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PubMed2005

Plasmalogen metabolism-related enzymes in rat brain during aging: influence of n-3 fatty acid intake.

Plasmalogens (Pls) are phospholipids containing a vinyl-ether bond at the sn-1 position of the glycerol backbone. They represent between 1/2 and 2/3 of the ethanolamine phospholipids in the brain. During aging, the Pls content in human brain falls down. However, the role of Pls metabolism-related enzymes in the regulation of Pls levels remains to be determined. Dihydroxyacetone phosphate acyltransferase (DHAP-AT) is the enzyme involved in the first step of Pls biosynthesis. In the brain, a phospholipase A2, which selectively acts on Pls, has been isolated (Pls-PLA2s). In this work, we aimed to evaluate the impact of DHAP-AT (a key enzyme of Pls biosynthesis) and Pls-PLA2 (a specific Pls degradation enzyme) on the evolution of Pls content in the rat brain during aging. The influence of n-3 fatty acid intake was also evaluated. Littermates from two generations of n-3 deficient rats were fed an equilibrated diet containing either alpha-LNA alone or with two doses of DHA. After weaning, 3, 9 or 21 months of diet, rats were sacrificed. Enzymatic assays were performed, Pls levels were assessed and the sn-2 position of ethanolamine Pls was analyzed. DHAP-AT activity significantly increased between weaning and 3 months with a concomitant increase of brain Pls, which reached maximal levels after 9 months. Then, Pls levels and DHAP-AT activity significantly decreased while Pls-PLA2s activity significantly increased. Dietary n-3 fatty acids had no effect on DHAP-AT activity and on Pls levels. In conclusion, the increase of brain Pls content in the first part of the life may be related to the high increase of DHAP-AT activity, probably stimulated by DHA. In aged animals, the decrease of Pls levels may mainly be caused to an increase of their degradation by Pls-PLA2. Dietary DHA may not oppose the physiologic aging.

Acyltransferases↗
PubMed2006

Plasmalogens in the retina: in situ hybridization of dihydroxyacetone phosphate acyltransferase (DHAP-AT)--the first enzyme involved in their biosynthesis--and comparative study of retinal and retinal pigment epithelial lipid composition.

Plasmalogens (Pls) are phospholipids containing a vinyl-ether bond in the sn-1 position of the glycerol backbone. The physiological role of Pls is still enigmatic, especially within the eye where their deficiency leads to developmental abnormalities. In order to learn more about the functions of Pls in the posterior eye, we evaluated retinal Pl content as well as the expression of the first enzyme involved in Pls biosynthesis, dihydroxyacetone phosphate acyltransferase (DHAP-AT) in the retina. In situ hybridization of DHAP-AT mRNA was performed on rat eye sections. The Pl contents of calf retina and retinal pigment epithelium (RPE) samples were determined by high-performance liquid chromatography, thin-layer chromatography, and gas chromatography. DHAP-AT was highly expressed in the inner segment of photoreceptors and in the RPE, suggesting two distinct sites for Pl biosynthesis. Plasmenyl-ethanolamine was the prominent class of Pls in both neural retina and RPE (28-29% of the total phospho-ethanolamine-glycerides). According to the nature of the alkenyl residue linked to the sn-1 position of Pls, the most striking finding was the greater proportion of octadecanal-aldehyde in the sn-1 position of plasmenyl-ethanolamine of the neural retina compared to all the other classes of Pls in the neural retina and the RPE. These findings might be relevant to the biological functions of Pls against oxidative stress and in the formation of lipid rafts.

Acyltransferases↗
PubMed2003

Endothelin-1 decreases ethanolamine plasmalogen levels and evokes PAF production in brain microvessels.

Treatment of brain microvessels with Endothelin-1 evoked a decrease in ethanolamine plasmalogen levels by calcium-independent phospholipase A(2). In contrast, the diacyl molecular forms of ethanolamine phospholipids were unaffected. Evidence also shows that Endothelin type A receptors are involved. Concomitantly, PAF production mediated by CoA-independent transacylase was observed. This is the first evidence of involvement of these pathways on the Endothelin-1 mechanism of action on the blood-brain barrier.

Animals↗
PubMed2000

Effects of transient ethanol exposure on the incorporation of [(3)H]ethanolamine into plasmalogen in the differentiating CG-4 oligodendrocyte cell line.

We investigated the potential teratogenic effects of ethanol (EtOH) on myelination by monitoring its effects on the labeling of the myelin-typical lipid, ethanolamine plasmalogen (EPl), in the CG-4 cell line of differentiating oligodendrocytes (OLGs). On 5 different days during the first 8 days of OLG development, cells were labeled for 24 hr with [(3)H]ethanolamine to label EPl and diacyl-ethanolamine phosphoglycerols (diacyl-EPG), and the amount of labeled lipid expressed on each day was determined in the presence and absence of 25-120 mM EtOH. At early stages of development, a lower amount of [(3)H]EPl per cell was found in cells exposed to EtOH. The ratio of [(3)H]EPl to [(3)H]diacyl-EPG in cells exposed to 25, 50, or 120 mM EtOH was decreased by 50% after 4 days of differentiation compared with that in control cells. By adding or withdrawing EtOH at specific days of differentiation, we showed that EtOH inhibited the increased labeling of EPl if it was present for the first 48 hr of differentiation, and subsequent withdrawal failed to relieve the inhibition. Addition of EtOH anytime after the first day of differentiation did not inhibit the increased labeling of EPl. The results show that the increased labeling of EPl in differentiating OLGs resulted from an EtOH-sensitive, developmentally programmed, transient process active only during the first 2 days of differentiation.

Animals↗
PubMed1999

Synthesis of plasmalogens in eye lens epithelial cells.

The present paper describes cloning and sequencing of the mouse cDNA encoding dihydroxyacetonephosphate acyltransferase (DAPAT), the peroxisomal key enzyme of plasmalogen (PM) biosynthesis. Using monospecific antibodies, we localized DAPAT and alkyl dihydroxyacetonephosphate synthase to peroxisomes of mouse lens epithelial cells (LECs) and determined their enzymatic activity. By electrospray ionization mass spectrometry of mouse lens lipid extracts, we identified phosphatidyl ethanolamine including plasmenyl ethanolamine species as major constituents. Our data demonstrate the capacity of LECs to synthesize PMs and the high coincidence between deficiency of PM and early manifestation of cataract in patients with peroxisomal disorders suggests that ether-bonded lipids may play an important role in maintaining lens transparency.

Acyltransferases↗
PubMed2001

Regional distribution of ethanolamine plasmalogen in the hippocampal CA1 and CA3 regions and cerebral cortex of the gerbil.

Although ethanolamine plasmalogens (EtnPm) are the predominant phospholipids in neural tissue, their physiological role has not been clarified. The biophysical conformation of EtnPm in the proteoliposome enhances the activity of the sodium-calcium exchanger, which has been proposed to induce intracellular calcium ion accumulation during ischemia and early reperfusion. The levels of EtnPm in the areas of the gerbil brain selectively vulnerable to ischemia, namely the hippocampal CA1 and CA3 regions and the cerebral cortex, were measured by high-performance thin-layer chromatography and gas-liquid chromatography. The concentration of EtnPm in the CA1 region, which is the most vulnerable to ischemic and anoxic stress, was 2.6- and 2.7-fold higher than that in the CA3 region and cerebral cortex, respectively. The significantly higher concentration of EtnPm in the hippocampal CA1 region may enhance sodium-calcium exchanger activity and play an important role in the vulnerability of this region to ischemia.

Animals↗
PubMed1990

Simple method for the analysis of glycerol enol ethers derived from plasmalogens in complex lipid mixtures and subsequent determination of the aldehydic components by gas chromatography-mass spectrometry.

Glycerol enol ethers, obtained by the reduction of plasmalogens with lithium aluminum hydride, can be converted into glycerol alk-(1)-enyl ether bismethyl ethers with diazomethane in the presence of silica gel. Their mass spectra allow the position of the enol ether group in glycerol unit to be deduced. Branches in the aldehydic components of the glycerol alk-(1)-enyl ether bismethyl ethers can be identified unequivocally by preparation of the 2-alkyl-1,3-dithiolanes, desulphurization with Raney nickel and deuterium to hydrocarbons and subsequent analysis by gas chromatography-mass spectrometry.

Aldehydes↗
PubMed2006

Analysis of fatty aldehyde composition, including 12-methyltridecanal, in plasmalogens from longissimus muscle of concentrate- and pasture-fed bulls.

In a large study, 64 German Holstein and German Simmental bulls were randomly allocated to either an indoor concentrate system or periods of pasture feeding followed by a finishing period on a concentrate containing linseed to enhance the contents of beneficial fatty acids in beef. This paper reports the diet effects on the concentration of 12-methyltridecanal (12-MT) and further fatty aldehydes released from plasmalogens in the phospholipids of longissimus muscle of the bulls. Because of the trace level of the important odorant 12-MT in beef, the determination of fatty aldehydes in phospholipids was done by acidic hydrolysis and the reaction of the aldehydes with 2,4-DNPH followed by high-pressure liquid chromatography (HPLC) analysis. The diet affected the 12-MT concentrations in the muscle phospholipids of both breeds. Pasture feeding significantly increased the 12-MT concentrations up to 350 microg/100 g fresh muscle in the muscle phospholipids of German Holstein and German Simmental bulls as compared with the concentrate-fed bulls. Furthermore, pasture feeding resulted in a significant increase of n-octadecanal in the muscle phospholipids of both breeds up to 39.5 mg/100 g fresh muscle. The concentration of n-hexadecanal was not affected by the diet. Pasture feeding as compared to concentrate feeding significantly decreased the concentration of n-octadec-9-enal in the muscle phospholipids. Summarizing, pasture feeding increased the 12-MT concentration, which can be associated with meat of more intensive aroma and better taste.

Aldehydes↗
PubMed2004

A novel antioxidant action of ethanolamine plasmalogens in lowering the oxidizability of membranes.

We have demonstrated a novel antioxidant action of ethanolamine plasmalogens both in protecting cholesterol from oxidation by free radicals and in lowering the oxidizability of membranes, along with the action of scavenging radicals, by the oxygen-uptake method using large unilamellar vesicles and the water-soluble azo-radical initiator, AAPH [2,2'-azobis-(2-amidino-propane) dihydrochloride].

Antioxidants↗
PubMed1989

Quantitative analysis of phospholipids and demonstration of plasmalogen in human neutrophil subcellular fractions by high-performance liquid chromatography.

The subcellular distribution of phospholipids in unstimulated neutrophils was investigated by high-performance liquid chromatography of lipid extracts of granule and plasma membranes obtained from Percoll density gradients. The mobile phase contained acetonitrile:methanol:85% phosphoric acid (131:3:0.8 v/v/v). Post-nuclear supernatants contained 2.3 micrograms lipid phosphorus/mg protein. Phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine were demonstrated in azurophil granules, specific granules and in a combined fraction of secretory granules and plasma membranes. Separate estimates of each phospholipid class by peak areas obtained by high-performance liquid chromatography showed that secretory granules and plasma membranes contained most of the phosphatidylinositol and phosphatidylcholine (p less than 0.005 vs peaks areas obtained in azurophil and specific granules), whereas a major part of the phosphatidylethanolamine was located in the specific granules (p less than 0.005 vs peak areas obtained in azurophil granules, and plasma membrane and secretory granules). High-performance liquid chromatography proved to be a useful principle for the demonstration of plasmalogen because the acidic solvent caused hydrolysis of phosphatidalethanolamine, which was recovered as lysophosphatidylethanolamine. Additionally, sphingomyelin was demonstrated in all subfractions by thin-layer chromatography.

Cell Membrane↗
PubMed1981

On the role of long-chain aldehydes in mammalian plasmalogen biosynthesis.

[1-3H, 1-14C]Palmitaldehyde (3H:14C = 15) was injected intracerebrally to 18-day-old rats and incorporation of radioactivity into brain lipids was followed over a 24-h period. The substrate was metabolized primarily by oxidation to palmitic acid with loss of tritium and, to a lesser extent, by reduction to hexadecanol. The alkyl moieties of the ethanolamine phospholipids showed considerably lower 3H:14C ratios than the substrate, indicating a substantial participation in either lipid synthesis by tritium-free alcohols derived from 14C-labeled fatty acids. Virtually no 3H radioactivity was found in alkenyl moieties, indicating stereospecificity of both reduction of aldehyde and dehydrogenation of alkyl to alkenyl glycerolipid. The data are consistent with the general concept that plasmalogen biosynthesis proceeds exclusively through fatty alcohols and alkyl glycerolipids and that fatty aldehydes cannot be utilized directly.

Aldehydes↗
PubMed2006

Calcium-independent phospholipase A2-catalyzed plasmalogen hydrolysis in hypoxic human coronary artery endothelial cells.

Thrombin stimulation of human coronary artery endothelial cells (HCAEC) results in activation of a membrane-associated, calcium-independent phospholipase A(2) (iPLA(2)) that selectively hydrolyzes membrane plasmalogen phospholipids. Rupture of an atherosclerotic plaque and occlusion of the coronary vasculature results in a coronary ischemic event in which HCAEC in the ischemic area would be exposed to dramatic decreases in oxygen tension in addition to thrombin exposure. We exposed HCAEC to hypoxia in the presence or absence of thrombin stimulation and measured iPLA(2) activation, membrane phospholipid hydrolysis, and the accumulation of biologically active phospholipid metabolites. HCAEC exposed to hypoxia, thrombin stimulation, or a combination of the two conditions demonstrated an increase in iPLA(2) activity and an increase in arachidonic acid release from plasmenylcholine. Thrombin stimulation of normoxic HCAEC did not result in an accumulation of choline lysophospholipids, but hypoxia alone and in combination with thrombin stimulation led to a significant accumulation of lysoplasmenylcholine (LPlsCho). We propose that the presence of hypoxia inhibits LPlsCho catabolism, at least in part, as a result of the accumulation of long-chain acylcarnitines. The combination of increased production and decreased catabolism of LPlsCho is necessary for its accumulation. Pretreatment with bromoenol lactone to inhibit iPLA(2) blocked membrane phospholipid hydrolysis and production of membrane phospholipid-derived metabolites. The increase in iPLA(2) activity and the subsequent accumulation of membrane phospholipid-derived metabolites in HCAEC exposed to hypoxia or thrombin stimulation alone, and particularly in combination, have important implications in inflammation and arrhythmogenesis in atherosclerosis/thrombosis and subsequent myocardial ischemia.

Arachidonic Acid↗
PubMed2000

Induction of Ca-independent PLA(2) and conservation of plasmalogen polyunsaturated fatty acids in diabetic heart.

Diabetes-induced changes in phospholipase A(2) (PLA(2)) activity have been measured in several tissues but are undefined in diabetic myocardium. We measured ventricular PLA(2) activity in control, streptozotocin-induced diabetic, and insulin-treated diabetic rats and characterized myocardial phospholipids to determine whether diabetes altered myocardial phospholipid metabolism. Increased membrane-associated Ca(2+)-independent PLA(2) (iPLA(2)) activity was observed in diabetes that was selective for arachidonylated phospholipids. Increased iPLA(2) activity was accompanied by an increase in choline lysophospholipids. Diabetes was associated with marked alterations in the phospholipid composition of the myocardium, characterized by decreases in esterified arachidonic and docosahexaenoic acids and increases in linoleic acid. The decrease in polyunsaturated fatty acids was confined to diacylphospholipids, whereas the relative amount of these fatty acids in plasmalogens was increased. Diabetes-induced changes in PLA(2) activity, lysophospholipid production, and alterations in phospholipid composition were all reversed by insulin treatment of diabetic animals. Diabetes-induced changes in membrane phospholipid content and phospholipid hydrolysis may contribute to some of the alterations in myocardial function that are observed in diabetic patients.

Animals↗
PubMed2004

2-chlorohexadecanal derived from hypochlorite-modified high-density lipoprotein-associated plasmalogen is a natural inhibitor of endothelial nitric oxide biosynthesis.

OBJECTIVE: Myeloperoxidase, a heme enzyme that is present and active in human atherosclerotic lesions, provides a source for the generation of proinflammatory chlorinated reactants contributing to endothelial dysfunction. Modification of high-density lipoprotein (HDL) by hypochlorous acid/hypochlorite (HOCl/OCl-) [correction]-generated in vivo by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes-forms a proatherogenic lipoprotein particle that binds to and is internalized by endothelial cells. METHODS AND RESULTS: Here we show that HDL, modified with physiologically relevant HOCl concentrations, attenuates the expression and activity of vasculoprotective endothelial nitric oxide synthase. HOCl-HDL promotes dislocalization of endothelial nitric oxide synthase from the plasma membrane and perinuclear location of human umbilical venous endothelial cells. We could identify 2-chlorohexadecanal as the active component mediating this inhibitory activity. This chlorinated fatty aldehyde is formed during HOCl-mediated oxidative cleavage of HDL-associated plasmalogen. CONCLUSIONS: 2-Chlorohexadecanal, produced by the myeloperoxidase-hydrogen peroxide-chloride system of activated phagocytes may act as a mediator of vascular injury associated with ischemia-reperfusion injury, glomerulosclerosis, and atherosclerosis.

Aldehydes↗
PubMed1976

On the biosynthesis of plasmalogens during myelination in the rat. VIII[1]. Incorporation of 1-[1-14C] alkyl-2-acyl-3-sn-glycerophosphoethanolamine with different fatty acids.

The uptake of 14C labelled alkyl chains into the alkenyl chains of plasmalogens was estimated 12, 24, 48 and 72 h after intracerebral administration of different substrates to 14 day-old rats We used as substrates 1-[1-14C] alkyl-3-sn-glycerophosphoethanolamines, containing in the 2-position of the glycerol residue a stearoyl (substrate I), an oleoyl (II), an archidonoyl (III), a 4, 7, 10, 13, 16, 19-docosahexaenoyl (IV) or no acyl residue (substrate V, so-called lysoether phosphatide). 1) If the fatty acid in the 2-position of the substrate is a saturated one (as in experiment I), the recovery of radioactive alkyl chains is relatively high, but their desaturation is very slow and seems not to reach its maximum even after 72 h. 2) If a substrate with an unsaturated fatty acid in the 2-position is applied, the number of radioactive chains (alkyl plus alkenyl) depends on the chain length and/or the number of double bonds in the fatty acids. The desaturation of the alkyl chains, however, reaches its maximum about 48 h after application (except for substrate IV). 3) Not only is the recovery of radioactivity in the glycerophosphoethanolamine lipids by far the highest in experiment V at any time, but also the total activity of the alkenyl chains has already reached a maximum 24 h after application.

Animals↗
PubMed1999

Mechanisms of interaction of a plasmalogenic analog of platelet-activating factor with human platelets.

The interaction of a plasmalogenic analog of platelet-activating factor (1-O-alk-1;-enyl-2-acetyl-sn-glycero-3-phosphocholine; 1-alkenyl-PAF) with human platelets was studied. 1-Alkenyl-PAF induced an increase in intracellular Ca2+ concentration and inhibition of adenylate cyclase at significantly higher concentrations than PAF. 1-Alkenyl-PAF inhibits PAF-induced platelet aggregation but has no effect on ADP- or thrombin-induced aggregation of human platelets. In contrast to PAF, 1-alkenyl-PAF increases [3H]PGE1 binding with human platelets. The properties of 1-alkenyl-PAF as an agonist or antagonist of PAF receptors apparently depend on its concentration in the cell medium. Under physiological conditions 1-alkenyl-PAF might be a natural PAF antagonist acting in the human cardiovascular system.

Adenylyl Cyclase Inhibitors↗
PubMed1992

A novel CoA-independent transacetylase produces the ethanolamine plasmalogen and acyl analogs of platelet-activating factor (PAF) with PAF as the acetate donor in HL-60 cells.

In this study, we demonstrate the presence of a unique membrane-associated transacetylase that transfers the acetate group from platelet-activating factor (PAF) to lysoplasmalogen (in the presence of EDTA and sodium acetate) with the formation of 1-alk-1-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine (alk-1-enylacetyl-GPE). The identity of alk-1-enylacetyl-GPE was confirmed by acid hydrolysis, phospholipases A2 or C treatment and derivatization by fluorodinitrobenzene. The transacetylase has no requirement for Ca2+, Mg2+, or CoA and a broad pH optimum (7.0-8.0) with Km values of 12.0 microM for PAF and 106.4 microM for lysoplasmalogens. The enzyme activity from the isolated membrane fraction is not changed when whole cells are supplemented with 20:4, induced to differentiate into granulocytes, or treated with ionophore A23187. Radyllyso-sn-glycero-3-phosphocholine (GPC), radyllyso-GPE, acyllyso-sn-glycero-3-phosphoserine (GPS), acyllyso-sn-glycero-3-phosphoinositol (GPI), alkyllyso-sn-glycero-3-phosphate (GP), acyllyso-GP, or cis-9-octadecen-1-ol can also serve as acetate acceptors, whereas alkylglycerol, acylglycerol, or cholesterol are inactive. Differences in substrate acceptor specificity, sensitivity toward phenylmethylsulfonyl fluoride, and response to temperature suggest that the CoA-independent transacetylase and the CoA-independent transacylase that transfers long-chain acyl moieties are two separate enzymes. With intact differentiated HL-60 cells, [3H]acetate from [3H]PAF can be incorporated into alk-1-enylacetyl-GPE in the presence of ionophore A23187, but not in its absence. Moreover, phospholipase A2 inhibitors (p-bromophenacyl bromide and mepacrine) block the transacetylation process in whole cell system. These results indicate the production of alk-1-enyllyso-GPE is a rate-limiting factor for the subsequent transacetylation step during cell activation. We conclude that the transacetylase may participate in the biosynthesis of ethanolamine plasmalogen and acyl analogs of PAF, in vivo, fine-tuning of PAF biological responses, and cross-talk between de novo and remodeling pathways of PAF biosynthesis.

Acetates↗
PubMed1991

Evidence that hydrolysis of ethanolamine plasmalogens triggers synthesis of platelet-activating factor via a transacylation reaction.

Addition of 1-O-alk-1'-enyl-2-lyso-sn-glycero-3-phosphoethanolamine (alkenyl-lyso-GPE) to human neutrophil membrane preparations containing 1-O-[3H]hexadecyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (1-O-[3H]alkyl-2-arachidonoyl-GPC) resulted in rapid deacylation of the 1-O-[3H]alkyl-2-arachidonoyl-GPC to 1-O-[3H]alkyl-2-lyso-GPC (lyso-platelet-activating factor, lyso-PAF). When acetyl-CoA was included in the incubation mixture, the [3H]lyso-PAF was converted to [3H]PAF. Studies of [3H]arachidonate-labeled neutrophils permeabilized with Staphlococcus aureus alpha-toxin revealed a major shift of labeled [3H]arachidonate from the choline to the ethanolamine-containing phosphoglycerides upon addition of alkenyl-lyso-GPE. The studies indicated that lyso-PAF is formed in the system by the transfer of arachidonate from 1-O-alkyl-2-arachidonoyl-GPC to the alkenyl-lyso-GPE by a CoA-independent transacylase reaction. Mass measurements revealed a rapid loss of arachidonate from 1-radyl-2-acyl-GPE and a concomitant increase in alkenyl-lyso-GPE upon stimulation of the neutrophils by ionophore A23187. Based on these and other findings, a pathway is proposed that may play a significant, if not obligatory, role in the synthesis of PAF in intact stimulated neutrophils. It has been widely accepted that phospholipase A2 acts directly on 1-O-alkyl-2-arachidonoyl-GPC as the first step in the synthesis of PAF via formation of lyso-PAF. In the proposed scheme, phospholipase A2, upon stimulation, acts rapidly on ethanolamine plasmalogen selectively releasing arachidonic acid and generating alkenyl-lyso-GPE. The CoA-independent transacylase then selectively transfers arachidonate from 1-radyl-2-arachidonoyl-GPC to the alkenyl-lyso-GPE generating lyso-PAF, which is then acetylated to form PAF. The interactions outlined can account for the synthesis of 1-acyl-2-acetyl-GPC, 1-O-alk-1'-enyl-2-acetyl-GPE, and eicosanoids, in parallel with PAF.

Acylation↗