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Biophysical Journal Jun 2023Lipid asymmetry in plasma membrane of eukaryotes is ubiquitous. The first measurements reported compositional asymmetry: phosphatidylethanolamine and phosphatidylserine...
Lipid asymmetry in plasma membrane of eukaryotes is ubiquitous. The first measurements reported compositional asymmetry: phosphatidylethanolamine and phosphatidylserine are mostly on the cytoplasmic leafet, while phosphatidylcholine and sphingomyelin are mostly on the exoplasmic leaflet. More recent experiments using lipidomics have evidenced the presence of saturation asymmetry between the two leaflets. A question that naturally arises is why such an asymmetry? To complicate matters, it is still largely unknown in which leaflet cholesterol lies. Here, we use chemical potentials to mimic flippase proteins responsible for maintenance of compositional asymmetry in silico. We show that saturation asymmetry naturally arises as a byproduct of phospholipid number asymmetry and sphingomyelin contents, thereby showing that some reported asymmetries may naturally result from others and do not necessarily require being externally driven. We also show that plasmalogen lipids' tendency to be highly unsaturated is also natural. Additionally, we tackle the problem of cholesterol and show that, while it is influenced by all asymmetries, the resulting cholesterol asymmetry tends to be fairly mild.
Topics: Sphingomyelins; Cell Membrane; Phospholipids; Membranes; Cholesterol
PubMed: 36476992
DOI: 10.1016/j.bpj.2022.12.004 -
Lipids in Health and Disease Apr 2019Growing evidence suggests that ethanolamine plasmalogens (PlsEtns), a subtype of phospholipids, have a close association with Alzheimer's disease (AD). Decreased levels... (Review)
Review
Growing evidence suggests that ethanolamine plasmalogens (PlsEtns), a subtype of phospholipids, have a close association with Alzheimer's disease (AD). Decreased levels of PlsEtns have been commonly found in AD patients, and were correlated with cognition deficit and severity of disease. Limited studies showed positive therapeutic outcomes with plasmalogens interventions in AD subjects and in rodents. The potential mechanisms underlying the beneficial effects of PlsEtns on AD may be related to the reduction of γ-secretase activity, an enzyme that catalyzes the synthesis of β-amyloid (Aβ), a hallmark of AD. Emerging in vitro evidence also showed that PlsEtns prevented neuronal cell death by enhancing phosphorylation of AKT and ERK signaling through the activation of orphan G-protein coupled receptor (GPCR) proteins. In addition, PlsEtns have been found to suppress the death of primary mouse hippocampal neuronal cells through the inhibition of caspase-9 and caspase-3 cleavages. Further in-depth investigations are required to determine the signature molecular species of PlsEtns associated with AD, hence their potential role as biomarkers. Clinical intervention with plasmalogens is still in its infancy but may have the potential to be explored for a novel therapeutic approach to correct AD pathology and neural function.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Biomarkers; Cell Death; Cognitive Dysfunction; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Neurons; Plasmalogens; Proto-Oncogene Proteins c-akt; Receptors, G-Protein-Coupled; Severity of Illness Index; Signal Transduction
PubMed: 30992016
DOI: 10.1186/s12944-019-1044-1 -
Frontiers in Cell and Developmental... 2022Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and... (Review)
Review
Retina is rich in lipids and dyslipidemia causes retinal dysfunction and eye diseases. In retina, lipids are not only important membrane component in cells and organelles but also fuel substrates for energy production. However, our current knowledge of lipid processing in the retina are very limited. Peroxisomes play a critical role in lipid homeostasis and genetic disorders with peroxisomal dysfunction have different types of ocular complications. In this review, we focus on the role of peroxisomes in lipid metabolism, including degradation and detoxification of very-long-chain fatty acids, branched-chain fatty acids, dicarboxylic acids, reactive oxygen/nitrogen species, glyoxylate, and amino acids, as well as biosynthesis of docosahexaenoic acid, plasmalogen and bile acids. We also discuss the potential contributions of peroxisomal pathways to eye health and summarize the reported cases of ocular symptoms in patients with peroxisomal disorders, corresponding to each disrupted peroxisomal pathway. We also review the cross-talk between peroxisomes and other organelles such as lysosomes, endoplasmic reticulum and mitochondria.
PubMed: 36187472
DOI: 10.3389/fcell.2022.982564 -
Brain Research Bulletin Sep 2023After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term... (Review)
Review
Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome.
After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties ("brain fog"), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions. Of great interest, recent evidence revealed a significant reduction of plasmalogen contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms. Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.
Topics: Humans; Fatigue Syndrome, Chronic; Plasmalogens; Post-Acute COVID-19 Syndrome; COVID-19; Inflammation
PubMed: 37423295
DOI: 10.1016/j.brainresbull.2023.110702 -
European Journal of Preventive... Oct 2023To evaluate the associations of dietary indices and quantitative cardiorespiratory fitness (CRF) measures in a large, community-based sample harnessing metabolomic...
AIMS
To evaluate the associations of dietary indices and quantitative cardiorespiratory fitness (CRF) measures in a large, community-based sample harnessing metabolomic profiling to interrogate shared biology.
METHODS AND RESULTS
Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise tests for CRF quantification (via peak VO2) and completed semi-quantitative food frequency questionnaires. Dietary quality was assessed by the Alternative Healthy Eating Index (AHEI) and Mediterranean-style Diet Score (MDS), and fasting blood concentrations of 201 metabolites were quantified. In 2380 FHS participants (54 ± 9 years, 54% female, body mass index 28 ± 5 kg/m2), 1 SD higher AHEI and MDS were associated with 5.2% (1.2 mL/kg/min, 95% CI 4.3-6.0%, P < 0.0001) and 4.5% (1.0 mL/kg/min, 95% CI 3.6-5.3%, P < 0.0001) greater peak VO2 in linear models adjusted for age, sex, total daily energy intake, cardiovascular risk factors, and physical activity. In participants with metabolite profiling (N = 1154), 24 metabolites were concordantly associated with both dietary indices and peak VO2 in multivariable-adjusted linear models (FDR < 5%). Metabolites that were associated with lower CRF and poorer dietary quality included C6 and C7 carnitines, C16:0 ceramide, and dimethylguanidino valeric acid, and metabolites that were positively associated with higher CRF and favourable dietary quality included C38:7 phosphatidylcholine plasmalogen and C38:7 and C40:7 phosphatidylethanolamine plasmalogens.
CONCLUSION
Higher diet quality is associated with greater CRF cross-sectionally in a middle-aged community-dwelling sample, and metabolites highlight potential shared favourable effects on cardiometabolic health.
Topics: Middle Aged; Humans; Female; Male; Cardiorespiratory Fitness; Health Status; Exercise; Diet, Healthy; Diet, Mediterranean
PubMed: 37164358
DOI: 10.1093/eurjpc/zwad113 -
Innovation (Cambridge (Mass.)) Jan 2023Myelin is a specialized cell membrane indispensable for rapid nerve conduction. The high abundance of membrane lipids is one of myelin's salient features that contribute... (Review)
Review
Myelin is a specialized cell membrane indispensable for rapid nerve conduction. The high abundance of membrane lipids is one of myelin's salient features that contribute to its unique role as an insulator that electrically isolates nerve fibers across their myelinated surface. The most abundant lipids in myelin include cholesterol, glycosphingolipids, and plasmalogens, each playing critical roles in myelin development as well as function. This review serves to summarize the role of lipid metabolism in myelination and myelin maintenance, as well as the molecular determinants of myelin lipid homeostasis, with an emphasis on findings from genetic models. In addition, the implications of myelin lipid dysmetabolism in human diseases are highlighted in the context of hereditary leukodystrophies and neuropathies as well as acquired disorders such as Alzheimer's disease.
PubMed: 36588745
DOI: 10.1016/j.xinn.2022.100360 -
Brain Research Bulletin Jan 2023Neuroinflammation (NF) is defined as the activation of brain glial cells that are found in neurodegenerative diseases including Alzheimer's disease (AD). It has been... (Review)
Review
Neuroinflammation (NF) is defined as the activation of brain glial cells that are found in neurodegenerative diseases including Alzheimer's disease (AD). It has been known that an increase in NF could reduce the memory process in the brain but the key factors, associated with NF, behind the dysregulation of memory remained elusive. We previously reported that the NF and aging processes reduced the special phospholipids, plasmalogens (Pls), in the murine brain by a mechanism dependent on the activation of transcription factors, NF-kB and c-MYC. A similar mechanism has also been found in postmortem human brain tissues with AD pathologies and in the AD model mice. Recent evidence showed that these phospholipids enhanced memory and reduced neuro-inflammation in the murine brain. Pls can stimulate the cellular signaling molecules, ERK and Akt, by activating the membrane-bound G protein-coupled receptors (GPCRs). Therefore, recent findings suggest that plasmalogens could be one of the key phospholipids in the brain to enhance memory and inhibit NF.
Topics: Animals; Mice; Humans; Plasmalogens; Signal Transduction; Alzheimer Disease; Cognition; Brain; NF-kappa B
PubMed: 36347405
DOI: 10.1016/j.brainresbull.2022.11.005 -
Antioxidants (Basel, Switzerland) Jan 2023One of the richest tissues in lipid content and diversity of the human body is the brain. The human brain is constitutively highly vulnerable to oxidative stress. This... (Review)
Review
One of the richest tissues in lipid content and diversity of the human body is the brain. The human brain is constitutively highly vulnerable to oxidative stress. This oxidative stress is a determinant in brain aging, as well as in the onset and progression of sporadic (late-onset) Alzheimer's disease (sAD). Glycerophospholipids are the main lipid category widely distributed in neural cell membranes, with a very significant presence for the ether lipid subclass. Ether lipids have played a key role in the evolution of the human brain compositional specificity and functionality. Ether lipids determine the neural membrane structural and functional properties, membrane trafficking, cell signaling and antioxidant defense mechanisms. Here, we explore the idea that ether lipids actively participate in the pathogenesis of sAD. Firstly, we evaluate the quantitative relevance of ether lipids in the human brain composition, as well as their role in the human brain evolution. Then, we analyze the implications of ether lipids in neural cell physiology, highlighting their inherent antioxidant properties. Finally, we discuss changes in ether lipid content associated with sAD and their physiopathological implications, and propose a mechanism that, as a vicious cycle, explains the potential significance of ether lipids in sAD.
PubMed: 36829852
DOI: 10.3390/antiox12020293 -
Protein & Cell Feb 2018Ether lipids, such as plasmalogens, are peroxisome-derived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached... (Review)
Review
Ether lipids, such as plasmalogens, are peroxisome-derived glycerophospholipids in which the hydrocarbon chain at the sn-1 position of the glycerol backbone is attached by an ether bond, as opposed to an ester bond in the more common diacyl phospholipids. This seemingly simple biochemical change has profound structural and functional implications. Notably, the tendency of ether lipids to form non-lamellar inverted hexagonal structures in model membranes suggests that they have a role in facilitating membrane fusion processes. Ether lipids are also important for the organization and stability of lipid raft microdomains, cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants, and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Here, we review the biology of ether lipids and their potential significance in human disorders, including neurological diseases, cancer, and metabolic disorders.
Topics: Animals; Disease; Ether; Humans; Lipid Metabolism; Lipids
PubMed: 28523433
DOI: 10.1007/s13238-017-0423-5 -
Scientific Reports Feb 2023The underlying mechanisms linking physical activity to better health are not fully understood. Here we examined the associations between physical activity and small...
The underlying mechanisms linking physical activity to better health are not fully understood. Here we examined the associations between physical activity and small circulatory molecules, the metabolome, to highlight relevant biological pathways. We examined plasma metabolites associated with self-reported physical activity among 2217 participants from the Airwave Health Monitoring Study. Metabolic profiling was conducted using the mass spectrometry-based Metabolon platform (LC/GC-MS), measuring 828 known metabolites. We replicated our findings in an independent subset of the study (n = 2971) using untargeted LC-MS. Mendelian randomisation was carried out to investigate potential causal associations between physical activity, body mass index, and metabolites. Higher vigorous physical activity was associated (P < 0.05/828 = 6.03 × 10) with circulatory levels of 28 metabolites adjusted for age, sex and body mass index. The association was inverse for glutamate and diacylglycerol lipids, and direct for 3-4-hydroxyphenyllactate, phenyl lactate (PLA), alpha-hydroxy isovalerate, tiglylcarnitine, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, isobutyrylcarnitine, imidazole lactate, methionine sulfone, indole lactate, plasmalogen lipids, pristanate and fumarate. In the replication panel, we found 23 untargeted LC-MS features annotated to the identified metabolites, for which we found nominal associations with the same direction of effect for three features annotated to 1-(1-enyl-palmitoyl)-2-oleoyl-GPC (P-16:0/18:1), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2), 1-stearoyl-2-dihomo-linolenoyl-GPC (18:0/20:3n3 or 6). Using Mendelian randomisation, we showed a potential causal relationship between body mass index and three identified metabolites. Circulatory metabolites are associated with physical activity and may play a role in mediating its health effects.
Topics: Humans; Metabolome; Metabolomics; Exercise; Fatty Acids; Lactates
PubMed: 36759570
DOI: 10.1038/s41598-022-26377-7