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)

A mutation in the lipoprotein lipase (LPL) gene, resulting in the substitution of asparagine by serine at residue 291 (LPL-S291), was found to occur in young survivors of a myocardial infarction from Sweden, combined hyperlipidemic subjects from the United Kingdom, and type III hyperlipidemic subjects from Germany at allelic carrier frequencies no different from those found in companion healthy control subjects (3.63 vs. 3.37; 1.85 vs. 1.60; and 2.00 vs. 1.56%, respectively). In a group of 620 healthy middle-aged men from the United Kingdom with baseline and three subsequent annual lipid measurements, mean plasma triacylglycerol (TG), (but not plasma cholesterol) concentrations in carriers of the mutation were significantly elevated over non-carriers (1.95 vs. 1.61 mmol/l, P = 0.05, and 5.83 vs. 5.65 mmol/l, P = 0.29, respectively). When these healthy control subjects were divided according to tertiles of body mass index (BMI), as expected, non-carriers whose BMI was in the upper two tertiles (BMI > or = 25.0 kg/m2) had higher plasma TG concentrations than those in the lowest tertile (1.90 vs. 1.54 mmol/l), but this difference was much greater in LPL-S291 carriers (2.33 vs. 1.36 mmol/l, P = 0.01, BMI x genotype interaction, P = 0.02). To confirm this effect, a second group of 319 healthy subjects from the United Kingdom was screened for LPL-S291. The allelic frequency of the mutation was found to be 1.88% and the effect on plasma lipid concentrations was very similar to that observed in the first control group (plasma TG, 2.31 vs. 1.27 mmol/l, P < 0.001 for LPL-S291 carriers vs. non-carriers, respectively). As before, those carriers whose BMI was in the top two tertiles for this sample (BMI > or = 23.3 kg/m2) had higher plasma TG concentrations than non-carriers (2.31 vs. 1.42 mmol/l). Thus, the LPL-S291 variant may predispose individuals to elevated plasma TG concentrations under conditions such as increased BMI.
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PMID:Interaction of the lipoprotein lipase asparagine 291-->serine mutation with body mass index determines elevated plasma triacylglycerol concentrations: a study in hyperlipidemic subjects, myocardial infarction survivors, and healthy adults. 857 37

Aspergillus oryzae IFO4202 produces at least two extracellular lipolytic enzymes L1 and L2 (cutinase, and mono- and diacylglycerol lipase, respectively). Southern hybridization of restriction enzyme-digested genomic DNA fragments with 23-mer oligonucleotides synthesized according to the amino acid sequence of the L2 as probe suggested the presence of the L2 gene (tentatively designated as mdlB) and an additional weakly hybridizing region. A fragment containing the genomic mdlB gene was cloned in Escherichia coli. Nucleotide sequencing of the fragment revealed an open reading frame, comprising 1021 nucleotides, which contains two introns (51 and 52 nucleotides). Putative polyadenylation signals were found 182 and 287 bp downstream of the stop codon. The deduced amino acid sequence of the mdlB gene corresponds to 306 amino acid residues including a leader sequence of 28 amino acids and is highly similar to that of the mdlA gene of Penicillium camembertii. Three residues presumed to form the catalytic triad (serine, aspartic acid and histidine) of lipases were also conserved.
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PMID:Cloning and nucleotide sequence of the mono- and diacylglycerol lipase gene (mdlB) of Aspergillus oryzae. 880 3

Phenylboronates are competitive inhibitors of serine. hydrolases including lipases. We studied the effect of m-aminophenylboronate on triglyceride-hydrolyzing activity of hepatic lipase (EC 3.1,1.3). m-Aminophenylboronate inhibited hepatic lipase activity with a Ki value of 55 microM. Furthermore, m-aminophenylboronate protected hepatic lipase activity from inhibition by di-isopropyl fluorophosphate, an irreversible active site inhibitor of serine hydrolases. Inhibition of hepatic lipase activity by m-aminophenylboronate was pH-dependent. The inhibition was maximal at pH 7.5, while at pH 10 it was almost non-existent. These data were used to develop a purification procedure for postheparin plasma hepatic lipase and lipoprotein lipase. The method is a combination of m-aminophenylboronate and heparin-Sepharose affinity chromatographies. Hepatic lipase was purified to homogeneity as analyzed on sodium dodecyl sulfate polyacrylamide gel electrophoresis. The specific activity of purified hepatic lipase was 5.46 mmol free fatty acids h-1 mg-1 protein with a total purification factor of 14,400 and a final recovery of approximately 20%. The recovery of hepatic lipase activity in m-aminophenylboronate affinity chromatography step was 95%. The purified lipoprotein lipase was a homogeneous protein with a specific activity of 8.27 mmol free fatty acids h-1 mg-1. The purification factor was 23,400 and the final recovery approximately 20%. The recovery of lipoprotein lipase activity in the m-aminophenylboronate affinity chromatography step was 87%. The phenylboronate affinity chromatography step can be used for purification of serine hydrolases which interact with boronates.
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PMID:Inhibition of hepatic lipase by m-aminophenylboronate. Application of phenylboronate affinity chromatography for purification of human postheparin plasma lipases. 884 15

Allelic frequencies of polymorphic variants at the lipoprotein lipase gene locus on chromosome 8 have been measured in subjects with premature coronary heart disease and/or dyslipidemia. One of the polymorphic variants involves a termination codon in exon 9 at the position of serine 447, which produces a truncated protein. Michaelis constants and Vmax for triolein and chylomicrons appear identical for the variant and native enzymes. Another informative polymorphism is a Hind 111 restriction site in intron 8 that shows marked asymmetric allelic distribution in subjects with hypertriglyceridemia/low-high-density lipoprotein and in subjects with premature coronary heart disease. It is hoped that this marker may lead to the identification of an etiological mutation in its vicinity to account for these disease associations.
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PMID:Common genetic determinants of dyslipidemia: the hypertriglyceridemia/low-high-density lipoprotein syndrome. 890 13

Lipoprotein lipase hydrolyzes the triglyceride-rich core of chylomicrons and very low density lipoproteins. It is also a ligand, in vitro, for binding of lipoproteins to the low density lipoprotein receptor-related protein and may play a central role in the receptor-mediated removal of triglyceride-rich lipoproteins. The aim of the present study was to determine to which lipoprotein subclass the enzyme is bound in preheparin plasma and when released into plasma by heparin injection. Tetrahydrolipstatin, a potent inhibitor of serine lipases, was used to block lipolytic activity, thereby preventing changes in plasma lipoproteins due to ex vivo lipolysis. To analyze the distribution pattern of lipoprotein lipase dimers among lipoprotein classes, a specific ELISA was used and gel filtration was performed in pre- and postheparin plasma from five subjects with triglyceride ranging from 69 to 522 mg/dl. When lipolytic activity was not inhibited, lipoprotein lipase dimers eluted in association with low and high density lipoproteins, reproducing results previously obtained by several groups of investigators. However, in pre- and postheparin samples treated with tetrahydrolipstatin, most of the dimeric enzyme was found associated with very low density lipoprotein particles. In conclusion in pre- and postheparin samples most of the lipoprotein lipase dimers are associated with very low density lipoproteins when ex vivo lipolytic activity is inhibited, which supports the hypothesis that, in vivo, lipoprotein lipase may affect the receptor-mediated removal of these particles. Moreover, it suggests that the association between lipoprotein lipase and cholesterol-rich lipoproteins might be an ex vivo phenomenon due to lack of inhibition of lipolytic activity.
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PMID:Dimeric lipoprotein lipase is bound to triglyceride-rich plasma lipoproteins. 897 91

Rat platelets secrete two types of phospholipases upon stimulation; one is type II phospholipase A2 and the other is serine-phospholipid-selective phospholipase A. In the current study we purified serine-phospholipid-selective phospholipase A and cloned its cDNA. The final preparation, purified from extracellular medium of activated rat platelets, gave a 55-kDa protein band on SDS-polyacrylamide gel electrophoresis. [3H]Diisopropyl fluorophosphate, an inhibitor of the enzyme, labeled the 55-kDa protein, suggesting that this polypeptide possesses active serine residues. The cDNA for the enzyme was cloned from a rat megakaryocyte cDNA library. The predicted 456-amino acid sequence contains a putative short N-terminal signal sequence and a GXSXG sequence, which is a motif of an active serine residue of serine esterase. Amino acid sequence homology analysis revealed that the enzyme shares about 30% homology with mammalian lipases (lipoprotein lipase, hepatic lipase, and pancreatic lipase). Regions surrounding the putative active serine, histidine, and aspartic acid, which may form a "lipase triad," were highly conserved among these enzymes. The recombinant protein, which we expressed in Sf9 insect cells using the baculovirus system, hydrolyzed a fatty acyl residue at the sn-1 position of lysophosphatidylserine and phosphatidylserine, but did not appreciably hydrolyze phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, and triglyceride. The present enzyme, named phosphatidylserine-phospholipase A1, is the first phospholipase that exclusively hydrolyses the sn-1 position and has a strict head group specificity for the substrate.
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PMID:Serine phospholipid-specific phospholipase A that is secreted from activated platelets. A new member of the lipase family. 899 22

We have shown previously that the stem cell factor (SCF) receptor undergoes phosphorylation on serine residues following ligand stimulation, and that this phopshorylation is dependent mainly on the activity of protein kinase C (PKC). In the present study, we have further investigated the molecular mechanisms behind SCF-stimulated activation of PKC, and found that SCF does not activate phosphatidylinositol-specific phospholipase C. In contrast, phospholipase D (PLD) is activated in response to SCF in a dose-dependent manner. Activation of PLD was not inhibited by calphostin C, an inhibitor of PKC. On the other hand, inhibitors of phosphatidylinositol PtdIns 3'-kinase (PtdIns 3'-kinase), i.e. wortmannin and LY294002, inhibited SCF-induced PLD activation. Moreover, a mutant SCF receptor in which Tyr721, which is responsible for activation of PtdIns 3'-kinase, is mutated to a phenylalanine residue was unable to mediate activation of PLD. Thus, PtdIns 3'-kinase appears to be essential for SCF-induced PLD activation. Furthermore, we demonstrate that phosphatidic acid (PtdH), generated through the action of PLD in response to SCF, is metabolized to diacylglycerol by dephosphorylation. Diacylglycerol can then activate PKC, and, moreover, after deacylation by a diacylglycerol lipase, yield arachidonic acid, an important second messenger in cell signaling.
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PMID:Involvement of phosphatidylinositol 3'-kinase in stem-cell-factor-induced phospholipase D activation and arachidonic acid release. 931 Mar 72

The mechanisms whereby cell adhesion molecules (CAMs) promote axonal growth and synaptic plasticity are poorly understood. Here we show that the neurite outgrowth stimulated by NCAM-mediated fibroblast growth factor (FGF) receptor activation in cerebellar granule cells is associated with increased GAP-43 phosphorylation on serine-41. In contrast, neither NCAM nor FGF was able to stimulate neurite outgrowth in similar neurons from mice in which the GAP-43 gene had been deleted by homologous recombination. Integrin-mediated neurite outgrowth was unaffected by GAP-43 deletion. Both neurite outgrowth and rapid phosphorylation of GAP-43 in isolated growth cones required the first three Ig domains of a NCAM-Fc chimera and were stimulated maximally at 5 micrograms/ml (approximately 50 nM). Likewise, GAP-43 phosphorylation in isolated growth cones also was stimulated by an L1-Fc chimera. Both neurite outgrowth and NCAM-stimulated GAP-43 phosphorylation were inhibited by antibodies to the FGF receptor and a diacylglycerol lipase inhibitor (RHC80267) that blocks the production of arachidonic acid in response to activation of the FGF receptor. Direct activation of the FGF receptor and the arachidonic acid cascade with either basic FGF or melittin also resulted in increased GAP-43 phosphorylation. These data suggest that the stimulation of neurite outgrowth by NCAM requires GAP-43 function and that GAP-43 phosphorylation in isolated growth cones occurs via an FGF receptor-dependent increase in arachidonic acid.
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PMID:Neurite outgrowth stimulated by neural cell adhesion molecules requires growth-associated protein-43 (GAP-43) function and is associated with GAP-43 phosphorylation in growth cones. 985 80

Hepatic lipase (HL) is an enzyme that is made primarily by hepatocytes (and also found in adrenal gland and ovary) and hydrolyzes phospholipids and triglycerides of plasma lipoproteins. It is secreted and bound to the hepatocyte surface and readily released by heparin. It is a member of the lipase superfamily and is homologous to lipoprotein lipase and pancreatic lipase. The enzyme can be divided into an NH2-terminal domain containing the catalytic site joined by a short spanning region to a smaller COOH-terminal domain. The NH2-terminal portion contains an active site serine in a pentapeptide consensus sequence, Gly-Xaa-Ser-Xaa-Gly, as part of a classic Ser-Asp-His catalytic triad, and a putative hinged loop structure covering the active site. The COOH-terminal domain contains a putative lipoprotein-binding site. The heparin-binding sites may be distributed throughout the molecule, with the characteristic elution pattern from heparin-sepharose determined by the COOH-terminal domain. Of the three N-linked glycosylation sites, Asn-56 is required for efficient secretion and enzymatic activity. HL is hypothesized to directly couple HDL lipid metabolism to tissue/cellular lipid metabolism. The potential significance of the HL pathway is that it provides the hepatocyte with a mechanism for the uptake of a subset of phospholipids enriched in unsaturated fatty acids and may allow the uptake of cholesteryl ester, free cholesterol, and phospholipid without catabolism of HDL apolipoproteins. HL can hydrolyze triglyceride and phospholipid in all lipoproteins, but is predominant in the conversion of intermediate density lipoproteins to LDL and the conversion of post-prandial triglyceride-rich HDL into the postabsorptive triglyceride-poor HDL. HL plays a secondary role in the clearance of chylomicron remnants by the liver. Human post-heparin HL activity is inversely correlated with intermediate density lipoprotein cholesterol concentration only in subjects with a hyperlipidemia involving VLDL. This is consistent with intermediate-density lipoproteins being a substrate for HL. HDL cholesterol has been reported to be inversely correlated to HL activity, and on this basis it has been suggested that lowering HL would increase HDL cholesterol. However, the correlation could also be due to a common hormonal factor such as estrogen, which has been shown to up-regulate apoAI and HDL cholesterol and lower HL. A striking feature of severe deficiency of HL is the increase in HDL cholesterol and apolipoprotein AI and an approximately 10-fold increase in HDL triglyceride. Hyper-alpha-triglyceridemia is not a feature of antiatherogenic HDL. HL binds not only to heparan, but also to the LDL receptor-related protein. It has been suggested that enzymatically inactive HL can play a role in hepatic lipoprotein uptake, forming a "bridge" by binding to the lipoprotein and to the cell surface. This raises the interesting possibility that production and secretion of mutant inactive HL could promote clearance of VLDL remnants. We have described a rare family with HL deficiency. Affected patients are compound heterozygotes for a mutation of Ser267 to Phe that results in an inactive enzyme and a mutation of Thr383 to Met that results in impaired secretion and reduced specific activity. Human HL deficiency in the context of a second factor causing hyperlipidemia is strongly associated with premature coronary artery disease. Recently, it has been reported that mutations affecting the structure of HL (e.g., T383M) are relatively frequent in the Finnish population. A C-to-T polymorphism in the promotor region of the HL gene is associated with lowered HL activity and less strongly with increased HDL cholesterol. In summary, there is a good understanding of what HL does in lipoprotein metabolism; however, there is little understanding of its physiological importance, that is, why HL does what it does. (ABSTRACT TRUNCATED)
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PMID:Hepatic lipase deficiency. 988 75

A new lipoprotein lipase-like gene has been cloned from endothelial cells through a subtraction methodology aimed at characterizing genes that are expressed with in vitro differentiation of this cell type. The conceptual endothelial cell-derived lipase protein contains 500 amino acids, including an 18-amino acid hydrophobic signal sequence, and is 44% identical to lipoprotein lipase and 41% identical to hepatic lipase. Comparison of primary sequence to that of lipoprotein and hepatic lipase reveals conservation of the serine, aspartic acid, and histidine catalytic residues as well as the 10 cysteine residues involved in disulfide bond formation. Expression was identified in cultured human umbilical vein endothelial cells, human coronary artery endothelial cells, and murine endothelial-like yolk sac cells by Northern blot. In addition, Northern blot and in situ hybridization analysis revealed expression of the endothelial-derived lipase in placenta, liver, lung, ovary, thyroid gland, and testis. A c-Myc-tagged protein secreted from transfected COS7 cells had phospholipase A1 activity but no triglyceride lipase activity. Its tissue-restricted pattern of expression and its ability to be expressed by endothelial cells, suggests that endothelial cell-derived lipase may have unique functions in lipoprotein metabolism and in vascular disease.
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PMID:Cloning of a unique lipase from endothelial cells extends the lipase gene family. 1031 35


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