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PubMed1990

Biosynthesis of phosphatidic acid by glycerophosphate acyltransferases in rat liver mitochondria and microsomes.

The acyltransferases that catalyze the synthesis of phosphatidic acid from labelled sn-[14C]glycero-3-phosphate and fatty acyl carnitine or coenzyme A derivatives have been shown to be present in both isolated mitochondria and microsomes from rat liver. The major reaction product was phosphatidic acid in both subcellular fractions. A small quantity of lysophosphatidic acid and neutral lipids were produced as by-products. Divalent cations had significant effects on both mitochondrial and microsomal fractions in stimulating acylation using palmitoyl CoA, but not when palmitoyl carnitine was used as the acyl donor. Palmitoyl CoA and palmitoyl carnitine could be used for acylation by both mitochondria and microsomes. Mitochondria were more permeable to palmitoyl carnitine and readily used it as the substrate for acylation. On the other hand, microsomes yielded a better rate with palmitoyl CoA and the rate of acylation from palmitoyl carnitine in microsomes was correlated with the degree of mitochondrial contamination. The enzymes were partially purified from Triton X-100 extracts of subcellular fractions. Based on the differences of substrate utilization, products formed, divalent cation effects, molecular weights, and polarity, the mitochondrial and microsomal acyltransferases appeared to be different enzymes.

Acylation↗
PubMedDate not supplied

Increased phosphatidic acid and decreased lysophosphatidic acid in response to thrombin is associated with inhibition of platelet aggregation.

Thromboxane A2, produced from the arachidonic acid released from platelet phospholipids by phospholipase A2, stimulates platelet aggregation. It remains unresolved whether additional products of platelet phospholipase A2 might promote aggregation. To address this question, we have used aspirin-treated platelets to block thromboxane A2 formation and studied the influence of the phospholipase A2 inhibitor U10029A on platelet aggregation and secretion in response to thrombin. U10029A at 100 microM markedly inhibited platelet aggregation, but had no effect on platelet secretion. Since this concentration of U10029A effectively blocked lysophosphatidic acid (LPA) formation, LPA was added and found to substantially reverse the inhibitory effect of U10029A in these platelets. Furthermore, the action of U10029A was not due to inhibition of phosphatidate phosphohydrolase because U10029A, unlike propranolol, did not inhibit this enzyme. Although it is not possible to conclusively rule out an effect of U10029A in addition to its inhibition of phospholipase A2, our results reveal that a product of phospholipase A2 other than thromboxane A2 is important for platelet aggregation, but not for secretion in response to thrombin. Our data suggest that this product is LPA. Since the amount of phosphatidic acid (PA) increased dramatically concurrent with inhibition of platelet aggregation, it is safe to conclude that PA has no direct role to promote platelet aggregation in response to thrombin.

Arachidonic Acid↗
PubMed1989

Transfer of phosphatidic acid from liposomes to cells is collision dependent.

The kinetics of lipid transfer from unilamellar liposomes to cells in monolayer culture were determined for a fluorescent phosphatidic acid, 1-palmitoyl-2-[6-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminocaproyl] -sn-glycerol 3-phosphate (C6-NBD-PA), and for the analogous phosphatidic acid without the fluorescent NBD group, 1-palmitoyl-2-caproyl-sn-[U-14C] glycerol 3-phosphate (C6-[14C]PA). Initial rates of liposome-to-cell transfer were measured at 2 degrees C under conditions in which the concentration of diffusible monomer in the aqueous medium was constant during the course of an experiment and was independent of total liposome concentration. Rates were similar for C6-NBD-PA and C6-[14C]PA, indicating that the NBD group does not significantly alter the transfer kinetics. It was found that liposome-to-cell transfer was dependent on 1) the mole fraction of diffusible lipid in the liposomes, 2) the liposome concentration, and 3) the cell density. The dependence of rate on the liposome concentration (observed under conditions in which aqueous monomer concentration remained constant) cannot be explained by a liposome-to-cell transfer mechanism involving the free diffusion of monomers through the aqueous medium. Instead, the data are consistent with a collision-dependent mechanism of monomer transfer that occurs when liposome and cell membranes come into contact but do not fuse.

Animals↗
PubMed1994

Interleukin-1 stimulates phosphatidic acid-mediated phospholipase D activity in human mesangial cells.

Previous studies suggest that signal transduction mediated by interleukin-1 (IL-1), acting through an IL-1 receptor type found on T-cells and mesangial cells, may use phosphatidylethanolamine (PE) as a signaling molecule. Evidence presented here indicates that stimulation of human mesangial cells by IL-1 results in activation of a phospholipase D (PLD) that hydrolyzes PE to phosphatidic acid (PA). PLD acts on a subfraction of PE enriched in 1-o-alkyl and 1-o-alkenyl, sn-2-unsaturated species, generating a unique PA subspecies 30-120 s after stimulation. This PA species is subsequently converted to diradylglycerols by phosphatidate phosphohydrolase. The PE-directed PLD activity is abolished by antibodies against the IL-1 type I receptor and against IL-1. This specific PLD activity is also stimulated by low concentrations of 1,2-sn-dilinoleoyl PA, but not by high concentrations of 1-palmitoyl or 1-oleoyl lyso-PA. Blockade of PLD activation by IL-1 antibodies or antibody against the IL-1 receptor is bypassed by stimulation of human mesangial cells with 1,2-sn-dilinoleoyl PA. A novel system of signal cytokine mediation through PA self-amplification is indicated.

Gas Chromatography-Mass Spectrometry↗
PubMed2003

Pulmonary phosphatidic acid phosphatase and lipid phosphate phosphohydrolase.

The lung contains two distinct forms of phosphatidic acid phosphatase (PAP). PAP1 is a cytosolic enzyme that is activated through fatty acid-induced translocation to the endoplasmic reticulum, where it converts phosphatidic acid (PA) to diacylglycerol (DAG) for the biosynthesis of phospholipids and neutral lipids. PAP1 is Mg(2+) dependent and sulfhydryl reagent sensitive. PAP2 is a six-transmembrane-domain integral protein localized to the plasma membrane. Because PAP2 degrades sphingosine-1-phosphate (S1P) and ceramide-1-phosphate in addition to PA and lyso-PA, it has been renamed lipid phosphate phosphohydrolase (LPP). LPP is Mg(2+) independent and sulfhydryl reagent insensitive. This review describes LPP isoforms found in the lung and their location in signaling platforms (rafts/caveolae). Pulmonary LPPs likely function in the phospholipase D pathway, thereby controlling surfactant secretion. Through lowering the levels of lyso-PA and S1P, which serve as agonists for endothelial differentiation gene receptors, LPPs regulate cell division, differentiation, apoptosis, and mobility. LPP activity could also influence transdifferentiation of alveolar type II to type I cells. It is considered likely that these lipid phosphohydrolases have critical roles in lung morphogenesis and in acute lung injury and repair.

Animals↗
PubMed1980

Potassium and angiotensin II increase the concentrations of phosphatidic acid, phosphatidylinositol, and polyphosphoinositides in rat adrenal capsules in vitro.

We examined the effects of K+ and angiotensin II, the major regulators of aldosterone secretion, on phospholipid metabolism during incubation of glomerulosa-rich, adrenal capsules. Addition of increasing amounts of K+ and angiotensin II to the incubation media elicited progressive increases in corticosterone production and capsular concentrations of phosphatidic acid, phosphatidyl-inositol, and polyphosphoinositides. These effects are similar to those previously reported for ACTH in the whole adrenal cortex. A common mechanism, i.e., activation of the phosphatidate-polyphosphoinositide cycle, may be operative in the action of steroidogenic agents in their target tissues.

Adrenal Glands↗
PubMed1981

Parathyroid hormone and adenosine-3',5'-monophosphate acutely increase phospholipids of the phosphatidate-polyphosphoinositide pathway in rabbit kidney cortex tubules in vitro by a cycloheximide-sensitive process.

Parathyroid hormone (PTH) rapidly increased to concentrations of phosphatidic acid, phosphatidylinositol, diphosphoinositide, and triphosphoinositide during incubations of rabbit kidney cortical tubules in vitro. These effects were preceded by increases in cAMP, which also induced virtually identical increases in these phospholipids. Pretreating the tubules with cycloheximide inhibited these phospholipid effects of PTH and cAMP. These findings are similar to those reported for ACTH and cAMP in the adrenal cortex. Hormones that utilize cAMP as their "second messenger" may influence membrane structure and function via stimulation of the phosphatidate-polyphosphoinositide pathway.

Animals↗
PubMed1994

Relative contribution of phosphoinositides and phosphatidylcholine hydrolysis to the actions of carbamylcholine, thyrotropin (TSH), and phorbol esters on dog thyroid slices: regulation of cytidine monophosphate-phosphatidic acid accumulation and phospholipase-D activity. I. Actions of carbamylcholine, calcium ionophores, and TSH.

The actions of carbamylcholine (Cchol), the ionophores A23187 and thapsigargin, and TSH on [3H]cytidine monophosphate-phosphatidic acid ([3H]CAMP-PA) accumulation were studied in prelabeled dog thyroid slices to evaluate phosphatidic acid (PA) generation and inositol recycling by phosphatidylinositol (PtdIns) synthesis. The effects of the same agonists were also measured on phosphatidylbutanol generation in [3H]palmitate- or [3H]myristate-prelabeled slices to assess the activity of phospholipase-D (PLD) and on the effluxes of myo-[3H]inositol and [3H]choline induced by these agents from prelabeled slices. Cchol (10(-6)-10(-4) M) increased inositol phosphate (InsP) generation, with no change in inositol efflux, and contracted the intracellular inositol pool. This suggests a stimulation of PtdIns synthesis as well as hydrolysis. The muscarinic agonist provoked a dramatic accumulation of CMP-PA in the presence of lithium chloride (10 mM), which suggests that when InsP hydrolysis is inhibited, inositol limits the rate of CMP-PA incorporation into PtdIns. Cchol also increased phosphatidylbutanol formation. The latter two actions of Cchol were reproduced by A23187 (10(-5) M) and thapsigargin (2 x 10(-6) M) and were inhibited by calphostin-C, an inhibitor of the regulatory site of protein kinase-C. Cchol also induced increased free choline efflux, with a decreased choline phosphate relative content of the medium. TSH (10 mU/ml) stimulated free inositol efflux and induced a slight and proportional increase in [3H]inositol incorporation in phosphoinositides and InsP. The hormone also increased PA and CMP-PA accumulation exclusively in the presence of the PA phosphatase inhibitor propranolol (10(-4) M), but had no detectable action on PLD activity. None of these effects of TSH was reproduced by forskolin or potentiated by lithium chloride (10 mM). The data demonstrate the existence in thyroid tissue of a PLD-hydrolyzing phosphatidylcholine that was stimulated by Cchol and increased intracellular Ca2+, but not by TSH. The results obtained, besides confirming that TSH does not stimulate PtdInsP2-PLC or affect phosphatidylcholine hydrolysis, suggest that the hormone, instead, stimulates de novo PtdIns synthesis and/or inositol transport. The physiological relevance of these actions of Cchol, increased intracellular Ca2+, and TSH in thyroid metabolism could be related to their divergent effects on thyroid cell metabolism.

Animals↗
PubMed2000

Intracellular transport of phosphatidic acid and phosphatidylcholine into lipid bodies: use of fluorescent lipids to study lipid-body formation in an oleaginous fungus.

Fluorescent phosphatidic acid and phosphatidylcholine were used to characterize lipid-transport pathways into lipid bodies in an oleaginous fungus, Mortierella ramanniana var. angulispora. Several characteristics of the lipid transport such as temperature dependence and ATP dependence were evaluated. The transport depicted by these fluorescent lipids was consistent with metabolism of radiolabelled lipids, indicating that fluorescent lipids are useful to study lipid-body formation in this fungus. The results dissect lipid transport of phosphatidic acid and phosphatidylcholine into lipid bodies and reveal regulatory steps for lipid-body formation in this fungus.

Adenosine Triphosphate↗
PubMed1975

Radiophosphate (32-PO4) incorporation into phosphatidic acid of lead-poisoned and normalred cells.

Radiophosphate incorporation into phosphatidic acid is decreased in the red cells of lead-poisoned humans and rabbits. The decrease in activity is not related to the length of red cell survival nor to the differences in osmotic fragility observed in the lead-poisoned cells. Incorporation of radiophosphate into phosphatidic acid of normal red cells is sulfhydryl dependent and occurs at the cell surface. Lipid composition of the red cell membrane of the lead-poisoned humans and rabbits is normal.

Acetates↗
PubMed2001

Propranolol increases phosphatidic acid level via activation of phospholipase D.

AIM: To investigate the propranolol-induced phospholipase D (PLD) activity, its contribution to the increase in the level of phosphatidic acid, and the role of protein kinase C (PKC) in this event. METHODS: A combination of [3H]-myristate labeling, transphosphatidylation reaction, lipid extraction, and thin layer chromatography was used to measure the PLD activity. PKC inhibitors and prolonged phorbol-12-myristate-13-acetate (PMA) treatment were used to study the involvement of PKC in propranolol-induced PLD activation. Immunoblotting was used to detect the intracellular levels of PKC. RESULTS: Treatment of A-549 cells with propranolol in the presence of butanol, resulted in the rapid activation of PLD. Propranolol induced the formation of phosphatidylbutanol (PBut), a unique product of PLD, at the expense of phosphatidic acid (PA) formation. Pretreatment of cells with PKC inhibitors Ro-31-8220, staurosporine, and rottlerin increased the propranolol-induced PLD. Down-regulation of PKC by prolonged treatment of cells with PMA also potentiated the propranolol-induced PLD activity. CONCLUSION: Propranolol induces rapid activation of PLD activity, which results in the increase in intracellular level of PA. The data also indicate that propranolol-induced PLD activity could be negatively regulated by PKC.

Enzyme Activation↗
PubMed1992

Proposed role of phosphatidic acid in the extracellular control of the transition from G2 phase to mitosis exerted by epidermal growth factor in A431 cells.

Epidermal growth factor (EGF) has been shown to cause an inhibition of A431 cells in G2 phase within approximately 10 min, i.e., shortly before mitosis (Kinzel et al., Cancer Res., 50: 7932-7936, 1990). This system has been used to study the proposed role phospholipid metabolites, particularly phosphatidic acid (PA), may play (Kaszkin et al., Cancer Res., 51: 4328-4335, 1991) in the extracellular control of cells at the physiological restriction site in G2 phase. A431 cells responded to EGF with a dose-dependent formation of phosphatidic acid (PA) which correlated with the dose-dependent G2 delay as well as with their time courses. The G2 delay induced by EGF as well as PA mobilization were effected in conditioned medium or in fresh medium containing bovine serum albimun instead of serum, i.e., under the conditions necessary for precursor studies to be carried out. The major pathway of PA formation was probably via phospholipase C-mediated breakdown of phosphatidylinositol and diacylglycerol kinase: (a) the dose response of PA formation correlated with that of total inositol phosphate accumulation; (b) little diacylglycerol was found and then only at a high EGF concentration; (c) prelabeling with [1-14C]arachidonic acid resulting in a large specific labeling of phosphatidylinositol led to an EGF-induced, dose-dependent formation of radioactive arachidonyl-PA (correlated with that of total PA and inositol phosphate), but in the presence of a primary alcohol not to the formation of radioactive phosphatidylalcohol; (d) prelabeling with [1-14C]oleic acid led to the EGF-induced formation of labeled PA, which in the presence of a primary alcohol was only slightly reduced to the advantage of very low levels of labeled phosphatidyl alcohol, thus demonstrating that an EGF-effected activation of phospholipase D did occur but contributed little to the general PA level. An alternative mobilization of PA was attempted with the phorbolester 12-O-tetradecanoylphorbol-13-acetate (TPA), which was shown to activate phospholipase D in A431 cells and to elicit PA from a phospholipid pool which was not significantly labeled with radioactive arachidonic acid. The TPA-induced degree of PA formation and of the G2 delay correlated. Both phenomena were considerably larger with fresh medium containing 0.5% bovine serum albumin instead of serum than in conditioned medium.(ABSTRACT TRUNCATED AT 400 WORDS)

Drug Synergism↗
PubMedDate not supplied

Inhibitory effect of epinephrine on phosphatidate activity in isolated rat hepatocytes.

The variations in phosphatidate phosphohydrolase activity were investigated in the post-mitochondrial fraction of isolated rat hepatocytes incubated for short periods with epinephrine, dibutyryl cyclic AMP or oleate. Epinephrine decreased the enzyme activity by 42% at 1 microM concentration. The inhibitory effect was abolished in the presence of a beta-adrenoceptor antagonist, propranolol, but was not affected by the alpha-adrenoceptor agonist, phenylephrine, or the agonist, phentolamine. Dibutyryl-cAMP inhibited the enzyme activity by 49%. The presence of the cyclic-AMP phosphodiesterase inhibitor, aminophyline, together with epinephrine slightly increased the enzyme inhibition. Oleate stimulated the enzyme activity (100%) and its effect was antagonized by dibutyryl-cyclic AMP (24%) and by epinephrine (15%). The results indicate that epinephrine acts on rat hepatocytes via beta-adrenoceptor activation and cAMP may be involved in the mechanism by which phosphatidate phosphohydrolase is regulated.

Animals↗
PubMed1977

A rapid and sensitive radiochemical assay for phosphatidic acid phosphohydrolase activity.

A technique is described for the radiochemical assay of phosphatidic acid phosphohydrolase activity in rat brain. Radiochemically pure 32P-labeled phosphatidic acid of known specific radioactivity and structure, which was biosynthesized in vitro by the diacylglycerol kinase of E. coli, was used as the substrate. As little as 5 microgram of microsomal or mitochondrial protein can be used for the assay, and product formation in the picomole range can be determined accurately. This procedure should be useful in situations where only limited amounts of tissue are available.

Animals↗
PubMed1990

Phosphatidic acid modulates DNA synthesis, phospholipase C, and platelet-derived growth factor mRNAs in cultured mesangial cells. Role of protein kinase C.

Increases in cell phosphatidic acid content occur in response to a wide variety of agonists, many of which have growth promoting properties. These changes have correlated with calcium flux, enzyme activation, gene induction, or cell proliferation. In the current studies we show that exogenous phosphatidic acid (PA) and phosphatidylserine stimulate phosphoinositide hydrolysis and DNA synthesis in cultured human renal mesangial cells. These phospholipids also induce mRNAs for platelet-derived growth factor (PDGF). The activation of phospholipase C by PA appears to be desensitized via protein kinase C as brief preincubation with phorbol ester abrogates the effect. PA-induced DNA synthesis is only partly mediated via protein kinase C as co-incubation with the inhibitor staurosporine blunts DNA synthesis by only one-third. In contrast, induction of PDGF A-chain mRNA is almost totally inhibited by staurosporine. We propose that changes in endogenous phospholipids such as PA or phosphatidylserine may serve as common signaling pathway for a variety of growth factors. Induction of PDGF proto-oncogenes via protein kinase C may represent one mechanism by which this cell activation occurs.

Alkaloids↗
PubMed1990

Lysophosphatidic acid, but not phosphatidic acid, is a potent Ca2(+)-mobilizing stimulus for fibroblasts. Evidence for an extracellular site of action.

Lysophosphatidic acid (LPA) is a potent mitogen for quiescent fibroblasts. Among the earliest detectable responses to LPA is GTP-dependent phosphoinositide hydrolysis (van Corven, E. J., Groenink, A., Jalink, K., Eichholtz, T., and Moolenaar, W. H. (1989) Cell 59, 45-54). Here we describe the Ca2(+)-mobilizing properties of LPA in human fibroblasts and present evidence suggesting that previously reported Ca2(+)-mobilizing effects of phosphatidic acid are attributable to contamination with LPA. Addition of LPA (1-oleoyl or 1-palmitoyl) to fibroblasts evokes the formation of inositol 1,4,5-trisphosphate accompanied by an immediate but transient rise in [Ca2+]i which originates primarily from intracellular stores. The Ca2+ response is dose-dependent with a half-maximal effect at LPA concentrations as low as 10 ng/ml, far below the reported half-maximal effect for DNA synthesis (5-10 micrograms/ml). LPA-induced Ca2+ release is also observed in various other cell types, both normal and transformed, but not in Jurkat T cells and neutrophils. The Ca2(+)-mobilizing action of LPA is specific, in that 1,2-dioleoyl-phosphatidic acid (when prepared free of LPA contaminants), other lysophospholipids, monoacylglycerol, and free fatty acids have no effect. Furthermore, LPA, unlike lysophosphatidylcholine, does not cause detectable membrane leakiness, even when added at high concentrations (500 micrograms/ml). The LPA-induced Ca2+ signal is blocked completely by tetradecanoylphorbol acetate, but is not affected by prior stimulation of the cells with Ca2(+)-mobilizing agonists such as bradykinin or histamine. In contrast, pretreating the cells with a low dose of LPA desensitizes the Ca2+ response to subsequent addition of higher doses. This homologous desensitization is not inhibited by staurosporine, nor by down-regulating protein kinase C with tetradecanoylphorbol acetate, suggesting independence of functional protein kinase C activity. Addition of La3+ instantaneously blocks inositol phosphate production and Ca2+ mobilization in response to LPA, but not to bradykinin, most likely due to formation of inactive La3(+)-LPA complexes, suggesting that LPA acts at an extracellular site on the plasma membrane to trigger GTP-dependent phosphoinositide breakdown.

Bradykinin↗
PubMed1988

Activation of the human neutrophil by calcium-mobilizing ligands. II. Correlation of calcium, diacyl glycerol, and phosphatidic acid generation with superoxide anion generation.

Calcium and protein kinase C (Ca2+/phospholipid-dependent enzyme) have been proposed to act as signals in triggering superoxide anion (O2-) generation by neutrophils. We have probed the adequacy and necessity of calcium and diacylglycerol (DG), activators of protein kinase C, in eliciting O2- generation and degranulation. Activation of neutrophils by the ligand 10(-7) M fMet-Leu-Phe triggered elevation of cytosolic calcium (fura-2) and a rapid, biphasic increase in labeled DG in [14C]glycerol and [3H]arachidonate prelabeled cells. Buffering of the fMet-Leu-Phe-induced elevation of cytosolic calcium with MAPTAM (a cell permeant EGTA analogue) inhibited O2- generation by 90% and degranulation by 50%, concordant with a role of calcium in signaling. However, buffering the increase in calcium also decreased DG. Since phosphatidylinositol 4,5-bisphosphate breakdown in response to fMet-Leu-Phe was not inhibited and phosphatidic acid levels were enhanced in MAPTAM pretreated cells, the removal of calcium may enhance further DG metabolism. Thus, a requirement for calcium could not be differentiated from a requirement for DG, and the profound inhibition of O2- generation in the presence of MAPTAM may reflect removal of DG. Four stimuli, fMet-Leu-Phe, 10(-7) M leukotriene B4, 100 micrograms/ml concanavalin A, and 200 nM ionomycin elevated cytosolic calcium and triggered release of specific granules, but only fMet-Leu-Phe and concanavalin A triggered substantial O2- generation. Nevertheless, all four stimuli significantly increased labeled DG. Therefore, elevated DG and elevated calcium may be necessary but do not appear adequate to elicit O2- generation. Only fMet-Leu-Phe and concanavalin A triggered generation of phosphatidic acid (PA) together with DG. Correlation of O2- generation with PA may reflect a requirement for PA per se or for a specific pool of DG that can be further metabolized to PA.

Calcium↗
PubMed1986

Influence of postnatal hypoxia on 32P-labeling of polyphosphoinositides and phosphatidic acid in striatum synaptosomes from rat brain.

Striatum synaptosomes prepared from adult rats which had been exposed to postnatal hypoxia incorporate 32P-phosphate into phosphatidylinositol-4,5-trisphosphate (PI-4,5-P2) with decreased rate. 32P-incorporation amounted to 57% of the control for PI-4,5-P2 labeling and was slightly diminished for phosphatidic acid and PI-4-P. Exposure to hypoxia of adult rats did not affect inositol phospholipid labeling. The inhibitory effect of dopamine on 32P-phosphate incorporation was reduced only after postnatal hypoxia. 32P-incorporation rates and the dopamine inhibitory effect were not influenced by external calcium. A working hypothesis is suggested for the dopamine action on specific receptors which may be linked to the polyphosphoinositide metabolism and membrane calcium release. The long lasting effects of an early postnatal hypoxia on 32P-incorporation rates into polyphosphoinositides and phosphatidic acid could reflect the role of the proposed dopamine receptor interaction.

Animals↗