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Disease Models & Mechanisms Jan 2020Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are...
Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with C-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted.This article has an associated First Person interview with the joint first authors of the paper.
Topics: Administration, Oral; Animals; Biological Availability; Chondrodysplasia Punctata, Rhizomelic; Disease Models, Animal; Docosahexaenoic Acids; Drug Stability; Mice; Mice, Inbred C57BL; Motor Activity; Peroxisomal Targeting Signal 2 Receptor; Plasmalogens; Vinyl Compounds
PubMed: 31862688
DOI: 10.1242/dmm.042499 -
Biochemistry Apr 2018Tafazzin is the mitochondrial enzyme that catalyzes transacylation between a phospholipid and a lysophospholipid in remodeling. Mutations in tafazzin cause Barth...
Tafazzin is the mitochondrial enzyme that catalyzes transacylation between a phospholipid and a lysophospholipid in remodeling. Mutations in tafazzin cause Barth syndrome, a potentially life-threatening disease with the major symptom being cardiomyopathy. In the tafazzin-deficient heart, cardiolipin (CL) acyl chains become abnormally heterogeneous unlike those in the normal heart with a single dominant linoleoyl species, tetralinoleoyl CL. In addition, the amount of CL decreases and monolysocardiolipin (MLCL) accumulates. Here we determine using high-resolution P nuclear magnetic resonance with cryoprobe technology the fundamental phospholipid composition, including the major but oxidation-labile plasmalogens, in the tafazzin-knockdown (TAZ-KD) mouse heart as a model of Barth syndrome. In addition to confirming a lower level of CL (6.4 ± 0.1 → 2.0 ± 0.4 mol % of the total phospholipid) and accumulation of MLCL (not detected → 3.3 ± 0.5 mol %) in the TAZ-KD, we found a substantial reduction in the level of plasmenylcholine (30.8 ± 2.8 → 18.1 ± 3.1 mol %), the most abundant phospholipid in the control wild type. A quantitative Western blot revealed that while the level of peroxisomes, where early steps of plasmalogen synthesis take place, was normal in the TAZ-KD model, expression of Far1 as a rate-determining enzyme in plasmalogen synthesis was dramatically upregulated by 8.3 (±1.6)-fold to accelerate the synthesis in response to the reduced level of plasmalogen. We confirmed lyso-plasmenylcholine or plasmenylcholine is a substrate of purified tafazzin for transacylation with CL or MLCL, respectively. Our results suggest that plasmenylcholine, abundant in linoleoyl species, is important in remodeling CL in the heart. Tafazzin deficiency thus has a major impact on the cardiac plasmenylcholine level and thereby its functions.
Topics: Acylation; Acyltransferases; Animals; Barth Syndrome; Disease Models, Animal; Mice; Mice, Transgenic; Mitochondria, Heart; Mitochondrial Proteins; Plasmalogens; Transcription Factors
PubMed: 29557170
DOI: 10.1021/acs.biochem.8b00042 -
Lipids in Health and Disease Nov 2012Many disorders with plasmalogen deficiency have been reported. Replenishment or replacement of tissue plasmalogens of these disorders would be beneficial to the patients...
BACKGROUND
Many disorders with plasmalogen deficiency have been reported. Replenishment or replacement of tissue plasmalogens of these disorders would be beneficial to the patients with these disorders, but effects of dietary plasmalogen on mammals have not been reported.
METHODS
Plasmalogens were purified from chicken skin. The purified plasmalogens consisted of 96.4% ethanolamine plasmalogen (PlsEtn), 2.4% choline plasmalogen (PlsCho) and 0.5% sphingomyelin (SM). A diet containing 0.1% the purified plasmalogens (PlsEtn diet) was given to rats. Relative composition of phospholipids was measured by a high performance liquid chromatography (HPLC) method that can separate intact plasmalogens and all other phospholipid classes by a single chromatographic run.
RESULTS
The PlsEtn diet given to Zucker diabetic fatty (ZDF) rats for 4 weeks caused decreases of plasma cholesterol and plasma phospholipid as compared to control diet. The other routine laboratory tests of plasma including triacylglycerol, glucose, liver and renal functions, albumin, and body weight were not different. Relative compositions of erythrocyte PlsEtn and phosphatidylethanolamine (PE) increased, and that of phosphatidylcholine (PC) decreased in PlsEtn diet group. The PlsEtn diet given to normal rats for 9 weeks again caused decrease of plasma cholesterol and phospholipid, and it induced increase of relative composition of PlsEtn of the erythrocyte membrane. The other routine laboratory tests of plasma and body weight were not different.
CONCLUSIONS
Dietary PlsEtn increases relative composition of PlsEtn of erythrocyte membranes in normal and ZDF rats, and it causes decreases of plasma cholesterol and plasma phospholipids. Dietary PlsEtn for 9 weeks seemingly causes no adverse effect to health of normal rats.
Topics: Animals; Cholesterol; Dietary Supplements; Erythrocyte Membrane; Male; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Plasmalogens; Rats; Rats, Zucker
PubMed: 23170810
DOI: 10.1186/1476-511X-11-161 -
Journal of Lipid Research Mar 1999Previously, this laboratory reported the isolation of variants, RAW. 12 and RAW.108, from the macrophage-like cell line RAW 264.7 that are defective in plasmalogen...
Previously, this laboratory reported the isolation of variants, RAW. 12 and RAW.108, from the macrophage-like cell line RAW 264.7 that are defective in plasmalogen biosynthesis [Zoeller, R.A. et al. 1992. J. Biol. Chem. 267: 8299-8306]. Fatty acid analysis showed significant changes in the mutants in the ethanolamine phospholipids (PE), the only phospholipid class in which the plasmalogen species, plasmenylethanolamine, contributes significantly. Within the PE fraction, docosapentaenoic (DPA; 22:5n-3) and docosahexaenoic (DHA; 22:6n-3) acids were reduced by approximately 50% in the variants while the levels of arachidonic acid (AA; 20:4n-6) remained unaffected. The decrease in DHA was accompanied by a 50% decrease in labeling PE with [3H]DHA over a 90-min period. Restoration of plasmenylethanolamine by supplementing the growth medium with sn -1-hexadecylglycerol (HG) completely reversed these changes in RAW. 108. Pre-existing pools of plasmenylethanolamine were not required for restoration of normal [3H]DHA labeling; addition of HG only during the labeling period was sufficient. Due to the loss of Delta1'-desaturase in RAW.12, HG supplementation resulted in the accumulation of plasmenylethanolamine's immediate biosynthetic precursor, plasmanylethanolamine. Even though this latter phospholipid contained only the ether functionality (lacking the vinyl ether double bond) it was sufficient to restore wild type-like fatty acid composition and DHA labeling of the ethanolamine phospholipids, identifying the ether bond as a structural determinant for this specificity. In summary, we have used these mutants to establish that the plasmalogen status of a cell can influence the levels of certain polyunsaturated fatty acids. These results support the notion that certain polyunsaturated fatty acids, such as DHA, can be selectively targeted to plasmalogens and that this targeting occurs during de novo biosynthesis, or shortly thereafter, through modification of nascent plasmalogen pools.
Topics: Animals; Arachidonic Acid; Cell Line; Docosahexaenoic Acids; Fatty Acids; Lipids; Macrophages; Mice; Oleic Acid; Phosphatidylcholines; Phosphatidylserines; Phospholipids; Plasmalogens
PubMed: 10064738
DOI: No ID Found -
Lipids Dec 2003Plasmalogens, a subclass of phospholipids, are widely distributed in human and animals, and are taken into the body as food. However, no data exist on the intestinal...
Plasmalogens, a subclass of phospholipids, are widely distributed in human and animals, and are taken into the body as food. However, no data exist on the intestinal absorption or fate of ingested plasmalogen. Here, we determined whether dietary plasmalogen is absorbed and whether blood and tissue concentrations increased in normal male Wistar rats by using four separate experiments. Phospholipids containing more than 20 wt% of plasmalogen extracted from the bovine brain were incorporated into test diets (10-15 wt%). In experiment 1, we estimated the absorption rate by measuring the plasmalogen vinyl ether bonds remaining in the alimentary tract of rats after the ingestion of 2 g of test diet containing 91 micromol plasmalogen. The absorption rate of plasmalogen was nearly 80 mol% after 4 h, comparable to the total phospholipid content in the test diet. In experiment 2, we observed no degradation of the plasmalogen vinyl ether bonds under in vitro conditions simulating those of the stomach and small intestinal lumen. In experiment 3 we confirmed a comparable absorption (36 mol%) by using a closed loop of the upper small intestine in anesthetized rats 90 min after injecting a 10 wt% brain phospholipid emulsion. Feeding a test diet containing 10 wt% brain phospholipids for 7 d increased plasmalogen concentration threefold in blood plasma and by 25% in the liver; however, no increases were seen in blood cells, skeletal muscle, brain, lungs, kidneys, or adipose tissue (experiment 4). We concluded that dietary plasmalogen is absorbed from the intestine and contributes to a large increase in plasmalogen levels in blood plasma.
Topics: Animals; Diet; Intestinal Mucosa; Liver; Male; Phospholipids; Plasmalogens; Rats; Rats, Wistar; Time Factors
PubMed: 14870925
DOI: 10.1007/s11745-003-1183-9 -
Analytical Chemistry Aug 2020Deficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature...
Deficient ether lipid biosynthesis in rhizomelic chondrodysplasia punctata and other disorders is associated with a wide range of severe symptoms including small stature with proximal shortening of the limbs, contractures, facial dysmorphism, congenital cataracts, ichthyosis, spasticity, microcephaly, and mental disability. Mouse models are available but show less severe symptoms. In both humans and mice, it has remained elusive which of the symptoms can be attributed to lack of plasmanyl or plasmenyl ether lipids. The latter compounds, better known as plasmalogens, harbor a vinyl ether double bond conferring special chemical and physical properties. Discrimination between plasmanyl and plasmenyl ether lipids is a major analytical challenge, especially in complex lipid extracts with many isobaric species. Consequently, these lipids are often neglected also in recent lipidomic studies. Here, we present a comprehensive LC-MS/MS based approach that allows unequivocal distinction of these two lipid subclasses based on their chromatographic properties. The method was validated using a novel plasmalogen-deficient mouse model, which lacks plasmanylethanolamine desaturase and therefore cannot form plasmenyl ether lipids. We demonstrate that plasmanylethanolamine desaturase deficiency causes an accumulation of plasmanyl species, a too little studied but biologically important substance class.
Topics: Animals; Chromatography, Liquid; Ethers; Female; Lipidomics; Male; Mice, Knockout; Molecular Structure; Oxidoreductases; Plasmalogens; Tandem Mass Spectrometry
PubMed: 32692545
DOI: 10.1021/acs.analchem.0c01933 -
Scientific Reports Aug 2017Endothelial cells (EC) are involved in regulating several aspects of lipid metabolism, with recent research revealing the clinicopathological significance of...
Endothelial cells (EC) are involved in regulating several aspects of lipid metabolism, with recent research revealing the clinicopathological significance of interactions between EC and lipids. Induced pluripotent stem cells (iPSC) have various possible medical uses, so understanding the metabolism of these cells is important. In this study, endothelial phenotype cells generated from human iPSC formed cell networks in co-culture with fibroblasts. Changes of plasmalogen lipids and sphingomyelins in endothelial phenotype cells generated from human iPSC were investigated by reverse-phase ultra-high-pressure liquid chromatography mass spectrometry (UHPLC-MS/MS) analysis. The levels of plasmalogen phosphatidylethanolamines (38:5) and (38:4) increased during differentiation of EC, while sphingomyelin levels decreased transiently. These changes of plasmalogen lipids and sphingomyelins may have physiological significance for EC and could be used as markers of differentiation.
Topics: Biomarkers; Cell Differentiation; Cell Line; Cell Separation; Cells, Cultured; Chromatography, Liquid; Endothelial Cells; Humans; Immunophenotyping; Induced Pluripotent Stem Cells; Phenotype; Plasmalogens; Tandem Mass Spectrometry
PubMed: 28839272
DOI: 10.1038/s41598-017-09980-x -
BioFactors (Oxford, England) Nov 2022Fatty acids and phospholipid molecules are essential for determining the structure and function of cell membranes, and they hence participate in many biological... (Review)
Review
Fatty acids and phospholipid molecules are essential for determining the structure and function of cell membranes, and they hence participate in many biological processes. Platelet activating factor (PAF) and its precursor plasmalogen, which represent two subclasses of ether phospholipids, have attracted increasing research attention recently due to their association with multiple chronic inflammatory, neurodegenerative, and metabolic disorders. These pathophysiological conditions commonly involve inflammatory processes linked to an excess presence of PAF and/or decreased levels of plasmalogens. However, the molecular mechanisms underlying the roles of plasmalogens in inflammation have remained largely elusive. While anti-inflammatory responses most likely involve the plasmalogen signal pathway; pro-inflammatory responses recruit arachidonic acid, a precursor of pro-inflammatory lipid mediators which is released from membrane phospholipids, notably derived from the hydrolysis of plasmalogens. Plasmalogens per se are vital membrane phospholipids in humans. Changes in their homeostatic levels may alter cell membrane properties, thus affecting key signaling pathways that mediate inflammatory cascades and immune responses. The plasmalogen analogs of PAF are also potentially important, considering that anti-PAF activity has strong anti-inflammatory effects. Plasmalogen replacement therapy was further identified as a promising anti-inflammatory strategy allowing for the relief of pathological hallmarks in patients affected by chronic diseases with an inflammatory component. The aim of this Short Review is to highlight the emerging roles and implications of plasmalogens in chronic inflammatory disorders, along with the promising outcomes of plasmalogen replacement therapy for the treatment of various PAF-related chronic inflammatory pathologies.
Topics: Humans; Plasmalogens; Platelet Activating Factor; Phospholipid Ethers; Cell Membrane; Chronic Disease
PubMed: 36370412
DOI: 10.1002/biof.1916 -
Journal of Oleo Science Dec 2020Plasmalogen, phospholipids with previously shown associations with dementia, has attracted attention as a substance found in some studies to improve cognitive function.... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Plasmalogen, phospholipids with previously shown associations with dementia, has attracted attention as a substance found in some studies to improve cognitive function. The effects of ascidian-derived plasmalogens on cognitive performance improvement were assessed in a randomized, double-blind, placebo-controlled study including Japanese adult volunteers with mild forgetfulness.
METHODS
Participants consumed either the active food containing ascidian-derived plasmalogen (1 mg as plasmalogen) or the placebo food for 12 weeks, and their cognitive performance was assessed by Cognitrax. Participants were randomly allocated into the intervention (ascidian-derived plasmalogen; 8 males, and 17 females; 45.6 ± 11.1 years) or the placebo (9 males, and 15 females; mean age, 46.4 ± 10.8 years) group.
RESULTS
Compared to the placebo group, the intervention group showed a significant increase score in composite memory (eight weeks: 3.0 ± 16.3 points, 12 weeks: 6.7 ± 17.5 points), which was defined as the sum of verbal and visual memory scores.
CONCLUSIONS
These results indicate the consumption of ascidian-derived plasmalogen maintains and enhances memory function. This study was registered at the University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR, registry no. UMIN000026297). This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Topics: Adult; Animals; Asian People; Cognition; Cognitive Dysfunction; Double-Blind Method; Female; Humans; Male; Memory; Middle Aged; Phytotherapy; Plasmalogens; Urochordata
PubMed: 33177278
DOI: 10.5650/jos.ess20167 -
Biochimica Et Biophysica Acta Nov 2011Fatty aldehydes are important components of the cellular lipidome. Significant interest has been developed towards the analysis of the short chain α,β-unsaturated and... (Review)
Review
Fatty aldehydes are important components of the cellular lipidome. Significant interest has been developed towards the analysis of the short chain α,β-unsaturated and hydroxylated aldehydes formed as a result of oxidation of polyunsaturated fatty acids. Multiple gas chromatography-mass spectrometry (GC/MS) and subsequently liquid chromatography-mass spectrometry (LC/MS) approaches have been developed to identify and quantify short-chain as well as long-chain fatty aldehydes. Due to the ability to non-enzymaticaly form Schiff bases with amino groups of proteins, lipids, and with DNA guanidine, free aldehydes are viewed as a marker or metric of fatty acid oxidation and not the part of intracellular signaling pathways which has significantly limited the overall attention this group of molecules have received. This review provides an overview of current GC/MS and LC/MS approaches of fatty aldehyde analysis as well as discusses technical challenges standing in the way of free fatty aldehyde quantitation.
Topics: Aldehydes; Chromatography, Liquid; Fatty Acids; Gas Chromatography-Mass Spectrometry; Halogenation; Humans; Mass Spectrometry; Plasmalogens
PubMed: 21930240
DOI: 10.1016/j.bbalip.2011.08.018