent of total HDL(2) protein (r = -0.52; P = 0.019); and iii) apoC-III as percent of total HDL(3) protein (r = -0.72; P = 0.0004). Plasma TRL apoC-III subspecie concentrations were significantly higher in the three hypertriglyceridemic groups (primary types III, IV, and V) compared to normals. TRL apoC-III(0) levels in patients with type IV and V were comparable (2.4 +/- 0.3 and 2.2 +/- 0.6 mg/dl, respectively). However, TRL apoC-III(1) and C-III(2) in patients with type V hyperlipoproteinemia were significantly higher (P < 0.01) than in patients with types IV or III hyperlipoproteinemia. Total plasma TG correlated positively with TRL apoC-III(0) (r = 0.56; P = 0.0004), TRL apoC-III(1) (r = 0.82; P = 0.0001) and TRL apoC-III(2) (r = 0.76; P = 0.0001). The slope of regression line relating total plasma TG with TRL apoC-III(1) was significantly steeper (P < 0.0001) than that for apoC-III(0). Thus, for a given interval of plasma TG, the change in concentration of TRL apoC-III(1) was much greater than that in TRL apoC-III(0). The development of the RIA and its combined use with analytical isoelectric focusing thus allows quantitation of this important glycopeptide and its subspecies in human plasma and its subfractions. Because apoC-III inhibits not only tissue lipoprotein lipase but also the hepatic uptake of triglyceride-rich lipoproteins and remnants, the data support the possibility that an abnormal metabolism of apoC-III subspecies may be linked pathogenetically to elevated plasma TG levels.-Kashyap, M. L., L. S. Srivastava, B. A. Hynd, P. S. Gartside, and G. Perisutti. Quantitation of human apolipoprotein C-III and its subspecies by radioimmunoassay and analytical isoelectric focusing: abnormal plasma triglyceride-rich lipoprotein apolipoprotein C-III subspecie concentrations in hypertriglyceridemia.
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PMID:Quantitation of human apolipoprotein C-III and its subspecie by radioimmunoassay and analytical isoelectric focusing: abnormal plasma triglyceride-rich lipoprotein apolipoprotein C-III subspecie concentrations in hypertriglyceridemia. 728 86

Purified bovine milk lipoprotein lipase has been covalently attached to CH-Sepharose with water-soluble carbodiimide. The immobilized enzyme retained enzymic activity and was stimulated 7-fold by the addition of human apolipoprotein C-II. Both [3H]heparin and 125I-labeled apolipoprotein C-II bound to the immobilized enzyme; unlabeled heparin and apolipoprotein C-II competed for binding of their respective labeled compounds. Apolipoprotein C-II did not compete for binding of [3H]heparin and vice versa. Human apolipoprotein C-III did not bind to the immobilized enzyme nor did it compete for apolipoprotein C-II binding. We conclude from these studies that both apolipoprotein C-II and heparin interact with immobilized lipoprotein lipase and that they have different binding sites.
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PMID:Preparation and properties of immobilized lipoprotein lipase. 743 56

We hypothesized that variation of nine candidate genes in lipoprotein metabolism would be associated with variation in fasting plasma lipoprotein variables in 718 Alberta Hutterites, a genetic isolate. We measured plasma lipids, lipoproteins, and apolipoproteins and analyzed DNA for genotypes of apolipoprotein (apo) B (APOB), paraoxonase (PON), lipoprotein lipase (LPL), VLDL receptor (VLDLR), apo CIII (APOC3), LDL receptor-related protein (LRP), hepatic lipase (HL), LDL receptor (LDLR), and apo E (APOE). Using a multivariate analysis, we found that (1) genotypes of APOB, PON, LPL, LDLR, and APOE were significantly associated with variation of plasma apo B-related traits; (2) genotypes of PON, LPL, and APOC3 were significantly associated with variation in plasma triglycerides; and (3) genotypes of VLDLR, APOC3, LDLR, and APOE were significantly associated with variation in plasma apo AI and HDL cholesterol. Regression analysis showed that between 3.2% and 7.8% of the total variation in plasma lipoproteins was accounted for by variation in the candidate genes tested. The observations demonstrate a modest but significant genetic component of variation in plasma lipoprotein levels that is due to the candidate genes studied in this normolipemic human genetic isolate.
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PMID:Multiple genetic determinants of variation of plasma lipoproteins in Alberta Hutterites. 760 Jan 18

Postprandial chylomicron remnant clearance was studied in six patients with familial combined hyperlipidemia (FCH) and seven control subjects by using an oral retinyl palmitate (RP) fat-loading test. The chylomicron remnant clearance (Sf < 1,000 fraction), expressed as the area under the RP curve (AUC-RP), was delayed in FCH subjects (65.05 +/- 12.84 hours x [mg/L]) compared with control subjects (25.1 +/- 5.4 hours x [mg/L]; p = 0.01). Postprandial lipoprotein particle size and composition in the Sf > 1,000 fraction were different between FCH and control subjects as analyzed by molecular-sieve chromatography. Fasting high density lipoprotein cholesterol was lower in FCH patients (0.54 +/- 0.09 mmol/L) than in control subjects (0.89 +/- 0.05 mmol/L; p < 0.01). Mean plasma postheparin lipoprotein lipase and hepatic lipase activities were similar between FCH patients (94 +/- 25 and 427 +/- 57 milliunits/mL, respectively) and control subjects (126 +/- 16 and 362 +/- 33 milliunits/mL, respectively). In FCH, a 54% reduction (p < 0.05) of plasma triglycerides to 2.63 +/- 0.41 mmol/L by drug treatment resulted in an enhanced, but not normalized, clearance of chylomicron remnants (39.4 +/- 6.0 hours x [mg/L]). Univariate regression analysis revealed that in FCH subjects the changes in fasting plasma apolipoprotein C-III concentrations after therapy were significantly associated with the changes in chylomicron remnant AUC-RP (r = 0.87; p = 0.02). Delayed elimination of atherogenic chylomicron remnants may contribute to the increased risk of premature atherosclerosis in FCH.
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PMID:Impaired chylomicron remnant clearance in familial combined hyperlipidemia. 849

The molecular mechanism by which hypolipidemic fibrates and antidiabetic thiazolidinediones exert their hypotriglyceridemic action are discussed. Increased activity of lipoprotein lipase (LPL), a key lipolytic enzyme, and decreased levels of apolipoprotein C-III (apo C-III) seem to explain the hypotriglyceridemic effects of compounds. Both fibrates and thiazolidinediones exert their action by activating transcription factors of the peroxisome proliferator activated receptor (PPAR) family, thereby modulating the expression of the LPL and apo C-II genes. First, treatment of rats with PPAR alpha activators, such as fibrates induced LPL mRNA and activity selectively in the liver. In contrast, the thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect on liver, but induce LPL mRNA and activity levels in adipose tissue. In hepatocytes, fibrates, unlike the thiazolidinediones, induce LPL mRNA levels, whereas in preadipocyte cell lines the PPAR gamma ligand induces LPL mRNA levels much quicker and to a higher extent than fibrates. Second, apo C-III mRNA and protein production strongly decrease in livers of fibrate but not thiazolidinedione-treated animals. Fibrates also reduced apo C-III production in primary cultures of rat and human hepatocytes. The modulation of the expression of the LPL and apo C-III genes by either PPAR alpha or gamma activators, correlates with the tissue-specific distribution of the respective PPARs: PPAR gamma expression is restricted to adipose tissues, whereas PPAR alpha is expressed predominantly in liver. In both the LPL and apo C-III genes, sequence elements responsible for the modulation of their expression by activated PPARs have been identified which supports that the transcriptional regulation of these genes by fibrates and thiazolidinediones contributes significantly to their hypotriglyceridemic effects in vivo. Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPAR gamma, fibrates exert their effects mainly in the liver via a PPAR alpha-mediated reduction in apo C-III production. This tissue specific transcriptional regulation of genes involved in lipid metabolism by PPAR activators and/or ligands might have important therapeutic implications.
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PMID:Regulation of triglyceride metabolism by PPARs: fibrates and thiazolidinediones have distinct effects. 922 59

Statins are hypolipidemic drugs which not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-reducing effect involves inhibition of de novo biosynthesis of cellular cholesterol through competitive inhibition of its rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA reductase, the mechanism by which they lower triglycerides remains unknown and forms the subject of the current study. Treatment of normal rats for 4 days with simvastatin decreased serum triglycerides significantly, whereas it increased high density lipoprotein cholesterol moderately. The decrease in triglyceride concentrations after simvastatin was caused by a reduction in the amount of very low density lipoprotein particles which were of an unchanged lipid composition. Simvastatin administration increased the lipoprotein lipase mRNA and activity in adipose tissue and heart. This effect on lipoprotein lipase was accompanied by decreased mRNA as well as plasma levels of the lipoprotein lipase inhibitor apolipoprotein C-III. These results suggest that the triglyceride-lowering effect of statins involves a stimulation of lipoprotein lipase-mediated clearance of triglyceride-rich lipoproteins.
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PMID:3-Hydroxy-3-methylglutaryl CoA reductase inhibitors reduce serum triglyceride levels through modulation of apolipoprotein C-III and lipoprotein lipase. 1038 82

The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazones are ligands for PPAR-gamma. PPAR-alpha activation mediates pleiotropic effects such as stimulation of lipid oxidation, alteration in lipoprotein metabolism and inhibition of vascular inflammation. PPAR-alpha activators increase hepatic uptake and the esterification of free fatty acids by stimulating the fatty acid transport protein and acyl-CoA synthetase expression. In skeletal muscle and heart, PPAR-alpha increases mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation through stimulating the muscle-type carnitine palmitoyltransferase-I. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha dependent stimulation of lipoprotein lipase and an inhibition of apolipoprotein C-III expressions, whereas the increase in plasma HDL cholesterol depends on an overexpression of apolipoprotein A-I and apolipoprotein A-II. PPARs are also expressed in atherosclerotic lesions. PPAR-alpha is present in endothelial and smooth muscle cells, monocytes and monocyte-derived macrophages. It inhibits inducible nitric oxide synthase in macrophages and prevents the IL-1-induced expression of IL-6 and cyclooxygenase-2, as well as thrombin-induced endothelin-1 expression, as a result of a negative transcriptional regulation of the nuclear factor-kappa B and activator protein-1 signalling pathways. PPAR activation also induces apoptosis in human monocyte-derived macrophages most likely through inhibition of nuclear factor-kappa B activity. Therefore, the pleiotropic effects of PPAR-alpha activators on the plasma lipid profile and vascular wall inflammation certainly participate in the inhibition of atherosclerosis development observed in angiographically documented intervention trials with fibrates.
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PMID:Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. 1043 61

More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158-->Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. To elucidate these additional risk factors, we analyzed normolipidemic and hyperlipidemic apoE2 homozygotes. Hyperinsulinemia was observed in 27 of 49 apoE2 homozygotes and associated with elevated lipid levels: hyperinsulinemic apoE2 homozygotes had type III hyperlipoproteinemia 6 times more often than apoE2 homozygotes with normal insulin levels (odds ratio 6.2, P=0.02). We screened the normolipidemic and hyperlipidemic apoE2 homozygotes for common variants in candidate genes involved in lipolysis-the APOA1-C3-A4 gene cluster, lipoprotein lipase, and hepatic lipase-and analyzed for associations with the expression of hyperlipidemia. In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)<0.001) and VLDL triglyceride (P(insulin by SstI)<0.01) and low levels of HDL (P(insulin by SstI)<0.02). In the normoinsulinemic group, no such relation of the SstI polymorphism with hyperlipidemia was observed. These data provide the first evidence for a combined effect of hyperinsulinemia and the SstI polymorphism on the expression of hyperlipidemia in apoE2 homozygotes.
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PMID:Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism. 1055 17


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