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)

Unilamellar liposomes prepared from purified phospholipids (phosphatidylcholine, phosphatidylethanolamine or sphingomyelin) and labeled cholesteryl linoleyl ether were used to study lipoprotein lipase-catalyzed transfer of cholesteryl ester into cells in culture. In mesenchymal rat heart cell cultures, the transfer of cholesteryl linoleyl ether and cholesteryl linoleate was similar and related to the activity of endogenously produced lipoprotein lipase. In human skin fibroblasts transfer of labeled cholesteryl linoleyl ether was proportional to the concentration of milk lipoprotein lipase added to the incubation medium. Liposomes prepared from phosphatidylcholine or phosphatidylethanolamine were much better donors of cholesteryl ether to normal and apolipoprotein E-B receptor-negative fibroblasts and to endothelial cells than those prepared from sphingomyelin. Lysophosphatidylcholine was formed during incubation with milk lipoprotein lipase but was not considered to be directly responsible for the lipoprotein lipase-catalyzed transfer of cholesteryl ether. This conclusion was drawn because in the absence of lipoprotein lipase addition of lysophosphatidylcholine to liposomes, or almost complete phospholipolysis by phospholipase A2, did not result in the transfer of cholesteryl linoleyl ether from liposomes to cells. Attachment of lipoprotein lipase to the cell surface was mandatory for the transfer of cholesteryl ether and could be prevented by heparin. High density apolipoprotein reduced also the transfer of cholesteryl linoleyl ether, even though it did not interfere with the binding of labeled milk lipoprotein lipase to cultured fibroblasts. The present results provide evidence that lipoprotein lipase, and not the products of phospholipid hydrolysis, is the ligand for the non-apolipoprotein E-B receptor-mediated transfer of cholesteryl ester to cells.
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PMID:Transfer of cholesteryl linoleyl ether from phosphatidylcholine and phosphatidylethanolamine liposomes to cultured cells catalyzed by lipoprotein lipase. 686 Jun 84

Thromboxane B2 biosynthesis from arachidonic acid was increased in platelets from hypercholesterolemic rabbits. The enzymic activity of phospholipase A2 which releases arachidonic acid, the precursor for the biosynthesis of thromboxane B2, showed hardly any change in hypercholesterolemic platelets. Phospholipase C and diglyceride lipase activities also were not changed in platelets from hypercholesterolemic rabbits. Furthermore, phospholipid concentration in platelets were not increased in this state. Thus, we conclude that the supply of precursor for thromboxane B2 biosynthesis was not increased in platelets from hypercholesterolemic rabbits as compared to controls. These results suggest that the enzyme activity of thromboxane B2 biosynthesis may be enhanced in platelets from hypercholesterolemic rabbits.
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PMID:Thromboxane B2 biosynthesis and phospholipids hydrolysis in platelets from hypercholesterolemic rabbits. 721 79

Membrane phospholipid degradation has been proposed to play a key role in hypoxic-ischemic brain injury. We tested the hypotheses that both nordihydroguaiaretic acid, a phospholipase A2 and lipoxygenase inhibitor, and RHC 80267, a diacylglycerol lipase inhibitor, would decrease the release of [3H]arachidonic acid metabolites from prelabeled cultures of astroglia subjected to combined glucose-oxygen deprivation and that these inhibitors would also decrease astroglial injury during combined glucose-oxygen deprivation. Both nordihydroguaiaretic acid and RHC 80267 significantly inhibited the release of [3H]arachidonic acid metabolites during combined glucose-oxygen deprivation. This suggests that two separate enzymic pathways, the phospholipase A2 pathway and the phospholipase C/diacylglycerol lipase pathway, contribute to the release of astroglial [3H]arachidonic acid metabolites during combined glucose-oxygen deprivation. However, both of these lipase inhibitors increased astroglial cell death during combined glucose-oxygen deprivation, probably due to inhibition of arachidonic acid release. We speculate that arachidonic acid release may be a mechanism of astroglial self-preservation during combined glucose-oxygen deprivation.
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PMID:Nordihydroguaiaretic acid and RHC 80267 potentiate astroglial injury during combined glucose-oxygen deprivation. 754 17

Experimental, clinical and epidemiological studies have implicated arachidonic acid and its metabolites as important mediators in colorectal carcinogenesis. Although arachidonic acid levels are increased in tumour membrane lipids, its availability for metabolic processes is not known. The activities of phospholipase A2 (PLA2) and diacylglycerol lipase therefore were assessed in tumour and normal mucosal specimens from 20 patients with colorectal cancer using 14C-radiolabelled substrates. The median (interquartile range) PLA2 activity was increased in tumour tissue (10.5 (6.0, 18.5) pmol arachidonic acid mg-1 h-1) compared with that in normal mucosa (5.6 (2.5, 8.5) pmol arachidonic acid mg-1 h-1) (P < 0.001, Wilcoxon signed rank test). Activity of diacylglycerol lipase was also greater in tumoral tissue (47.4 (21.6, 82.1) pmol arachidonic acid mg-1 h-1) than in mucosa (19.1 (9.4, 42.9) pmol arachidonic acid mg-1 h-1) (P < 0.005). There was no correlation between either PLA2 or diacylglycerol lipase activity and myeloperoxidase activity, suggesting that these increases were not directly attributable to tumour inflammatory cell infiltrate. Augmentation of arachidonic acid release in colorectal tumours may have implications for therapy.
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PMID:Activities of phospholipase A2 and diacylglycerol lipase are increased in human colorectal cancer. 761 89

Arachidonic acid has been implicated as a second messenger in insulin secretion on the basis of (1) mobilization of intracellular Ca2+ from the endoplasmic reticulum of islets and (2) amplification of voltage-dependent Ca2+ entry. The insulin secretagogues D-glucose and the muscarinic agonist carbachol both increase unesterified arachidonic acid accumulation in isolated islets. We now show that diacylglycerol, a product of phospholipase C action, is a major source of free arachidonic acid in islets. Diacylglycerol hydrolysis in islets occurs through a two-step process. In the first step, the sn-1 bond of 1-stearoyl-2-arachidonyl-sn-glycerol is hydrolyzed by a diacylglycerol lipase, giving rise to 2-arachidonyl-sn-glycerol. Next, the sn-2 bond of 2-arachidonyl-sn-glycerol is hydrolyzed by a monoacylglycerol lipase, which is the rate-limiting step, releasing unesterified arachidonic acid. Both diacylglycerol lipase and monoacylglycerol lipase are highly enriched in the plasma membrane of beta-cells. Diacylglycerol lipase activity in islet homogenates is selectively inhibited in a dose-dependent manner by the compound RHC-80267, a specific diacylglycerol lipase inhibitor. RHC-80267 inhibits glucose- and carbachol-induced insulin release from intact islets in a dose-dependent manner that parallels its inhibition of diacylglycerol lipase activity. Importantly, RHC-80267, at concentrations that almost completely inhibit diacylglycerol lipase activity and glucose- and carbachol-induced insulin secretion by islets, markedly inhibits glucose- and carbachol-induced increases in islet arachidonic acid levels, as measured by gas chromatography with electron-capture detection of its pentafluorobenzyl esters. RHC-80267 did not significantly affect islet glucose oxidation, phospholipase C, monoacylglycerol lipase, or phospholipase A2. Since glucose and carbachol are known to stimulate phospholipase C, our observations indicate that diacylglycerol is an important source of arachidonic acid and other free fatty acids in islets. Furthermore, production of arachidonic acid from the hydrolysis of diacylglycerol is essential for glucose- and carbachol-induced insulin secretion.
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PMID:Diacylglycerol hydrolysis to arachidonic acid is necessary for insulin secretion from isolated pancreatic islets: sequential actions of diacylglycerol and monoacylglycerol lipases. 794 36

Cerebellar neurons, cultured on monolayers of 3T3 fibroblasts or on a polylysine/laminin-coated substratum, responded to recombinant basic FGF by extending longer neurites. The response was biphasic reaching a maximum at 5 ng/ml FGF, but desensitising at 100-200 ng/ml FGF. The response to FGF could be inhibited by a tyrosine kinase inhibitor (the erbstatin analogue), by a diacylglycerol lipase inhibitor (RHC-80267) and by a combination of N- and L-type calcium channel antagonists or other agents that negate the effects of calcium influx into neurons. The response to FGF could be fully mimicked by arachidonic acid added directly to the cultures, or generated via activation of phospholipase A2 with melittin. The response to melittin, but not to FGF or arachidonic acid, was inhibited by 4-bromophenacyl bromide, a phospholipase A2 inhibitor. The response to arachidonic acid was also biphasic and high concentrations of this agent could cross-desensitise the FGF response and vice versa. The response to arachidonic acid could be fully inhibited by the agents that block or negate the effects of calcium influx into neurons, but was not inhibited by the tyrosine kinase or diacylglycerol lipase inhibitors. These data suggest that FGF stimulates neurite outgrowth by activating a cascade that involves activation of phospholipase C gamma to produce diacylglycerol, conversion of diacylglycerol to arachidonic acid by diacylglycerol lipase and the activation of voltage-gated calcium channels by arachidonic acid.
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PMID:Characterisation of the second messenger pathway underlying neurite outgrowth stimulated by FGF. 805 Mar 74

We have used monolayers of control 3T3 fibroblasts and 3T3 fibroblasts expressing transfected cell adhesion molecules (CAMs)--NCAM, N-cadherin, and L1--as a culture substrate for cerebellar neurones. The transfected CAMs promote neurite outgrowth by activating a second messenger pathway that culminates in calcium influx into neurones through N- and L-type calcium channels. We show that the same neurite outgrowth response can be directly induced by arachidonic acid (10 microM) and that this response can be inhibited by N- and L-type calcium channel antagonists. In cells, arachidonic acid can be generated by phospholipase A2 or by the sequential activities of a phospholipase C (to generate diacylglycerol) and diacylglycerol lipase. In the present study we show the neurite outgrowth stimulated by CAMs (but not by various other agents) can be abolished by an inhibitor of diacylglycerol lipase acting at a site upstream from calcium channel activation. The results suggest that arachidonic acid and/or one of its metabolites is the second messenger that activates calcium channels in the CAM signalling pathway leading to axonal growth, and this is supported by recent evidence that shows the same concentrations of arachidonic acid can increase voltage-dependent calcium currents in cardiac myocytes.
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PMID:The production of arachidonic acid can account for calcium channel activation in the second messenger pathway underlying neurite outgrowth stimulated by NCAM, N-cadherin, and L1. 811 7

alpha 1-Adrenergic receptors (ARs) are members of the G protein-coupled receptor superfamily. alpha 1-AR subtypes mediate the effects of the sympathetic nervous system, especially those involved in cardiac homeostasis. To investigate signal transduction by a novel subtype (alpha 1D), which we recently cloned, and to compare it with that by the previously characterized alpha 1B-AR, we assessed the ability of each subtype to activate polyphosphoinositide (PI) metabolism, cAMP accumulation, and arachidonic acid release in Chinese hamster ovary (CHO) and COS-1 cells expressing these subtypes after stable or transient transfection, respectively. In COS-1 and CHO cells, both the alpha 1D- and alpha 1B-AR were found to couple to PI hydrolysis through a pertussis toxin-insensitive G protein. Both alpha 1-AR subtypes also increased intracellular cAMP by an indirect mechanism, although this effect was observed only in COS-1 cells and not in CHO cells. Interestingly, alpha 1-AR-stimulated arachidonic acid release was also demonstrated for both subtypes in COS-1 cells. This release was mediated through phospholipase A2 activation and involved a pertussis toxin-sensitive G protein. alpha 1-AR-stimulated arachidonic acid release was dependent upon extracellular calcium and was inhibited by 1 microM nifedipine. Inhibitors of protein kinase C, phospholipase C, and diacylglycerol lipase did not alter alpha 1-AR-stimulated release of arachidonic acid. These findings indicate that in COS-1 cells alpha 1-AR-stimulated arachidonic acid release is most likely coupled to dihydropyridine-sensitive L-type calcium channels via a pertussis toxin-sensitive G protein. The influx of extracellular calcium then stimulates phospholipase A2 to release arachidonic acid. alpha 1-AR-stimulated arachidonic acid release could also be demonstrated in CHO cells and was pertussis toxin sensitive but nifedipine insensitive. These cells were also unresponsive to Bay K8644, indicating a lack of voltage-sensitive calcium channels in CHO cells. Nevertheless, alpha 1-AR activation increased intracellular Ca2+ levels, as assessed by fura-2 fluorescence studies. Neomycin blocked both alpha 1-AR-stimulated PI hydrolysis and increases in intracellular Ca2+ levels but did not inhibit the increase in arachidonic acid release. Taken together, these data indicate that in CHO cells alpha 1-ARs can couple directly to phospholipase A2 activation via a pertussis toxin-sensitive pathway. Thus, in these model systems we demonstrate for the first time that a single alpha 1-AR subtype can activate multiple distinct signal transduction pathways, in which receptor-effector coupling is modulated by distinct G proteins.
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PMID:Coupling of expressed alpha 1B- and alpha 1D-adrenergic receptor to multiple signaling pathways is both G protein and cell type specific. 823 29

The protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu) induced the release of both luteinizing hormone (LH) and growth hormone (GH) from proestrous rat anterior pituitary pieces in vitro. Phorbol 12,13-dibutyrate-induced LH, but not GH release was readily inhibited by the phospholipase A2 (PLA2) inhibitors, quinacrine, aristolochic acid, ONO-RS-082 and chloracysine. Furthermore, PDBu induced release of [3H]arachidonic acid ([3H]AA) from pre-labelled anterior pituitary tissue that was prevented in the presence of quinacrine, aristolochic acid and ONO-RS-082 but not the diglyceride lipase inhibitor RHC 80267. The effect of PDBu was completely inhibited by staurosporine and the selective PKC inhibitor Ro 31-8220 but only partially by low concentrations of H7; consistent with the involvement of both H7-sensitive and H7-resistant forms of PKC in the activation of PLA2 by PDBu. The protein synthesis inhibitor cycloheximide inhibited the release of both [3H]AA and LH that had been induced by PDBu, whereas LH release induced by the PLA2 activator mellitin was cycloheximide-insensitive. These results suggest that PKC activators may induce LH but not GH release from anterior pituitary tissue by a mechanism involving activation of a PLA2, brought about by a process which is reliant on protein synthesis.
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PMID:Differential involvement of phospholipase A2 in phorbol ester-induced luteinizing hormone and growth hormone release from rat anterior pituitary tissue. 824 10

In the present study, we investigated the mechanism by which bradykinin (BK) enhances [3H]arachidonic acid release in murine osteoblast-like MC3T3-E1 cells prelabeled with [3H]arachidonic acid. BK enhanced [3H]arachidonic acid release in a time- and concentration-dependent manner, when cells were stimulated in the presence, but not in the absence, of extracellular Ca2+. It appears that the BK-induced [3H]arachidonic acid release was attributed to the activation of phospholipase A2, since a phospholipase A2 inhibitor, mepacrine, significantly inhibited the BK enhancement of [3H]arachidonic acid release whereas a diacylglycerol lipase inhibitor, RHC80267, failed to do so. Furthermore, it was found that a protein kinase C inhibitor, staurosporine, and down-regulation of protein kinase C by prolonged exposure of cells to phorbol 12-myristate 13-acetate inhibited the BK-induced [3H]arachidonic acid release. These results provide evidence that BK stimulation of MC3T3-E1 cells activates phospholipase A2 to liberate arachidonic acid by the mechanism which involves both Ca2+ and protein kinase C.
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PMID:The mechanism of bradykinin-induced arachidonic acid release in osteoblast-like MC3T3-E1 cells phospholipase A2 activation by bradykinin and its regulation by protein kinase C and calcium. 826 65


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