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)

The in vitro effects of prolactin (PRL) on lipoprotein lipase (LPL) activity and on LPL mRNA levels were studied in cultured mammary tissues derived from mid-pregnant mice. Mouse mammary gland tissues were initially incubated for 24 hr in M199 media containing 1 microg/ml insulin and 10(-7) M cortisol. A subsequent treatment of the tissues with 1 microg/ml PRL caused a 76% increase in heparin-releasable LPL (hrLPL) activity after 24 hr. A significant increase in LPL activity was detected 16 hr after PRL addition, but not at earlier times. PRL at 100 ng/ml elicited a maximum stimulation of LPL activity. When Northern hybridization techniques were employed, PRL was also found to increase the tissue content of LPL mRNA; this effect was initially detected after a 6-hr PRL treatment employing PRL concentrations of 50 ng/ml and above. Specificity studies revealed that only lactogenic hormones stimulated LPL activity and LPL mRNA accumulation in cultured mammary tissues. PRL also expressed a small (25% increase), but significant, effect on ATP citrate-lyase activity in mammary tissues cultured for more than 6 hr with the hormone.
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PMID:Prolactin's effects on lipoprotein lipase (LPL) activity and on LPL mRNA levels in cultured mouse mammary gland explants. 903 34

We investigated the effect of extracellular ATP on phosphatidylcholine-hydrolyzing phospholipase D activity and the role of phospholipase D activation in extracellular ATP-induced arachidonic acid release in cultured rat aortic smooth muscle cells. ATP significantly stimulated the formation of choline in a dose-dependent manner in the range between 0.01 and 0.5 mmol/L. However, ATP had no effect on the formation of phosphocholine. Staurosporine, an inhibitor of protein kinases, did not affect the ATP-induced formation of choline. ATP significantly stimulated arachidonic acid release in a dose-dependent manner in the range between 0.01 and 0.5 mmol/L. DL-Propranolol hydrochloride (propranolol), an inhibitor of phosphatidic acid phosphohydrolase, significantly inhibited the ATP-induced release of arachidonic acid. 1,6-Bis(cyclohexyloximinocarbonylamino)-hexane (RHC-80267), a potent and selective inhibitor of diacylglycerol lipase, reduced ATP-induced arachidonic acid release. Quinacrine, a phospholipase A2 inhibitor, suppressed ATP-induced arachidonic acid release. Both propranolol and RHC-80267 markedly inhibited the ATP-induced synthesis of 6-ketoprostaglandin F1 alpha, a stable metabolite of prostacyclin. These results strongly suggest that extracellular ATP activates phosphatidylcholine-hydrolyzing phospholipase D independently of protein kinase C in aortic smooth muscle cells and that the arachidonic acid release induced by extracellular ATP is mediated, at least in part, through phosphatidylcholine hydrolysis by phospholipase D activation.
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PMID:Involvement of phosphatidylcholine hydrolysis by phospholipase D in extracellular ATP-induced arachidonic acid release in aortic smooth muscle cells. 908 84

The effects of the diacylglycerol lipase inhibitor 1,6-bis-(cyclohexyloximinocarbonyl-amino)-hexane (RHC 80267) and the phospholipase A2 inhibitor N-(p-amylcinnamoyl)anthranilic acid (ACA) on insulin secretion and 86Rb+ efflux in mouse pancreatic islets were studied. RHC 80267 (35 microM) and ACA (100 microM) inhibited glucose (16.7 mM)-induced insulin secretion, but did not inhibit insulin secretion induced by K+ (40 mM) or the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 0.16 microM). K+ (40 mM) or TPA (0.16 microM) potentiated glucose (16.7 mM)-induced insulin secretion, and prevented inhibition of glucose (16.7 mM)-induced insulin secretion by RHC 80267 and ACA. In comparison, potentiation of glucose-induced insulin secretion by albumin-bound arachidonic acid (AA; 200 microM total; 10 microM free unbound) failed to counteract inhibition of glucose-induced insulin secretion by RHC 80267 or ACA, suggesting that inhibition of insulin secretion by these agents was not mediated by a decrease in AA accumulation in islets. Determination of 86Rb+ efflux, a marker of K+ channel activity, revealed that both RHC 80267 and ACA stimulated K+ efflux from islets. These effects of RHC 80267 and ACA were observed at both 3.3 and 16.7 mM glucose and persisted in Ca2+-free medium, suggesting that they may represent an opening of ATP-sensitive K+ channels. RHC 80267-mediated stimulation of 86Rb+ efflux was not mimicked by the diacylglycerol analog TPA (0.16 microM) and was not prevented by the diacylglycerol kinase inhibitor R 59022 (50 microM), suggesting that stimulation of 86Rb+ efflux did not reflect a conditional increase in diacylglycerol or in phosphatidic acid upon inhibition of diacylglycerol lipase. In contrast, TPA (0.16 microM) attenuated RHC 80267 and ACA stimulation of 86Rb+ efflux. Addition of AA (200 microM total; 10 microM free unbound) stimulated 86Rb+ efflux, suggesting that stimulation of 86Rb+ efflux by RHC 80267 and ACA was not due to a decrease in AA accumulation. This stimulation by AA was not dependent on AA metabolism because it persisted in the presence of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 50 microM) or the cyclooxygenase inhibitor indomethacin (50 microM). In contrast to RHC 80267 and ACA, AA stimulation of 86Rb+ efflux was attenuated in Ca2+-free medium, probably implicating Ca2+-sensitive K+ channels in AA regulation of 86Rb+ efflux. Parallel experiments with diazoxide (100 microM) revealed that RHC 80267 and ACA mimicked the effects of diazoxide, a specific activator of ATP-sensitive K+ channels in islets, on both insulin secretion and 86Rb+ efflux. In conclusion, it is suggested that RHC 80267 and ACA, independently of their action on AA release, may inhibit glucose-induced insulin secretion by the opening of ATP-sensitive K+ channels in islets.
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PMID:Inhibition of glucose-induced insulin secretion by the diacylglycerol lipase inhibitor RHC 80267 and the phospholipase A2 inhibitor ACA through stimulation of K+ permeability without diminution by exogenous arachidonic acid. 917 12

We have recently demonstrated the presence of phospholipase A2 (PLA2) activity in cells from bovine retinal pigment epithelium (RPE) [Jacob et al. (1996) J. Biol. Chem. 271, 19209-19218]. We report here our results on the characterization of this RPE-PLA2 activity. We show that RPE probably contains two types of PLA2 enzyme, as indicated by the results obtained with different PLA2-active fractions eluted from cation-exchange columns and treated with Ca2+/EGTA, dithiothreitol, p-bromophenacyl bromide or heat. These results, in addition to those from PLA2 assays using different substrates, also suggest that RPE-PLA2 enzymes are different from the well-known secretory, cytoplasmic and Ca2+-independent forms. Sequential extraction of RPE with (1) isotonic, (2) hypertonic and (3) detergent-containing PBS argues for the presence of weakly membrane-associated enzymes. Control experiments using 'back and forth' TLC allowed us to discriminate between PLA2 and phospholipase C/diacylglycerol lipase activity and confirmed that, in our assay conditions, the release of fatty acids was indeed due to PLA2 enzymes. These results, together with those obtained by treating RPE homogenates with H2SO4, guanosine 5'-[gamma-thio]triphosphate, ATP and different protease inhibitors, permitted us to make the first characterization of these RPE-PLA2 enzymes. We conclude that RPE contains novel types of PLA2 that are different from the secretory, cytoplasmic and Ca2+-independent forms.
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PMID:Bovine retinal pigment epithelium contains novel types of phospholipase A2. 935 16

In previous studies, we have shown that mouse RAW 264.7 macrophages possess pyrimidinoceptors, coupled to a phosphoinositide-specific phospholipase C, with a higher specificity for UTP than for ATP. In the current study, we explored the mechanism involved in the UTP-induced intracellular acidification seen in this cell line. UTP (30 microM) caused a reversible pHi decrease of 0.16 +/- 0.01 unit; this effect was not influenced by the removal of extracellular Cl- or Na+ ions or by pretreatment with 5-(N-ethyl-N-isopropyl)-amiloride (10 microM), 5-nitro-2-(3-phenylpropylamino)benzoic acid (100 microM), staurosporine (1 microM), or Ro 31-8220 (1 microM) but was completely abolished by the removal of extracellular Ca2+. UTP (30 microM), thapsigargin (1 microM), and ionomycin (1 microM) each induced a similar extent of external Ca2+-dependent acidification with a similar time-dependency, but the effects were nonadditive. To further investigate the Ca2+-dependent mechanism, we studied the involvement of arachidonic acid (AA) and eicosanoid metabolites. The addition of AA (10 microM) but not arachidic acid (100 microM) produced a reduction in pHi. UTP, thapsigargin, and ionomycin induced Ca2+-dependent AA release. Furthermore, 4-bromo-phenacyl bromide [30 microM, a phospholipase A2 (PLA2) inhibitor-, nordihydroguaiaretic acid (50 microM, a lipoxygenase inhibitor), and MK-886 (10 microM, a 5-lipoxygenase-activating protein inhibitor) abolished the UTP- or ionomycin-induced responses, whereas indomethacin (30 microM, a cyclooxygenase inhibitor) and baicalein (10 microM, a selective 12-lipoxygenase inhibitor) had no effect. MAFP (a cPLA2 inhibitor) and REV 5901 (a 5-lipoxygenase inhibitor as well as a competitive antagonist of peptide leukotrienes), but not RHC 80267 (a diacylglycerol lipase inhibitor), also inhibited the UTP-induced response. In contrast, the pHi response to AA was unaffected by the presence of 4-bromo-phenacyl bromide or the removal of extracellular Ca2+ ions but abolished by addition of NDGA. Exogenous 5-hydroperoxyeicosatetraenoic acid (2 microM) also produced marked acidification, and UTP and ionomycin both induced peptide leukotriene formation. In conclusion, this is the first report indicating that lipoxygenase metabolites act as mediators of the Ca2+-dependent acidification seen in macrophages in response to UTP or ionomycin via activation of cPLA2 and AA release.
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PMID:Lipoxygenase metabolites as mediators of UTP-induced intracellular acidification in mouse RAW 264.7 macrophages. 946 90

Progressive weight loss is a common feature of many types of cancer and is responsible not only for a poor quality of life and poor response to chemotherapy, but also a shorter survival time than is found in patients with comparable tumors without weight loss. Although anorexia is common, a decreased food intake alone is unable to account for the changes in body composition seen in cancer patients, and increasing nutrient intake is unable to reverse the wasting syndrome. Although energy expenditure is increased in some patients, cachexia can occur even with a normal energy expenditure. Various factors have been investigated as mediators of tissue wasting in cachexia. These include cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and leukemia inhibitory factor (LIF), as well as tumor-derived factors such as lipid mobilizing factor (LMF) and protein mobilizing factor (PMF), which can directly mobilize fatty acids and amino acids from adipose tissue and skeletal muscle respectively. Induction of lipolysis by the cytokines is thought to result from an inhibition of lipoprotein lipase (LPL), although clinical studies provide no evidence for an inhibition of LPL in the adipose tissue of cancer patients. Instead there is an increased expression of hormone sensitive lipase, the enzyme activated by LMF. Protein degradation in cachexia is associated with an increased activity of the ATP-ubiquitin-proteasome pathway. The biological activity of both the LMF and PMF was shown to be attenuated by eicosapentaenoic acid (EPA). Clinical studies show that this polyunsaturated fatty acid is able to stabilize the rate of weight loss and adipose tissue and muscle mass in cachectic patients with unresectable pancreatic cancer. Knowledge of the mechanism of cancer cachexia should lead to the development of new therapeutic agents.
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PMID:Wasting in cancer. 991 7

1. The role of smooth muscle-derived lipoprotein lipase (LPL) that translocates to the endothelium surface on vascular dysfunction during atherogenesis is unclear. Thus, the role of vascular LPL on blood vessel reactivity was assessed in transgenic mice that specifically express human LPL in the circulatory system. 2. Aortic free fatty acids (FFAs) were increased by 69% in the transgenic mice expressing human LPL in aortic smooth muscle cells (L2LPL) compared with their non-transgenic littermates (L2). 3. Contractility to KCl was increased by 33% in aortae of L2LPL mice. Maximal contraction to phenylephrine (PE) was comparable in L2 and L2LPL animals, while the frequency of tonus oscillation to PE increased by 104% in L2LPL mice. 4. In L2LPL animals, *NO mediated relaxation to acetylcholine (ACh) and ATP was reduced by 47 and 32%, respectively. In contrast, endothelium-independent relaxation to sodium nitroprusside (SNP) was not different in both groups tested. 5. ATP-initiated Ca(2+) elevation that triggers *NO formation was increased by 41% in single aortic endothelial cells freshly isolated from L2LPL animals. 6. In aortae from L2LPL mice an increased *O(2)(-) release occurred that was normalized by removing the endothelium and by the NAD(P)H oxidase inhibitor DPI and the PKC inhibitor GF109203X. 7. The reduced ACh-induced relaxation in L2LPL animals was normalized in the presence of SOD, indicating that the reduced relaxation is due, at least in part, to enhanced *NO scavenging by *O(2)(-). 8. These data suggest that despite normal lipoprotein levels increased LPL-mediated FFAs loading initiates vascular dysfunction via PKC-mediated activation of endothelial NAD(P)H oxidase. Thus, vascular LPL activity might represent a primary risk factor for atherosclerosis independently from cholesterol/LDL levels.
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PMID:Tissue-specific expression of human lipoprotein lipase in the vascular system affects vascular reactivity in transgenic mice. 1178 90

The maturation of lipoprotein lipase (LPL) into a catalytically active enzyme was believed to occur only after its transport from the endoplasmic reticulum (ER) to the Golgi apparatus. To test this hypothesis, LPL located in these two subcellular compartments was separated and compared. Heparin affinity chromatography resolved low affinity, inactive LPL displaying ER characteristics from a high affinity, active fraction exhibiting both ER and Golgi forms. The latter forms were further separated by beta-ricin chromatography and were found to have comparable activities per unit of LPL mass. Thus, LPL must reach a functional conformation in the ER. Active LPL, regardless of its cellular location, exhibited the expected dimer conformation. However, inactive LPL, found only in the ER, was highly aggregated. Kinetic analysis indicated a concurrent formation of LPL dimer and aggregate and indicated that the two forms have dissimilar fates. Whereas the dimer remained stable even when confined to the ER, the aggregate was degraded. Degradation rates were not affected by proteasomal or lysosomal inhibitors but were markedly reduced by ATP depletion. Lowering the redox potential in the ER by dithiothreitol caused the dimer to associate with calnexin, BiP, and protein-disulfide isomerase to form large, inactive complexes; dithiothreitol removal induced complex dissociation with restoration of the functional LPL dimer. In contrast, the LPL aggregate was only poorly associated with ER chaperones, appearing to be trapped in an irreversible, inactive conformation destined for ER degradation.
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PMID:Maturation of lipoprotein lipase in the endoplasmic reticulum. Concurrent formation of functional dimers and inactive aggregates. 3142 May 23

Lipids may serve as coupling factors in K(ATP)-independent glucose sensing in beta-cells. We have previously demonstrated that beta-cells harbor lipase activities, one of which is the hormone-sensitive lipase. Whether beta-cell lipases are critical for glucose-stimulated insulin secretion (GSIS) by providing lipid-derived signals from endogenous lipids is unknown. Therefore, using a lipase inhibitor (orlistat), we examined whether lipase inhibition reduces insulin secretion. Islet lipolysis stimulated by glucose and diglyceride lipase activity was abolished by orlistat. Incubation of rat islets with orlistat dose dependently inhibited GSIS; this inhibition was reversed by 1 mmol/l palmitate, suggesting that orlistat acts via impaired formation of an acylglyceride-derived coupling signal. Orlistat inhibited the potentiating effect of forskolin on GSIS, an effect proposed to be due to activation of a lipase. In perifused islets, orlistat attenuated mainly the second phase of insulin secretion. Because the rise in islet ATP/ADP levels in response to glucose and oxidation of the sugar were unaffected by orlistat whereas the second phase of insulin secretion was reduced, it seems likely that a lipid coupling factor involved in K(ATP)-independent glucose sensing has been perturbed. Thus, beta-cell lipase activity is involved in GSIS, emphasizing the important role of beta-cell lipid metabolism for insulin secretion.
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PMID:Inhibition of lipase activity and lipolysis in rat islets reduces insulin secretion. 1469 6

The "fuel gauge" AMP-activated protein kinase (AMPK) facilitates ATP production to meet energy demands during metabolic stress. Given the importance of lipoprotein lipase (LPL) in providing hearts with fatty acids (FA), the preferred substrate consumed by the heart, the objective of the present study was to investigate whether activation of AMPK influences LPL at its functionally relevant location, the coronary lumen. Hearts from overnight-fasted rats were first perfused with heparin to release LPL, and homogenates from these hearts were then used to measure total and phospho-AMPK-alpha by Western blotting. Manipulation of AMPK activity [with drugs like adenine 9-beta-D-arabinofuranoside (Ara-A) and insulin (that inhibit) or perhexiline and oligomycin (that stimulate)] and its influence on LPL was also determined. Fasting augmented the activity of both AMPK and luminal LPL on immediate removal of hearts, effects that still remained even after in vitro perfusion of hearts for 1 h. Inhibition of AMPK in fasted hearts using an inhibitor like Ara-A or through provision of insulin markedly lowered the enhanced luminal LPL activity. In contrast, AMPK activators, like perhexiline and oligomycin, produced a significant elevation in heparin-releasable LPL activity. Thus, with fasting or drugs that influence AMPK, a strong correlation between this metabolic switch and cardiac LPL activity was established. Our data suggest that, in addition to its direct role in promoting FA oxidation, AMPK-mediated recruitment of LPL to the coronary lumen could represent an immediate compensatory response by the heart to guarantee FA supply.
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PMID:The metabolic "switch" AMPK regulates cardiac heparin-releasable lipoprotein lipase. 1532 75


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