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)

In pancreatic islets the bulk of phosphoinositide-specific phospholipase C (PI-PLC) activity was cytosolic. The soluble enzyme was activated by submicromolar concentrations of Ca2+, independent of calmodulin. It was unaffected by glucose and a series of glycolytic intermediates, including glyceraldehyde 3-phosphate. These observations lend support to the hypothesis that glucose-stimulated inositol triphosphate production in islets may be secondary to and provoked by glucose-mediated Ca2+ influx. All four pyridine nucleotides stimulated PI-PLC. Phosphatidylinositol hydrolysis was also stimulated by dioleine and arachidonic acid, and by the polyamines, putrescine and spermine. Phosphatidylinositol hydrolysis was inhibited by chlorpromazine, tetracaine, ATP, 5'-AMP, inorganic pyrophosphate and by phosphatidylinositol 4,5-bisphosphate, phosphatidylcholine and phosphatidylserine--but not affected by phosphatidylethanolamine. The cyclic nucleotides, cAMP and cGMP had no effect on the enzyme, and GTP-gamma-S did not activate the enzyme event at very low Ca2+ concentrations. The diglyceride lipase inhibitor, RHC 80267, and the cyclooxygenase inhibitor, indomethacin, had no effect on PI-PLC activity.
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PMID:Characteristics of phosphoinositide-specific phospholipase C activity from mouse pancreatic islets. 166 77

Subcellular liver fractions from rats receiving a subcutaneous injection of turpentine, which causes a local inflammation, show an increased synthesis of Prostaglandin E2 and Prostaglandin F2 alpha which reaches a peak 90 minutes and 3 hours after treatment, respectively. Stimulation of phospholipase A2 activity of liver cell preparations seems to be responsible for the supply of arachidonic acid necessary to feed PG synthesis: this stimulation is accompanied by unchanged levels of diacylglycerol lipase, diacylglycerol kinase and protein kinase C activities and by an unchanged content of diacylglycerol in the liver tissue. This picture does not favour the hypothesis of an involvement of phospholipase C in the early stages after turpentine treatment. Determinations of GTP-ase activity in plasma membrane-rich liver preparations give ambiguous results, which do not allow any conclusion on the possible role of G-proteins in phospholipase A2 activation.
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PMID:Rat liver eicosanoid synthesis during turpentine-induced inflammation. 195 99

Using the double whole-cell patch-clamp technique, we determined that dialysis of cell pairs by GTP[S] potentiated electrical uncoupling induced by extracellular addition of carbamylcholine (CCh). An inhibitor of diglyceride lipase, RHC 80267, further potentiated CCh/GTP[S]-induced junctional channel closure, probably by accumulation of diacylglycerol. Moreover, the protein kinase C inhibitor polymyxin B completely blocked uncoupling elicited by CCh/GTP[S]. These results provide the first evidence suggesting that gap junction channel closure by cholinergic stimulation is mediated by a G-protein, which acts by increasing phosphatidylinositol biphosphate breakdown and protein kinase C activity.
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PMID:A G-protein mediates secretagogue-induced gap junctional channel closure in pancreatic acinar cells. 248 Sep 14

G protein regulation of human platelet membrane phospholipase A2 activity was investigated at pH 8.0 and 9.0 by studying the effects of the nonhydrolyzable GTP analogue, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), and of F-/Al3+ ions on arachidonic acid (AA) release. The membrane acted as the source of the enzyme, the substrate, and the G protein. At pH 8.0, 10 and 100 microM GTP gamma S stimulated AA mobilization at least 6-fold. Optimum AA release conditions required 1 mM Ca2+ and 5 mM Mg2+. Nonspecific nucleotide effect was excluded since similar stimulatory effects on AA release were not observed by ATP, GTP, ADP, and NADP. Although at pH 9.0 the GTP gamma S-stimulated AA release was greater than at pH 8.0, it constituted only 26% of the total. At both pH values the effect of F- (10 mM) in the presence of Al3+ (2 microM) was similar to that of GTP gamma S. The G protein inhibitor, guanosine 5'-O-(2-thiodiphosphate), inhibited the GTP gamma S-stimulated AA release by about 80% at pH 8.0 and by 100% at pH 9.0. To determine a possible contribution to AA mobilization by the phospholipase C and diacylglycerol lipase pathway, the effects of neomycin, a phospholipase C inhibitor, were investigated. 100 microM neomycin did not inhibit the GTP gamma S-stimulated AA release at pH 8.0 and only slightly so (17%) at pH 9.0. At pH 8.0 in the presence of Ca2+ the released fatty acids consisted mainly of arachidonic and docosahexaenoic acids (80 and 8%, respectively). GTP gamma S had no effect on the fatty acid profile but only on their quantity. These results provide evidence of G protein regulation of phospholipase A2 activity in isolated platelet membranes.
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PMID:Evidence of GTP-binding protein regulation of phospholipase A2 activity in isolated human platelet membranes. 251 18

Release of arachidonic acid (AA) from 1-stearoyl-2-[14C]arachidonyl-glycerophosphoinositol (PI) by plasma membrane-bound enzyme(s) is a calcium-dependent reaction and is markedly activated at 4 x 10(-4) M CaCl2. In the presence of Ca2+, the agonist of the cholinergic receptor (carbachol) enhances, in a dose-related manner, AA release. Moreover, GTP and its non-hydrolysable analogs GTP gamma S and GppNHp and also NaF additionally increase the carbachol-mediated liberation of AA from PI. On the contrary, in the absence of Ca2+ carbachol and GTP gamma S have no stimulatory effect on AA release. Guanosine-5'-O-2-thiodiphosphate GDP gamma S, which inhibits the function of GTP-binding proteins, also suppresses carbachol-mediated activation of AA release from PI. The stimulatory effect of carbachol and guanine nucleotides was observed exclusively in the brain plasma membrane (there was no effect on mitochondria, microsome and cytosolic enzymes). Quinacrine, the inhibitor of phospholipase A2, completely inhibits carbachol- and guanine nucleotide-activated AA release and greatly (by about 60-70%) decreases Ca(2+)-dependent AA liberation from phosphatidylinositol. These results indicate that GTP-binding protein(s) are involved in the regulation of carbachol-mediated AA release. The main pool of this acid is liberated from phosphatidylinositol by phospholipase A2 and only a small pool of AA may be released indirectly as the result of PI hydrolysis by sequential action of phospholipase C and diacylglycerol lipase.
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PMID:Guanine nucleotides and fluoride enhance carbachol-mediated arachidonic acid release from phosphatidylinositol. Evidence for involvement of GTP-binding protein in phospholipase A2 activation. 251 94

GTP or GTP gamma S alone caused low but significant liberation of arachidonic acid in saponin-permeabilized human platelets but not in intact platelets. GTP or GTP gamma S also enhanced thrombin-induced [3H]arachidonic acid release in permeabilized platelets. Inhibitors of the phospholipase C (neomycin)/diacylglycerol lipase (RHC 80267) pathway for arachidonate liberation did not reduce the [3H]arachidonic acid release. The loss of [3H]arachidonate radioactivity from phosphatidylcholine was almost equivalent to the increase in released [3H]arachidonic acid, suggesting the hydrolysis of phosphatidylcholine by phospholipase A2. The effect of GTP gamma S was greater at lower Ca2+ concentrations. These data indicate that the release of arachidonic acid by phospholipase A2 in saponin-treated platelets may be linked to a GTP-binding protein.
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PMID:Guanine nucleotides stimulate arachidonic acid release by phospholipase A2 in saponin-permeabilized human platelets. 311 31

Addition of a guanine nucleotide analog, guanosine 5'-O-(thiotriphosphate) (GTP gamma S)(1-100 microM) induced release of [3H]arachidonic acid from [3H]arachidonate-prelabeled rabbit neutrophils permeabilized with saponin. The chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced arachidonate release was enhanced by GTP gamma S, Ca2+, or their combination. Ca2+ alone (up to 100 microM) did not effectively stimulate lipid turnover. However, the combination of fMLP plus GTP gamma S elicited greater than additional effects in the presence of resting level of free Ca2+. The addition of 100 microM of GTP gamma S reduced the Ca2+ requirement for arachidonic acid liberation induced by fMLP. Pretreatment of neutrophils with pertussis toxin resulted in the abolition of arachidonate release and diacylglycerol formation. Neomycin (1 mM) caused no significant reduction of arachidonate release. In contrast, about 40% of GTP gamma S-induced arachidonate release was inhibited by a diacylglycerol lipase inhibitor, RHC 80267 (30 microM). These observations indicate that liberation of arachidonic acid is mediated by phospholipase A2 and also by phospholipase C/diacylglycerol lipase pathways. Fluoride, which bypasses the receptor and directly activates G proteins, induced arachidonic acid release and diacylglycerol formation. The fluoride-induced arachidonate release also appeared to be mediated by these two pathways. The loss of [3H]arachidonate was seen in phosphatidylinositol, phosphatidylcholine, and phosphatidylethanolamine. These data indicate that a G protein is involved between the binding of fMLP to its receptor and activation of phospholipase A2, and also that the arachidonic acid release is mediated by both phospholipase A2 and phospholipase C/diacylglycerol lipase.
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PMID:Stimulation of arachidonic acid release by guanine nucleotide in saponin-permeabilized neutrophils: evidence for involvement of GTP-binding protein in phospholipase A2 activation. 312 72

Familial combined hyperlipidemia (FCHL) is an oligogenic disorder, with family members having elevated apolipoprotein B-100 levels and either elevated plasma cholesterol or triglyceride levels or both. Obligate heterozygous parents of children with lipoprotein lipase (LPL) deficiency express a mild FCHL phenotype. Of patients with FCHL, 36% have diminished postheparin LPL activity and mass values that are comparable with those of obligate heterozygotes for LPL deficiency. It is hypothesized that heterozygosity for mutations in the LPL gene could contribute to FCHL in this subset of patients. Single-strand conformation polymorphism (SSCP) analysis, direct DNA sequencing, and Southern blot analysis were used to examine exons 1 through 9 and exon-intron junctions of the LPL gene in 20 patients with FCHL and low LPL activity and mass. One subject had a substitution (GAC-->AAC) in exon 2, changing Asp9 to Asn. Two subjects had a previously undescribed "silent" substitution (GTG-->GTA) in exon 3 at Val108. Three patients had a premature termination at codon 447 in exon 9 resulting in truncation of the mature protein by two amino acids. In addition to SSCP analysis, exons 4, 5, and 6, where almost all mutations in LPL-deficient patients have been found, were sequenced and no additional mutations were found. Southern blot analysis of the LPL gene revealed one subject with heterozygous loss of an EcoRI site but without an abnormality in Stu I restriction fragments; this mutation is therefore unlikely to be functionally significant. The substitutions identified at codons 9 and 447 have previously been found not to affect lipolytic activity when expressed in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. 819 76

The association of prostaglandin D2 (PGD2) production as well as arachidonic acid release with the phospholipase D (PLD)-linked mechanism was studied in rat peritoneal mast cells. Stimulation of mast cells with cross-linking of the high-affinity Fc receptor for IgE caused increases in the release of arachidonic acid and PGD2, which are suppressed almost completely by ethanol or RHC 80267, a diacylglycerol lipase inhibitor. Ethanol did not influence inositol phosphate release in response to an antigen. An increase in diacylglycerol, that is inhibited by propranolol, was observed, with a peak within 1 min. Antigen stimulation induced little production of lysophosphatidylcholine, while ionomycin as a control markedly induced the production. However, the phospholipase A2 (PLA2) activity in the cytosol of antigen-stimulated cells increased to the level in ionomycin-stimulated cells. The addition of the ADP-ribosylation factor-containing fraction prepared from bovine brain, that is known to specifically activate PLD, to permeabilized mast cells in the presence of GTP gamma S, apparently increased arachidonic acid and PGD2 release, but not in the presence of ethanol. Furthermore, arachidonic acid release by an antigen was enhanced by melittin, that activates PLA2, but PGD2 production was not. These results suggest that antigen-stimulated PGD2 production as well as arachidonic acid release are strongly associated with the sequential PLD-linked pathway.
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PMID:Importance of the phospholipase D-initiated sequential pathway for arachidonic acid release and prostaglandin D2 generation by rat peritoneal mast cells. 890 28

To address the hypothesis that tumor necrosis factor (TNF)-alpha has a role in obesity-associated insulin resistance or the regulation of in vivo lipid metabolism, mice with targeted disruption of the TNF-alpha gene were generated and studied. The absence of TNF-alpha protein in TNF-null (-/-) mice was confirmed. Lean or obese (gold-thioglucose [GTG]-injected) homozygous (-/-) mice were compared with lean or obese age- and sex-matched wild-type (+/+) mice derived from the same line at 13, 19, and 28 weeks of age. The following parameters were significantly affected in lean -/- versus +/+ mice: Body weight was not affected until week 28 (decreased by 14%); epididymal fat pad weight also decreased (25%) at this time, as did percentage body fat (16%), while percentage body protein was increased 13%. Fed plasma insulin levels decreased 47% (28 weeks), triglyceride levels decreased (all three ages; maximum 35% at 19 weeks), and fed plasma leptin decreased 33% (28 weeks). Fasting glucose was slightly (10%) reduced, but the glucose response to an oral glucose tolerance test (OGTT) was not affected. There was a trend (NS) toward increased total adipose tissue lipoprotein lipase in -/- versus +/+ mice. GTG-treatment resulted in obese -/- and +/+ mice with equal mean body weights (42 and 58% increased weight versus lean mice). The following parameters were significantly different in obese -/- mice: fasting plasma glucose decreased 13% (28 weeks), fed plasma insulin decreased 67% (28 weeks), and insulin response to OGTT was decreased by 50%. For both groups of obese mice, glucose levels during the OGTT were substantially increased compared with those in lean mice; however, mean stimulated glucose levels were 20% lower in obese -/- versus +/+ mice. We conclude 1) that TNF-alpha functions to regulate plasma triglycerides and body adiposity and 2) that although TNF-alpha contributes to reduced insulin sensitivity in older or obese mice, the absence of TNF-alpha is not sufficient to substantially protect against insulin resistance in the GTG hyperphagic model of rodent obesity.
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PMID:Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. 928 59


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