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International Journal of Molecular... Jul 2023Adult hippocampal neurogenesis (AHN) is associated with hippocampus-dependent cognitive function, and its initiation is attributed to neural stem cells (NSCs)....
Adult hippocampal neurogenesis (AHN) is associated with hippocampus-dependent cognitive function, and its initiation is attributed to neural stem cells (NSCs). Dysregulated AHN has been identified in Alzheimer's disease (AD) and may underlie impaired cognitive function in AD. Modulating the function of NSCs and stimulating AHN are potential ways to manipulate AD. Plasmalogen (PLA) are a class of cell membrane glycerophospholipids which exhibit neuroprotective properties. However, the effect of PLA on altered AHN in AD has not been investigated. In our study, PLA(10μg/mL) -attenuated Aβ (1-42) (5μM) induced a decrease in NSC viability and neuronal differentiation of NSCs, partially through regulating the Wnt/β-catenin pathway. Additionally, AD mice were supplemented with PLA (67mg/kg/day) for 6 weeks. PLA treatment improved the impaired AHN in AD mice, including increasing the number of neural stem cells (NSCs) and newly generated neurons. The memory function of AD mice was also enhanced after PLA administration. Therefore, it was summarized that PLA could regulate NSC differentiation by activating the Wnt/β-catenin pathway and ameliorate AD-related memory impairment through up-regulating AHN.
PubMed: 37569610
DOI: 10.3390/ijms241512234 -
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 -
Journal of Lipid Research Feb 2023Lysoplasmalogens are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X receptor (LXR)...
Lysoplasmalogens are a class of vinyl ether bioactive lipids that have a central role in plasmalogen metabolism and membrane fluidity. The liver X receptor (LXR) transcription factors are important determinants of cellular lipid homeostasis owing to their ability to regulate cholesterol and fatty acid metabolism. However, their role in governing the composition of lipid species such as lysoplasmalogens in cellular membranes is less well studied. Here, we mapped the lipidome of bone marrow-derived macrophages (BMDMs) following LXR activation. We found a marked reduction in the levels of lysoplasmalogen species in the absence of changes in the levels of plasmalogens themselves. Transcriptional profiling of LXR-activated macrophages identified the gene encoding transmembrane protein 86a (TMEM86a), an integral endoplasmic reticulum protein, as a previously uncharacterized sterol-regulated gene. We demonstrate that TMEM86a is a direct transcriptional target of LXR in macrophages and microglia and that it is highly expressed in TREM2/lipid-associated macrophages in human atherosclerotic plaques, where its expression positively correlates with other LXR-regulated genes. We further show that both murine and human TMEM86a display active lysoplasmalogenase activity that can be abrogated by inactivating mutations in the predicted catalytic site. Consequently, we demonstrate that overexpression of Tmem86a in BMDM markedly reduces lysoplasmalogen abundance and membrane fluidity, while reciprocally, silencing of Tmem86a increases basal lysoplasmalogen levels and abrogates the LXR-dependent reduction of this lipid species. Collectively, our findings implicate TMEM86a as a sterol-regulated lysoplasmalogenase in macrophages that contributes to sterol-dependent membrane remodeling.
Topics: Animals; Humans; Mice; Liver X Receptors; Macrophages; Membrane Glycoproteins; Membrane Proteins; Receptors, Immunologic; Sterols; Transcription Factors
PubMed: 36592658
DOI: 10.1016/j.jlr.2022.100325 -
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 -
Journal of the American Society For... Aug 2023Lipid peroxidation is a key component in the pathogenesis of numerous disease states, where the oxidative damage of lipids frequently leads to membrane dysfunction and...
Lipid peroxidation is a key component in the pathogenesis of numerous disease states, where the oxidative damage of lipids frequently leads to membrane dysfunction and subsequent cellular death. Glycerophosphoethanolamine (PE) is the second most abundant phospholipid found in cellular membranes and, when oxidized, has been identified as an executor of ferroptotic cell death. PE commonly exists in the plasmalogen form, where the presence of the vinyl ether bond and its enrichment in polyunsaturated fatty acids make it especially susceptible to oxidative degradation. This results in a multitude of oxidized products complicating identification and often requiring several analytical techniques for interpretation. In the present study, we outline an analytical approach for the structural characterization of intact oxidized products of arachidonate-containing diacyl and plasmalogen PE. Intact oxidized PE structures, including structural and positional isomers, were identified using complementary liquid chromatography techniques, drift tube ion mobility, and high-resolution tandem mass spectrometry. This work establishes a comprehensive method for the analysis of intact lipid peroxidation products and provides an important pathway to investigate how lipid peroxidation initially impacts glycerophospholipids and their role in redox biology.
Topics: Chromatography, Liquid; Plasmalogens; Tandem Mass Spectrometry; Oxidation-Reduction; Glycerophospholipids
PubMed: 37369083
DOI: 10.1021/jasms.3c00083 -
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 -
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 -
Biochimica Et Biophysica Acta. Reviews... Aug 2018Cancer is irrevocably linked to aberrant metabolic processes. While once considered a vestigial organelle, we now know that peroxisomes play a central role in the... (Review)
Review
Cancer is irrevocably linked to aberrant metabolic processes. While once considered a vestigial organelle, we now know that peroxisomes play a central role in the metabolism of reactive oxygen species, bile acids, ether phospholipids (e.g. plasmalogens), very-long chain, and branched-chain fatty acids. Immune system evasion is a hallmark of cancer, and peroxisomes have an emerging role in the regulation of cellular immune responses. Investigations of individual peroxisome proteins and metabolites support their pro-tumorigenic functions. However, a significant knowledge gap remains regarding how individual functions of proteins and metabolites of the peroxisome orchestrate its potential role as a pro-tumorigenic organelle. This review highlights new advances in our understanding of biogenesis, enzymatic functions, and autophagic degradation of peroxisomes (pexophagy), and provides evidence linking these activities to tumorigenesis. Finally, we propose avenues that may be exploited to target peroxisome-related processes as a mode of combatting cancer.
Topics: Antineoplastic Agents; Autophagy; Carcinogenesis; Humans; Neoplasms; Organelle Biogenesis; Peroxisomes; Reactive Oxygen Species
PubMed: 30012421
DOI: 10.1016/j.bbcan.2018.07.004 -
EBioMedicine Jun 2024Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various...
Development and validation of a plasmalogen score as an independent modifiable marker of metabolic health: population based observational studies and a placebo-controlled cross-over study.
BACKGROUND
Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various cardiometabolic conditions. Here we devised, a plasmalogen score (Pls Score) that mirrors a metabolic signal that encompasses the levels of PE(P) and PE and captures the natural variation in circulating plasmalogens and perturbations in their metabolism associated with disease, diet, and lifestyle.
METHODS
We utilised, plasma lipidomes from the Australian Obesity, Diabetes and Lifestyle study (AusDiab; n = 10,339, 55% women) a nationwide cohort, to devise the Pls Score and validated this in the Busselton Health Study (BHS; n = 4,492, 56% women, serum lipidome) and in a placebo-controlled crossover trial involving Shark Liver Oil (SLO) supplementation (n = 10, 100% men). We examined the association of the Pls Score with cardiometabolic risk factors, type 2 diabetes mellitus (T2DM), cardiovascular disease and all-cause mortality (over 17 years).
FINDINGS
In a model, adjusted for age, sex and BMI, individuals in the top quintile of the Pls Score (Q5) relative to Q1 had an OR of 0.31 (95% CI 0.21-0.43), 0.39 (95% CI 0.25-0.61) and 0.42 (95% CI 0.30-0.57) for prevalent T2DM, incident T2DM and prevalent cardiovascular disease respectively, and a 34% lower mortality risk (HR = 0.66; 95% CI 0.56-0.78). Significant associations between diet and lifestyle habits and Pls Score exist and these were validated through dietary supplementation of SLO that resulted in a marked change in the Pls Score.
INTERPRETATION
The Pls Score as a measure that captures the natural variation in circulating plasmalogens, was not only inversely related to cardiometabolic risk and all-cause mortality but also associate with diet and lifestyle. Our results support the potential utility of the Pls Score as a biomarker for metabolic health and its responsiveness to dietary interventions. Further research is warranted to explore the underlying mechanisms and optimise the practical implementation of the Pls Score in clinical and population settings.
FUNDING
National Health and Medical Research Council (NHMRC grant 233200), National Health and Medical Research Council of Australia (Project grant APP1101320), Health Promotion Foundation of Western Australia, and National Health and Medical Research Council of Australia Senior Research Fellowship (#1042095).
PubMed: 38861870
DOI: 10.1016/j.ebiom.2024.105187 -
Brain Pathology (Zurich, Switzerland) Nov 2015Peroxisomes are organelles with diverse metabolic tasks including essential roles in lipid metabolism. They are of utmost importance for the normal functioning of the... (Review)
Review
Peroxisomes are organelles with diverse metabolic tasks including essential roles in lipid metabolism. They are of utmost importance for the normal functioning of the nervous system as most peroxisomal disorders are accompanied with neurological symptoms. Remarkably, the cerebellum exquisitely depends on intact peroxisomal function both during development and adulthood. In this review, we cover all aspects of cerebellar pathology that were reported in peroxisome biogenesis disorders and in diseases caused by dysfunction of the peroxisomal α-oxidation, β-oxidation or ether lipid synthesis pathways. We also discuss the phenotypes of mouse models in which cerebellar pathologies were recapitulated and search for connections with the metabolic abnormalities. It becomes increasingly clear that besides the most severe forms of peroxisome dysfunction that are associated with developmental cerebellar defects, milder impairments can give rise to ataxia later in life.
Topics: Animals; Cerebellum; Humans; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes
PubMed: 26201894
DOI: 10.1111/bpa.12290