-
Frontiers in Cell and Developmental... 2022Plasmalogens are a specific type of glycerophospholipid found in especially high levels in neuronal membranes. Decreased blood and brain levels of docosahexaenoic acid...
Plasmalogens are a specific type of glycerophospholipid found in especially high levels in neuronal membranes. Decreased blood and brain levels of docosahexaenoic acid (DHA) containing plasmalogens are associated with decreased cognition and neuromuscular function in humans. Administration of 1-O-alkyl-2-acylglycerol (AAG) plasmalogen precursors containing DHA at the sn-2 position dose-dependently increase blood DHA plasmalogens and are neuroprotective in animal models of neurodegeneration at doses between 10 and 50 mg/kg. We conducted an investigational clinical trial in 22 cognitively impaired persons to evaluate the effects of an escalating oral dosing regimen of DHA-AAG from 900 to 3,600 mg/day over a 4-month period on blood serum plasmalogen and non-plasmalogen phospholipids and oxidative stress biomarkers. Safety, tolerability and therapeutic effects on cognition and mobility were also evaluated. DHA plasmalogen levels increased with increasing dose and remained significantly elevated at all treatment doses and durations. DHA plasmalogen levels were positively associated with catalase activity and negatively associated with malondialdehyde (MDA) levels. DHA-AAG supplementation normalized catalase activity in persons with low baseline catalase activity, normalized MDA levels in persons with high baseline MDA levels, and normalized superoxide dismutase activity in persons with high baseline SOD activity. Cognition improved in nine participants, was unchanged in nine, and declined in four. Mobility improved in twelve, was unchanged in five and declined in four participants. Changes in cognition and mobility were statistically significant versus a random outcome. Baseline DHA-plasmalogen levels were not predictive of clinical response. DHA-AAG was well tolerated at all dosages and no adverse reactions were observed.
PubMed: 35874835
DOI: 10.3389/fcell.2022.864842 -
FEBS Letters Sep 2017The H-Ras-like suppressor (HRASLS) is a protein family consisting of five members in humans. Despite their discovery as tumor suppressors, we demonstrated that all these... (Review)
Review
The H-Ras-like suppressor (HRASLS) is a protein family consisting of five members in humans. Despite their discovery as tumor suppressors, we demonstrated that all these proteins are phospholipid-metabolizing enzymes, such as phospholipase (PL) A /A and acyltransferase. We thus proposed to rename HRASLS1-5 as PLA/acyltransferase (PLAAT)-1-5. Notably, PLAATs exhibit N-acyltransferase activity to biosynthesize N-acylated ethanolamine phospholipids, including N-acyl-plasmalogen, which serve as precursors of bioactive N-acylethanolamines. Furthermore, the overexpression of PLAAT-3 in animal cells causes disappearance of peroxisomes and a remarkable reduction in plasmalogen levels. This finding might be related to the inhibitory effect of PLAAT-3 on the chaperone activity of the peroxin PEX19. In this article, we will review our recent findings about PLAAT proteins, with special reference to their roles in peroxisome biogenesis and plasmalogen metabolism.
Topics: Animals; Diacylglycerol O-Acyltransferase; Ethanolamines; Humans; Membrane Proteins; Peroxisomes; Phospholipases A1; Phospholipases A2; Plasmalogens
PubMed: 28796890
DOI: 10.1002/1873-3468.12787 -
Journal of Genetics and Genomics = Yi... Jul 2021Ferroptosis is a cell death modality triggered by excessive lipid peroxidation. Two recent studies (Zou et al., 2020; Cui et al., 2021) not only reveal critical roles...
Ferroptosis is a cell death modality triggered by excessive lipid peroxidation. Two recent studies (Zou et al., 2020; Cui et al., 2021) not only reveal critical roles of ether-linked phospholipids as an additional source for providing polyunsaturated fatty acid-containing phospholipids in driving ferroptosis but also suggest a context-dependent role of TMEM189-mediated vinyl-ether phospholipid (plasmalogen) synthesis in ferroptosis.
Topics: Ferroptosis
PubMed: 34167916
DOI: 10.1016/j.jgg.2021.05.003 -
Frontiers in Cell and Developmental... 2021Plasmalogens are a subclass of cell membrane glycerophospholipids that typically include vinyl- ether bond at the sn-1 position and polyunsaturated fatty acid at the... (Review)
Review
Plasmalogens are a subclass of cell membrane glycerophospholipids that typically include vinyl- ether bond at the sn-1 position and polyunsaturated fatty acid at the sn-2 position. They are highly abundant in the neuronal, immune, and cardiovascular cell membranes. Despite the abundance of plasmalogens in a plethora of cells, tissues, and organs, the role of plasmalogens remains unclear. Plasmalogens are required for the proper function of integral membrane proteins, lipid rafts, cell signaling, and differentiation. More importantly, plasmalogens play a crucial role in the cell as an endogenous antioxidant that protects the cell membrane components such as phospholipids, unsaturated fatty acids, and lipoproteins from oxidative stress. The incorporation of vinyl-ether linked with alkyl chains in phospholipids alter the physicochemical properties (e.g., the hydrophilicity of the headgroup), packing density, and conformational order of the phospholipids within the biomembranes. Thus, plasmalogens play a significant role in determining the physical and chemical properties of the biomembrane such as its fluidity, thickness, and lateral pressure of the biomembrane. Insights on the important structural and functional properties of plasmalogens may help us to understand the molecular mechanism of membrane transformation, vesicle formation, and vesicular fusion, especially at the synaptic vesicles where plasmalogens are rich and essential for neuronal function. Although many aspects of plasmalogen phospholipid involvement in membrane transformation identified through experiments and membrane mimic systems, remain to be confirmed , the compiled data show many intriguing properties of vinyl-ether bonded lipids that may play a significant role in the structural and morphological changes of the biomembranes. In this review, we present the current limited knowledge of the emerging potential role of plasmalogens as a modulator of the biomembrane morphology.
PubMed: 34368127
DOI: 10.3389/fcell.2021.673917 -
Marine Drugs Jun 2023Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1--alkyl-glycerols...
Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1--alkyl-glycerols (AGs), as precursors for plasmalogen synthesis, have high biological activity, making them a promising substance for pharmacology. This study aimed to investigate the effect of AGs from squid on lung function, fatty acid and plasmalogen levels, and cytokine and adipokine production in obese patients with asthma. The investigational trial included 19 patients with mild asthma associated with obesity who received 0.4 g of AGs daily for three months in addition to their standard treatment. The effects of AGs were evaluated at one and three months of treatment. The results of the study demonstrated that intake of AGs increased the FEV1 and FEV1/VC ratios, and significantly decreased the ACQ score in 17 of the 19 patients after three months of treatment. The intake of AGs increased concentration of plasmalogen and n-3 PUFA in plasma, and modified leptin/adiponectin production by adipose tissue. The supplementation of AGs decreased the plasma levels of inflammatory cytokines (TNF-α, IL-4, and IL-17a), and oxylipins (TXB2 and LTB4), suggesting an anti-inflammatory property of AGs. In conclusion, 1--alkyl-glycerols could be a promising dietary supplement for improving pulmonary function and reducing inflammation in obese asthma patients, and a natural source for plasmalogen synthesis. The study highlighted that the beneficial effects of AG consumption can be observed after one month of treatment, with gradual improvement after three months of supplementation.
Topics: Animals; Fatty Acids; Plasmalogens; Glycerol; Decapodiformes; Obesity; Asthma; Inflammation; Cytokines
PubMed: 37367676
DOI: 10.3390/md21060351 -
Lipids in Health and Disease Jun 2011Plasmalogens are ether phospholipids required for normal mammalian developmental, physiological, and cognitive functions. They have been proposed to act as membrane...
BACKGROUND
Plasmalogens are ether phospholipids required for normal mammalian developmental, physiological, and cognitive functions. They have been proposed to act as membrane antioxidants and reservoirs of polyunsaturated fatty acids as well as influence intracellular signaling and membrane dynamics. Plasmalogens are particularly enriched in cells and tissues of the human nervous, immune, and cardiovascular systems. Humans with severely reduced plasmalogen levels have reduced life spans, abnormal neurological development, skeletal dysplasia, impaired respiration, and cataracts. Plasmalogen deficiency is also found in the brain tissue of individuals with Alzheimer disease.
RESULTS
In a human and great ape cohort, we measured the red blood cell (RBC) levels of the most abundant types of plasmalogens. Total RBC plasmalogen levels were lower in humans than bonobos, chimpanzees, and gorillas, but higher than orangutans. There were especially pronounced cross-species differences in the levels of plasmalogens with a C16:0 moiety at the sn-1 position. Humans on Western or vegan diets had comparable total RBC plasmalogen levels, but the latter group showed moderately higher levels of plasmalogens with a C18:1 moiety at the sn-1 position. We did not find robust sex-specific differences in human or chimpanzee RBC plasmalogen levels or composition. Furthermore, human and great ape skin fibroblasts showed only modest differences in peroxisomal plasmalogen biosynthetic activity. Human and chimpanzee microarray data indicated that genes involved in plasmalogen biosynthesis show cross-species differential expression in multiple tissues.
CONCLUSION
We propose that the observed differences in human and great ape RBC plasmalogens are primarily caused by their rates of biosynthesis and/or turnover. Gene expression data raise the possibility that other human and great ape cells and tissues differ in plasmalogen levels. Based on the phenotypes of humans and rodents with plasmalogen disorders, we propose that cross-species differences in tissue plasmalogen levels could influence organ functions and processes ranging from cognition to reproduction to aging.
Topics: Animals; Biosynthetic Pathways; Cells, Cultured; Diet, Vegetarian; Erythrocytes; Female; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; Gorilla gorilla; Humans; Male; Pan paniscus; Pan troglodytes; Peroxisomes; Phospholipids; Phylogeny; Plasmalogens; Pongo pygmaeus
PubMed: 21679470
DOI: 10.1186/1476-511X-10-101 -
Brain Research Bulletin Feb 2023On the basis of findings that cultured rat hepatocytes secrete lipoprotein with a high plasmalogen content and the occurrence of this lipid in human serum, it has been... (Review)
Review
On the basis of findings that cultured rat hepatocytes secrete lipoprotein with a high plasmalogen content and the occurrence of this lipid in human serum, it has been suggested that hepatocytes play a role in the supply of plasmalogens to tissues. We tested this hypothesis in a mouse with a hepatocyte-specific defect in peroxisomes, an organelle essentially required for plasmalogen biosynthesis. We analyzed plasmalogens in lipid extracts of forebrain, liver and five further tissues and in plasma by reaction with dansylhydrazine in hydrochloric acid, which cleaves the vinyl ether of plasmalogens and forms a fluorescent dansylhydrazone, which we quantified by reversed phase high performance liquid chromatography. Reaction with dansylhydrazine in acetic acid was used to quantify free aldehydes as a control. Our results show normal levels of plasmalogens in plasma and in all tissues examined, including forebrain and the liver, irrespective of the inactivation of hepatic peroxisomes. None of the selected ether lipids analyzed by mass spectrometry in plasma and liver was decreased in the mice deficient in liver peroxisomes. In contrast, we found three plasmenylcholine species which were even significantly increased in the livers of these animals. Quantification of mRNA expression of plasmalogen biosynthetic enzymes revealed particularly low expression of fatty acyl-CoA reductase, the key regulatory enzyme of plasmalogen biosynthesis, in liver, with and without hepatic peroxisome deficiency. Our results do not support the suggested role of hepatocytes in supplying plasmalogens to tissues.
Topics: Animals; Mice; Dansyl Compounds; Hepatocytes; Peroxisome-Targeting Signal 1 Receptor; Plasmalogens
PubMed: 36584717
DOI: 10.1016/j.brainresbull.2022.12.007 -
Beilstein Journal of Organic Chemistry 2023Ether lipids are compounds present in many living organisms including humans that feature an ether bond linkage at the -1 position of the glycerol. This class of lipids... (Review)
Review
Ether lipids are compounds present in many living organisms including humans that feature an ether bond linkage at the -1 position of the glycerol. This class of lipids features singular structural roles and biological functions. Alkyl ether lipids and alkenyl ether lipids (also identified as plasmalogens) correspond to the two sub-classes of naturally occurring ether lipids. In 1979 the discovery of the structure of the platelet-activating factor (PAF) that belongs to the alkyl ether class of lipids increased the interest in these bioactive lipids and further promoted the synthesis of non-natural ether lipids that was initiated in the late 60's with the development of edelfosine (an anticancer drug). More recently, ohmline, a glyco glycero ether lipid that modulates selectively SK3 ion channels and reduces in vivo the occurrence of bone metastases, and other glyco glycero ether also identified as GAEL (glycosylated antitumor ether lipids) that exhibit promising anticancer properties renew the interest in this class of compounds. Indeed, ether lipid represent a new and promising class of compounds featuring the capacity to modulate selectively the activity of some membrane proteins or, for other compounds, feature antiproliferative properties via an original mechanism of action. The increasing interest in studying ether lipids for fundamental and applied researches invited to review the methodologies developed to prepare ether lipids. In this review we focus on the synthetic method used for the preparation of alkyl ether lipids either naturally occurring ether lipids (e.g., PAF) or synthetic derivatives that were developed to study their biological properties. The synthesis of neutral or charged ether lipids are reported with the aim to assemble in this review the most frequently used methodologies to prepare this specific class of compounds.
PubMed: 37701305
DOI: 10.3762/bjoc.19.96 -
Psychosomatic Medicine Jun 2022Metabolomic profiling may provide insights into biological mechanisms underlying the strong epidemiologic links observed between early abuse and cardiometabolic... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Metabolomic profiling may provide insights into biological mechanisms underlying the strong epidemiologic links observed between early abuse and cardiometabolic disorders in later life.
METHODS
We examined the associations between early abuse and midlife plasma metabolites in two nonoverlapping subsamples from the Nurses' Health Study II, comprising 803 (mean age = 40 years) and 211 women (mean age = 61 years). Liquid chromatography-tandem mass spectrometry assays were used to measure metabolomic profiles, with 283 metabolites consistently measured in both subsamples. Physical and sexual abuse before age 18 years was retrospectively assessed by validated questions integrating type/frequency of abuse. Analyses were conducted in each sample and pooled using meta-analysis, with multiple testing adjustment using the q value approach for controlling the positive false discovery rate.
RESULTS
After adjusting for age, race, menopausal status, body size at age 5 years, and childhood socioeconomic indicators, more severe early abuse was consistently associated with five metabolites at midlife (q value < 0.20 in both samples), including lower levels of serotonin and C38:3 phosphatidylethanolamine plasmalogen and higher levels of alanine, proline, and C40:6 phosphatidylethanolamine. Other metabolites potentially associated with early abuse (q value < 0.05 in the meta-analysis) included triglycerides, phosphatidylcholine plasmalogens, bile acids, tyrosine, glutamate, and cotinine. The association between early abuse and midlife metabolomic profiles was partly mediated by adulthood body mass index (32% mediated) and psychosocial distress (13%-26% mediated), but not by other life-style factors.
CONCLUSIONS
Early abuse was associated with distinct metabolomic profiles of multiple amino acids and lipids in middle-aged women. Body mass index and psychosocial factors in adulthood may be important intermediates for the observed association.
Topics: Adolescent; Adult; Body Mass Index; Child; Child Abuse; Child, Preschool; Female; Humans; Middle Aged; Retrospective Studies
PubMed: 35471987
DOI: 10.1097/PSY.0000000000001088 -
Journal of Oleo Science 2014In this study, we investigated the laboratory-scale preparation and characteristics of ethanolamine plasmalogen from marine invertebrates. The preparation method...
In this study, we investigated the laboratory-scale preparation and characteristics of ethanolamine plasmalogen from marine invertebrates. The preparation method consists of fractionation by acetone and ether treatment, and separation using column chromatography with silica gel and different eluents. Plasmalogen fractions (Pls fraction) were obtained from the viscera of the ascidian Halocynthia roretzi, and the prominent fatty acids were present as 20:5 (33.0%) and 22:6 (29.6%) n-3 polyunsaturated fatty acids (PUFA). The plasmalogen purity was 40%, and the alkenyl chains consisted of 18:0 (86.1%), 16:0 (5.9%) and 18:1 (4.9%). Precursor ion scanning in negative and positive ion modes using liquid chromatography tandem mass spectrometry (LC-MS/MS) enabled the profiling of phosphatidylethanolamine (PE) molecular species in ascidian viscera. Following LC-MS/MS with multiple reaction monitoring (MRM), the prominent plasmalogen species were found to be 18:0p/20:5 (30.4%) and 18:0p/22:6 (24.6%) (p at sn-1 position indicates alkenyl linkage). In conclusion, this preparative procedure using ascidian viscera as a source achieved 40% pure plasmalogen that was rich in n-3 PUFA. In addition, an LC-MS/MS assay enabled rapid analysis of plasmalogen species with selectivity and sensitivity. The present results will contribute to the understanding of dietary plasmalogen absorption and metabolism.
Topics: Acetone; Animals; Chemical Fractionation; Chromatography, Liquid; Ether; Fatty Acids, Omega-3; Phosphatidylethanolamines; Plasmalogens; Sensitivity and Specificity; Silica Gel; Tandem Mass Spectrometry; Urochordata
PubMed: 24717546
DOI: 10.5650/jos.ess13188