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PubMed1984

Differences in Ca2+ mobilization induced by alpha-adrenergic agonist and phosphatidic acid in cultured hepatocytes.

In an attempt to elucidate the relationship between phosphatidylinositol breakdown and alpha-adrenergic responses, effects of phosphatidic acid and phosphatidylinositol related metabolites on Ca2+ mobilization and glucose output in cultured hepatocytes were examined. Norepinephrine induced the net 45Ca2+ efflux from preloaded cells and stimulated glucose output via alpha-adrenergic receptor stimulation, whereas phosphatidic acid caused 45Ca2+ uptake to cells and did not stimulate glucose output. Myo-inositol-monophosphate, diglyceride and arachidonic acid, which are released by phosphatidylinositol breakdown, had no effect on 45Ca2+ efflux and glucose output in cells. These results suggest that phosphatidic acid and phosphatidylinositol related metabolites can not mimic the alpha-adrenergic actions in cultured hepatocytes.

Animals↗
PubMed1981

Postnatal development and sex differences in hepatic phosphatidate phosphohydrolase activity in the rat.

The mechanism leading to the difference in hepatic triacylglycerol metabolism between female and male rats was investigated by studying the ontogeny of hepatic soluble phosphatidate phosphohydrolase activity in feeding animals of both sexes. A sevenfold increase occurred within 12 hr of birth, returning to the adult level during the third postnatal day. The changes in enzyme activity were followed by similar changes in hepatic triacylglycerol concentrations. A sex difference was observed only in the adult rats, where the enzyme activity in the livers of feeding female rats was about 25% higher than that in the feeding males. The effects of gonadectomy and sex steroids were studied in a separate series of experiments on fasting animals. The activity of the soluble enzyme was 65% higher in the intact female rats than in the males, and that of the microsomal enzyme 130% higher. The activity ratio between the soluble and microsomal enzyme in the male rats was 4.3 on a liver wet weight basis with the methods used. Gonadectomy increased the soluble and microsomal activities by 25% and 80% respectively within 6 wk in the male rats. The soluble and microsomal activities were still at the same control levels 2 wk after the gonadectomy, the subcutaneous implants of testosterone or estradiol resulting in 10-fold increases in plasma hormone levels had no effects on these enzyme activities, although testosterone caused 50% decrease in the hepatic triacylglycerol concentration. These data indicate that, if hormonally mediated, the postnatal increase in phosphatidate phosphohydrolase activities is not related to sex steroids and also suggest that the basis of the sex difference in hepatic soluble phosphatidate phosphohydrolase activity remains to be established.

Aging↗
PubMed1993

Phosphatidic acid stimulates the rolipram-sensitive cyclic nucleotide phosphodiesterase from rat thymocytes.

The role of phospholipid metabolites in the modulation of cyclic AMP degradation during the early response of rat thymic lymphocytes to mitogenic stimulation was investigated by measuring their in vitro effect on the activity of five different cyclic nucleotide phosphodiesterase forms separated from thymocyte cytosol by means of an HPLC technique. Arachidonic acid was found to markedly inhibit four of the enzyme forms, with IC50 ranging from 14 to 60 microM, while its hydroperoxy and hydroxy derivatives proved inefficient. Dioctanoylglycerol, a biologically active diacylglycerol, was weakly inhibitory while phosphatidic acid, the diacylglycerol phosphorylated derivative, markedly stimulated the two cyclic-AMP-specific type-IV forms identified in thymocyte cytosol, by 50 and 70%. In intact cells labelled with tritiated arachidonate, the mitogenic lectin concanavalin A induced a rapid 4-5-fold increase in radiolabelled phosphatidic acid which peaked at 1 min, and remained elevated for at least 30 min. These observations suggest that phosphatidic acid formed during the mitogenic stimulation of T-cells might be responsible for an early activation of cyclic AMP degradation with, as a consequence, a lowering of cyclic AMP level, which is reported to be necessary for the occurrence of the first steps of mitogenesis.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Interference with the distribution and release of arachidonic acid in human keratinocytes by bradykinin, histamine and phosphatidic acid.

The effects of bradykinin, histamine, phosphatidic acid and leukotrienes B4 and C4 on the distribution and release of 14C-arachidonic acid in human keratinocytes in culture were investigated. Bradykinin, histamine, and phosphatidic acid were found to liberate 14C-arachidonic acid from membrane phospholipids, whereas leukotrienes B4 and C4 were ineffective in this respect. The decrease in the labeling of phospholipids was accompanied by increased labeling of the non-phosphorus lipids. The present study suggests that bradykinin, histamine, and phosphatidic acid may interfere with the distribution and release of arachidonic acid in human keratinocytes in culture.

Arachidonic Acid↗
PubMed2006

Roles of phosphatidate phosphatase enzymes in lipid metabolism.

Phosphatidate phosphatase (PAP) enzymes catalyze the dephosphorylation of phosphatidate, yielding diacylglycerol and inorganic phosphate. In eukaryotic cells, PAP activity has a central role in the synthesis of phospholipids and triacylglycerol through its product diacylglycerol, and it also generates and/or degrades lipid-signaling molecules that are related to phosphatidate. There are two types of PAP enzyme, Mg(2+) dependent (PAP1) and Mg(2+) independent (PAP2), but only genes encoding PAP2 enzymes had been identified until recently, when a gene (PAH1) encoding a PAP1 enzyme was found in Saccharomyces cerevisiae. This discovery has revealed a molecular function of the mammalian protein lipin, a deficiency of which causes lipodystrophy in mice. With molecular information now available for both types of PAP, the specific roles of these enzymes in lipid metabolism are being clarified.

Animals↗
PubMed1997

Coupling of ethanol metabolism to lipid biosynthesis: labelling of the glycerol moieties of sn-glycerol-3-phosphate, a phosphatidic acid and a phosphatidylcholine in liver of rats given [1,1-2H2]ethanol.

The mechanism behind ethanol-induced fatty liver was investigated by administration of [1,1-2H2]ethanol to rats and analysis of intermediates in lipid biosynthesis. Phosphatidic acid and phosphatidylcholine were isolated by chromatography on a lipophilic anion exchanger and molecular species were isolated by high-performance liquid chromatography in a non-aqueous system. The glycerol moieties of palmitoyl-linoleoylphosphatidic acid, the corresponding phosphatidylcholine and free sn-glycerol-3-phosphate were analysed by GC/MS of methyl ester t-butyldimethylsilyl derivatives. The deuterium labelling in the glycerol moiety of the phosphatidic acid was 2-3-times higher than in free sn-glycerol-3-phosphate, indicating that a specific pool of sn-glycerol-3-phosphate was used for the synthesis of phosphatidic acid in liver. The results indicate that NADH formed during ethanol oxidation is used in the formation of a pool of sn-glycerol-3-phosphate that gives rise to triacylglycerol and possibly fatty liver.

Animals↗
PubMed1999

Molecular characterization of the type 2 phosphatidic acid phosphatase.

Phosphatidic acid phosphatase (PAP) converts phosphatidic acid to diacylglycerol, thus regulating the de novo synthesis of glycerolipids and also signal transduction mediated by phospholipase D. We initially succeeded in the cDNA cloning of the mouse 35 kDa PAP bound to plasma membranes (type 2 enzyme). This work subsequently led us to the identification of two human PAP isozymes designated 2a and 2b. A third human PAP isozyme (2c) has also been described. The cloned enzymes are, in common, N-glycosylated and possess six transmembrane domains. The transmembrane dispositions of these enzymes are predicted and the catalytic sites are tentatively located in the 2nd and 3rd extracellular loops, thus suggesting that the type 2 PAPs may act as ecto-enzymes dephosphorylating exogenous substrates. Furthermore, the type 2 PAPs have been proposed to belong to a novel phosphatase superfamily consisting of a number of soluble and membrane-bound enzymes. In vitro enzyme assays show that the type 2 PAPs can dephosphorylate lyso-phosphatidate, ceramide-1-phosphate, sphingosine-1-phosphate and diacylglycerol pyrophosphate. Although the physiological implications of such a broad substrate specificity need to be further investigated, the type 2 PAPs appear to metabolize a wide range of lipid mediators derived from both glycero- and sphingolipids.

Amino Acid Sequence↗
PubMed1998

The selective activation of the cardiac sarcolemmal sodium-calcium exchanger by plasmalogenic phosphatidic acid produced by phospholipase D.

Since plasmalogens are the predominant phospholipid of cardiac sarcolemma, the activation of the sodium-calcium exchanger by either plasmenylethanolamine or plasmalogenic phosphatidic acid generated by phospholipase D was explored. Sodium-calcium exchange activity was 7-fold greater in proteoliposomes comprised of plasmenylethanolamine compared to proteoliposomes comprised of only plasmenylcholine. Phospholipase D treatment of proteoliposomes resulted in 1 mol % conversion of plasmenylcholine or phosphatidylcholine to their respective phosphatidic acid molecular species with a concomitant 8-fold or 2-fold activation of sodium-calcium exchange activity, respectfully. Thus, phospholipase D-mediated hydrolysis of plasmalogens to phosphatidic acid may be an important mechanism for the regulation of the sodium-calcium exchanger.

Animals↗
PubMed1997

Pertussis toxin- and PMA-insensitive calcium mobilization by sphingosine in CFPAC-1 cells: evidence for a phosphatidic acid-dependent mechanism.

In a pancreatic duct adenocarcinoma cell line (CFPAC-1) sphingosine (10 microM) induced both mobilization of intracellular Ca2+ and stimulation of inositol phosphates accumulation. Whereas this latter effect was significantly inhibited by treatment with pertussis toxin or by short-term incubation with phorbol 12-myristate 13-acetate, Ca2+ mobilization was completely insensitive to both treatments. Experiments with permeabilized cells showed that sphingosine or the sphingosine metabolites sphingosine-1-phosphate and sphingosylphosphorylcholine were unable to directly release Ca2+ from internal stores, whereas phosphatidic acid, but not arachidonic acid, was effective. Phosphatidic acid formation was markedly enhanced (2.9-fold over control) by sphingosine, this effect being significantly reduced by preincubation with the diacylglycerol kinase inhibitor R59022. Ca2+ mobilization by sphingosine was also cut down by preincubation with R59022. In conclusion, the results suggest that sphingosine activates phospholipase C through a mechanism functionally coupled through a G protein and under control of PKC. Mobilization of [Ca2+]i by sphingosine is independent of phospholipase C stimulation and likely due to elevation of phosphatidic acid generated by stimulation of diacylglycerol kinase activity.

Adenosine Triphosphate↗
PubMed2005

What makes the bioactive lipids phosphatidic acid and lysophosphatidic acid so special?

Phosphatidic acid and lysophosphatidic acid are minor but important anionic bioactive lipids involved in a number of key cellular processes, yet these molecules have a simple phosphate headgroup. To find out what is so special about these lipids, we determined the ionization behavior of phosphatidic acid (PA) and lysophosphatidic acid (LPA) in extended (flat) mixed lipid bilayers using magic angle spinning 31P NMR. Our data show two surprising results. First, despite identical phosphomonoester headgroups, LPA carries more negative charge than PA when present in a phosphatidylcholine bilayer. Dehydroxy-LPA [1-oleoyl-3-(phosphoryl)propanediol] behaves in a manner identical to that of PA, indicating that the difference in negative charge between LPA and PA is caused by the hydroxyl on the glycerol backbone of LPA and its interaction with the phosphomonoester headgroup. Second, deprotonation of phosphatidic acid and lysophosphatidic acid was found to be strongly stimulated by the inclusion of phosphatidylethanolamine in the bilayer, indicating that lipid headgroup charge depends on local lipid composition and will vary between the different subcellular locations of (L)PA. Our findings can be understood in terms of a hydrogen bond formed within the phosphomonoester headgroup of (L)PA and its destabilization by competing intra- or intermolecular hydrogen bonds. We propose that this hydrogen bonding property of (L)PA is involved in the various cellular functions of these lipids.

Cell Membrane↗
PubMed1989

Darmstoff analogues. 3. Actions of choline esters of acetal phosphatidic acids on visceral smooth muscle.

A number of naturally occurring phospholipids, e.g. the acetal phosphatidic acid derivatives that comprise Darmstoff (1) and the phosphatidylcholine derivative platelet activating factor (PAF), cause contraction of certain visceral smooth muscles and cause platelet activation. Because the Darmstoff phosphatidic acids and PAF are structurally similar, it was of interest to compare the biological actions of choline esters of Darmstoff with those of PAF and of the parent Darmstoff phosphatidic acids. To this end, [(2-pentadecyl-1,3-dioxolan-4-yl)methyl]phosphocholine (3a), [[2-(cis-8-heptadecenyl)-1,3-dioxolan-4-yl]methyl]phosphocho line (3b), and [[2-(cis-8-pentadecenyl)-1,3-dioxolan-4-yl]methyl]phosphocho line (3c) were synthesized. Compounds 3a, 3b, 3c, and PAF caused dose-dependent relaxation of taenia coli strips. In contrast, the unesterified materials 1a and 1b, as well as lyso-PAF, caused contraction in taenia coli strips. Thus, the contractile effect of Darmstoff is reversed on esterification with choline. In preparations of whole trachea, both 1a and 3a had contractile effects similar to those of PAF.

Animals↗
PubMed1979

The effects of barbiturates on the metabolism of phosphatidic acid and phosphatidylinositol in rat brain synaptosomes.

Barbiturates and diphenylhydantoin inhibit the carbamoylcholine-stimulated increase in 32P incorporation into phosphatidylinositol and phosphatidic acid, but have a relatively slight effect on the incorporation of 32P into these lipids in the absence of carbamoylcholine and no effect on 32P incorporation into phosphatidylcholine and phosphatidylethanolamine. Inhibition of the carbamoylcholine-stimulated increase was observed for pentobarbital, thiopental, phenobarbital, 5-(1,3-dimethylbutyl)-5-ethylbarbiturate, (+)- and (-)-5-ethyl-N-methyl-5-propylbarbituate and diphenylhydantoin. Similar concentrations of barbiturates and diphenylhydantoin were previously reported to inhibit the K+-stimulated Ca2+ influx, and therefore other agents that affect Ca2+ influx were tested to find whether they had any effect on 32P incorporation into these lipids. K+ (35 mM) increases 32P incorporation into phosphatidic acid, but to a smaller degree than 100 micrometer-carbamoylcholine, and its effect was inhibited by pentobarbital. Veratridine (75 micrometer) does not increase 32P incorporation into either phosphatidic acid or phosphatidylinositol, but did inhibit the carbamoylcholine-stimulated increase in 32P incorporation into phosphatidylinositol. The possible relationship between the phospholipid effect and stimulated Ca2+ influx is discussed.

Animals↗
PubMed1983

Relationship between fatty-acyl composition of diacylgalactosylglycerol and turnover of chloroplast phosphatidate.

Chloroplasts from plants that contain different proportions of the 2-hexadecatrienoyl-1-linolenoyl molecular species in total diacylgalactosylglycerol were examined for their ability to dephosphorylate phosphatidate that had been labelled in situ with [1-14C]acetate. The turnover rate of chloroplast phosphatidate may be related to the accumulation of a prokaryotic diacylgalactosylglycerol, suggesting that chloroplast phosphatidate phosphatase controls the fatty acyl composition of the diacylgalactosylglycerol synthesized in the intact plant.

Acetates↗
PubMed1984

Oleic acid promotes the activation and translocation of phosphatidate phosphohydrolase from the cytosol to particulate fractions of isolated rat hepatocytes.

The incubation of hepatocytes with 1-4mM-oleate increased the total activity of phosphatidate phosphohydrolase that was measured in the presence of Mg2+ to about 2-fold. This was accompanied by an increase in the proportion of the enzyme that was isolated with the particulate fractions. Conversely, the addition of up to 4mM-oleate decreased the recovery of phosphatidate phosphohydrolase in the cytosolic fraction from about 70% to 3% when hepatocytes were lysed with digitonin. Most of the increase in the membrane-associated phosphohydrolase activity was isolated after cell fractionation in the microsomal fraction that was enriched with the endoplasmic-reticulum marker arylesterase. It is proposed that the translocation of phosphatidate phosphohydrolase facilitates the increased synthesis of triacylglycerols in the liver when it is presented with an increased supply of fatty acids.

Animals↗
PubMed1985

Effects of cyclic AMP, glucocorticoids and insulin on the activities of phosphatidate phosphohydrolase, tyrosine aminotransferase and glycerol kinase in isolated rat hepatocytes in relation to the control of triacylglycerol synthesis and gluconeogenesis.

Rat hepatocytes were incubated in monolayer culture in modified Leibovitz L-15 medium containing either 10% (v/v) newborn-calf serum or 0.2% (w/v) fatty-acid-poor bovine serum albumin. The addition of 100 nM-dexamethasone increased the activities of both phosphatidate phosphohydrolase and tyrosine aminotransferase by about 3.5-fold after 8h, and these activities continued to rise until at least 24h. Incubating the hepatocytes in the albumin-containing medium with 10 microM- or 100 microM-8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate increased the activities of the phosphohydrolase and aminotransferase by 2.6- and 3.4-fold respectively after 8h. These increases were blocked by actinomycin D. The increases in the activities that were produced by the cyclic AMP analogue and dexamethasone were independent and approximately additive. Insulin when added alone did not alter the phosphohydrolase activity, but it increased the aminotransferase activity by 34%. The dexamethasone-induced increase in the phosphohydrolase activity was completely blocked by 7-144 microM-insulin, whereas that of the aminotransferase was only partly suppressed. Insulin had no significant Effects on the increases in the activities of phosphatidate phosphohydrolase and tyrosine aminotransferase that were produced by the cyclic AMP analogue, but this may be because the analogue is fairly resistant to degradation by the phosphodiesterase. The activity of glycerol kinase was not significantly changed by incubating the hepatocytes with insulin, dexamethasone and the cyclic AMP analogue alone or in combinations. It is proposed that high concentrations of cyclic AMP and glucocorticoids increase the total activity of phosphatidate phosphohydrolase in the liver and provide it with an increased capacity for synthesizing triacylglycerols and very-low-density lipoproteins, which is expressed when the availability of fatty acids is high. There appears to be a co-ordinated hormonal control of triacyglycerol synthesis and gluconeogenesis in diabetes and in metabolic stress to enable the liver to supply other organs with energy.

Animals↗
PubMed1988

The influence of phosphatidate bilayers on pig heart AMP deaminase. Crucial role of pH-dependent lipid-phase transition.

Phosphatidate bilayers composed of dilauroylphosphatidate, dimyristoylphosphatidate, dipalmitoylphosphatidate and dioleoylphosphatidate were prepared. Their interaction with AMP deaminase isolated from pig heart was investigated. Dioleoylphosphatidate bilayers were found to exert non-competitive inhibition on the AMP deaminase with a Ki of 15 x 10(-6) M. This inhibition is three orders of magnitude stronger than that exerted by orthophosphate. The phosphatidate species containing saturated fatty acids were either non-inhibitory or inhibited enzyme activity rather poorly. However, alkalinization of the medium from pH 6.5 to pH 7.9 led to the inhibition of pig heart AMP deaminase by dilauroylphosphatidate bilayers. This was accompanied by the fluidization of the saturated phosphatidate species, i.e. the lowering of their phase transition temperature in alkaline pH, as measured by light-scattering and fluorescence scans. The possible significance of these findings for the regulation of AMP deaminase activity in vivo by natural membranes is discussed.

AMP Deaminase↗
PubMed1992

Activation of phospholipase D by alpha-thrombin or epidermal growth factor contributes to the formation of phosphatidic acid, but not to observed increases in 1,2-diacylglycerol.

The receptor-mediated activation of a phosphatidylcholine-hydrolysing phospholipase D (PLD) has recently been described. We investigated the effect of alpha-thrombin and epidermal growth factor (EGF) on cellular PLD activity in order to determine the role of this enzyme in mitogen-induced increases in phosphatidic acid and sn-1,2-diacylglycerol. In the presence of ethanol, stimulation of [3H]myristic acid-labelled quiescent IIC9 cells with alpha-thrombin or EGF resulted in a rapid increase in radiolabelled phosphatidyl-ethanol which reached a plateau at 1 min, indicating the rapid and transient activation of PLD. We observed a concomitant decrease in the mitogen-stimulated increase of radiolabelled phosphatidic acid. In contrast, ethanol did not significantly effect the elevation of sn-1,2-diacylglycerol levels stimulated by alpha-thrombin or EGF as determined by measurement of sn-1,2-diacylglycerol mass or the appearance of [3H]1,2-diacylglycerol. A novel lipid, detected by two-dimensional t.l.c. analysis, was generated in [3H]myristic acid-labelled cells stimulated with alpha-thrombin, but not EGF, in the presence of ethanol. Treatment in vitro of cellular lipids isolated from [3H]myristic acid-labelled cultures with PLD in the presence of ethanol also resulted in the generation of this novel lipid species, supporting the role of this enzyme in its production. These data indicate that in quiescent IIC9 cells: (a) alpha-thrombin or EGF rapidly and transiently activates a PLD; (b) although this activation is responsible for part of the mitogen-induced increases in phosphatidic acid, it does not contribute to induced increases in sn-1,2-diacylglycerol; and (c) activation of this enzyme appears to be involved in the formation of a novel lipid generated in response to alpha-thrombin, but not EGF, in IIC9 fibroblasts.

Animals↗
PubMed1998

Identification of the phosphatidic acid phosphatase type 2a isozyme as an androgen-regulated gene in the human prostatic adenocarcinoma cell line LNCaP.

Differential display was used to identify novel androgen-regulated genes in the human prostatic adenocarcinoma cell line LNCaP. A 322-base pair cDNA fragment that was consistently induced by the synthetic androgen R1881 revealed 100% homology with the human phosphatidic acid phosphatase type 2a isozyme very recently reported by Kai et al. (PAP-2a; Kai., M., Wada, I., Imai, S.-i., Sakane, F., and Kanoh, H. (1997) J. Biol. Chem. 272, 24572-24578). The fragment was used to clone the corresponding cDNA from a human prostate library. The deduced amino acid sequence confirmed the identity with human PAP-2a. The inducibility of PAP-2a mRNA by androgens was confirmed by Northern blot hybridization. The effect was time- and dose-dependent with a maximal stimulation (4-fold) after 24 h of treatment with 10(-9) M R1881. The steroid specificity of PAP-2a mRNA regulation was found to be in agreement with the aberrant ligand specificity of the mutated androgen receptor in LNCaP cells, supporting the involvement of the androgen receptor in the induction process. Furthermore, low basal levels of PAP-2a mRNA and absence of androgen inducibility were observed in the poorly differentiated and androgen receptor-negative cell lines PC-3 and DU-145. Induction of PAP-2a mRNA was not affected by the protein synthesis inhibitor cycloheximide and was accompanied by a marked increase in PAP-2 activity as measured by the conversion of phosphatidic acid into diacylglycerol in membrane fractions of LNCaP. Comparison of the expression of PAP-2a mRNA in 50 different human tissues revealed ubiquitous expression. The highest levels, however, were observed in the prostate. Since PAP-2 plays a pivotal role in the control of signal transduction by lipid mediators such as phosphatidate, lysophosphatidate, and ceramide-1-phosphate, the ability of androgens to stimulate the expression and activity of this enzyme in prostatic cells may provide an important opportunity for cross-talk between signaling pathways involving lipid mediators and androgens.

Adenocarcinoma↗