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Redox Biology Jul 2021Emerging evidence suggests that the reduction of ethanolamine plasmalogen (PlsEtn) is associated with in Alzheimer's disease and metabolic diseases. However, the...
Emerging evidence suggests that the reduction of ethanolamine plasmalogen (PlsEtn) is associated with in Alzheimer's disease and metabolic diseases. However, the mechanistic bases for PlsEtn on the these diseases are not well understood. Plasmalogens are primarily synthesized in the liver and enriched in brain. To this end, the present study sought to investigate the potential role of PlsEtn on steatohepatitis and memory impairments and its underlying mechanism. Here we show that peroxisome dysfunction and impairment of PlsEtn synthesis pathway occurs in both of hippocampus and liver, resulting in the decrease of PlsEtn level in APP/PS1 mice and HFD-fed mice. shGNPAT induced PlsEtn deficiency in hepatocytes induces p75NTR enhancement leading to decreased lipolysis activity, thereby exacerbating steatosis. Moreover, in the brain, PlsEtn administration appears to not only improve steatosis but also prevent Alzheimer's disease through restoration of TrkA/p75NTR balance. Together, our findings reveal a molecular mechanistic insight into the preventive role of plasmalogen modulation against steatosis and memory impairments via p75NTR inhibition.
Topics: Alzheimer Disease; Animals; Cognition; Cognitive Dysfunction; Fatty Liver; Mice; Plasmalogens
PubMed: 33984602
DOI: 10.1016/j.redox.2021.102002 -
Journal of Nutritional Science and... 2022Plasmalogen, a phospholipid, exhibits preventive and therapeutic effects on dementia. Phospholipids improve fat metabolism, but it is unknown whether plasmalogen has an...
Plasmalogen, a phospholipid, exhibits preventive and therapeutic effects on dementia. Phospholipids improve fat metabolism, but it is unknown whether plasmalogen has an effect on fat metabolism. In this study, the effects of plasmalogen were determined by administering plasmalogen to KK-Ay mice. As a result, weight gain was significantly suppressed in the plasmalogen-treated group compared with the control group from 7 wk after the start of administration. In addition, plasmalogen administration increased uncoupling protein 1 (UCP1) expression in brown adipose tissue. The effect is thought to result from liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/PR domain containing 16 (PRDM16)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway activation via adrenergic β3 receptors. Furthermore, the expression of the carnitine palmitoyltransferase-1 (CPT-1) gene associated with thermogenic factors and β-oxidation was increased. We investigated the browning of white adipose tissue, but no increase in UCP1 gene expression was observed in perirenal adipose tissue, epididymis adipose tissue, mesenteric adipose tissue and inguinal region white adipose tissue. In contrast, plasmalogen increased the activity of AMPK, which is a central enzyme in lipid metabolism, in perirenal adipose tissue. Furthermore, the activity of the protein kinase A (PKA)/LKB1/AMPK/acetyl-coenzyme A carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD-1), and hormone-sensitive lipase (HSL) pathways was confirmed. Plasmalogen may inhibit weight gain by activating brown fat to increase heat production, inhibiting lipid synthesis, and promoting lipolysis in white fat.
Topics: AMP-Activated Protein Kinases; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Male; Mice; Plasmalogens; Uncoupling Protein 1; Weight Gain
PubMed: 35491205
DOI: 10.3177/jnsv.68.140 -
Redox Biology Apr 2021Glucokinase-maturity onset diabetes of the young (GCK-MODY) represents a rare genetic disorder due to mutation in the glucokinase (GCK) gene. The low incidence of...
Glucokinase-maturity onset diabetes of the young (GCK-MODY) represents a rare genetic disorder due to mutation in the glucokinase (GCK) gene. The low incidence of vascular complications in GCK-MODY makes it a natural paradigm for interrogating molecular mechanisms promoting vascular health under prolonged hyperglycemia. Clinical rate of misdiagnosis has remained high, and a reliable serum lipid biomarker that precedes genetic screening can facilitate correct diagnosis and treatment. Herein, we comprehensively quantitated 565 serum lipids from 25 classes in 105 subjects (42 nondiabetic controls, 30 GC K-MODY patients, 33 drug-naïve, and newly-onset T2D patients). At false-discovery rate (FDR) < 0.05, several phosphatidylcholines (PCs) and plasmalogen PCs were specifically increased in GCK-MODY, while triacylglycerols (TAGs) and diacylglycerols (DAGs) were reduced. Correlation matrices between lipids uncovered coregulation between plasmalogen PCs (PCps) and glycerolipid precursors was distinctly enhanced in GCK-MODY compared to T2D. Strengthened positive correlations between serum PCps and circulating HDLs was specifically observed in hyperglycemic subjects (i.e. T2D and GCK-MODY) compared to normglycemic controls, suggesting that HDL-PCps may elicit distinct physiological effects under hyperglycemia. Amongst GCK-MODY patients, individuals harboring variants of GCK mutations with elevated PCps also exhibited higher HDLs. Isolated HDLs displayed localized increases (p < 0.05) in very-long-chain PUFA-PCs and PCps in GCK-MODY. Protein analyses revealed elevated levels of HDL-resident ATGL (P = 0.003) and CEPT1 (P < 0.0001), which mediate critical steps of PCps production along the TAG-DAG-PC axis, in GCK-MODY relative to T2D. A panel of four lipids differentiated GCK-MODY from T2D with AUC of 0.950 (95% CI 0.903-9.997). This study provides the first evidence that enhanced recruitment of CEPT1 and ATGL onto HDLs essentially underlie the atheroprotective profiles associated with GCK-MODY. Resultant increases in the production of HDL-PCps and PUFA-PCs provides an active, circulating form of protection towards the vasculature of GCK-MODY, thereby lowering the incidence of vascular complications despite chronic exposure to hyperglycemia since birth.
Topics: Diabetes Mellitus, Type 2; Glucokinase; Humans; Mutation; Phosphatidylcholines; Plasmalogens
PubMed: 33450726
DOI: 10.1016/j.redox.2021.101855 -
Cell Reports. Medicine Oct 2021Obesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of...
Obesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodeling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodeling at the molecular level, we provide in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. We generate a human WAT reference lipidome by performing tissue-tailored preanalytical and analytical workflows, which allow accurate identification and semi-absolute quantification of 1,636 and 737 lipid molecular species, respectively. Deep lipidomic profiling allows identification of main lipid (sub)classes undergoing depot-/phenotype-specific remodeling. Previously unanticipated diversity of WAT ceramides is now uncovered. reference lipidome serves as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.
Topics: Adipose Tissue, White; Aged; Calibration; Ceramides; Chemical Fractionation; Ethanolamines; Fatty Acids, Unsaturated; Female; Humans; Lipidomics; Lipids; Male; Middle Aged; Phenotype; Plasmalogens; Triglycerides; Up-Regulation
PubMed: 34755127
DOI: 10.1016/j.xcrm.2021.100407 -
Investigative Ophthalmology & Visual... Aug 2022The etiology of exfoliation glaucoma (XFG) is poorly understood. We aimed to identify a prediagnostic plasma metabolomic signature associated with XFG.
PURPOSE
The etiology of exfoliation glaucoma (XFG) is poorly understood. We aimed to identify a prediagnostic plasma metabolomic signature associated with XFG.
METHODS
We conducted a 1:1 matched case-control study nested within the Nurses' Health Study and Health Professionals Follow-up Study. We collected blood samples in 1989-1990 (Nurses' Health Study) and 1993-1995 (Health Professionals Follow-up Study). We identified 205 incident XFG cases through 2016 (average time to diagnosis from blood draw = 11.8 years) who self-reported glaucoma and were confirmed as XFG cases with medical records. We profiled plasma metabolites using liquid chromatography-mass spectrometry. We evaluated 379 known metabolites (transformed for normality using probit scores) using multiple conditional logistic models. Metabolite set enrichment analysis was used to identify metabolite classes associated with XFG. To adjust for multiple comparisons, we used number of effective tests (NEF) and the false discovery rate (FDR).
RESULTS
Mean age of cases (n = 205) at diagnosis was 71 years; 85% were women and more than 99% were Caucasian; controls (n = 205) reported eye examinations as of the matched cases' index date. Thirty-three metabolites were nominally significantly associated with XFG (P < 0.05), and 4 metabolite classes were FDR-significantly associated. We observed positive associations for lysophosphatidylcholines (FDR = 0.02) and phosphatidylethanolamine plasmalogens (FDR = 0.004) and inverse associations for triacylglycerols (FDR < 0.0001) and steroids (FDR = 0.03). In particular, the multivariable-adjusted odds ratio with each 1 standard deviation higher plasma cortisone levels was 0.49 (95% confidence interval, 0.32-0.74; NEF = 0.05).
CONCLUSIONS
In plasma from a decade before diagnosis, lysophosphatidylcholines and phosphatidylethanolamine plasmalogens were positively associated and triacylglycerols and steroids (e.g., cortisone) were inversely associated with XFG risk.
Topics: Aged; Case-Control Studies; Cortisone; Exfoliation Syndrome; Female; Follow-Up Studies; Humans; Lysophosphatidylcholines; Male; Metabolomics; Phosphatidylethanolamines; Plasmalogens; Triglycerides
PubMed: 35951322
DOI: 10.1167/iovs.63.9.15 -
Psychiatry and Clinical Neurosciences Mar 2020Ethanolamine-containing phospholipids are synthesized in endoplasmic reticulum (ER) and mitochondria. ER stress and mitochondrial dysfunction have been implicated in...
AIM
Ethanolamine-containing phospholipids are synthesized in endoplasmic reticulum (ER) and mitochondria. ER stress and mitochondrial dysfunction have been implicated in bipolar disorder (BP). In this study, we aimed to examine the relationship of ethanolamine plasmalogen (PLE) and phosphatidylethanolamine (PTE) levels in blood plasma with BP.
METHODS
Plasma PLE and PTE levels were compared between 34 patients with BP (DSM-IV) and 38 healthy control participants matched for age, sex, and ethnicity (Japanese). Furthermore, the relationships of plasma PLE and PTE levels with clinical variables were explored.
RESULTS
Plasma PLE levels were significantly lower in patients with BP than in healthy controls (P = 0.0033). In subgroup analyses, plasma PLE levels were significantly lower in patients with BP type I (BP I) than in healthy controls (P = 0.0047); furthermore, plasma PTE levels were significantly lower in patients with BP I than in controls (P = 0.016) and patients with BP type II (BP II) (P = 0.010). Receiver-operating characteristic curve analysis revealed that the discriminatory power of plasma PTE levels for distinguishing between BP I and II was fair (area under the curve = 0.78; P = 0.0095). There were no significant correlations of plasma PLE or PTE levels with depression or manic symptoms in patients.
CONCLUSIONS
Plasma PLE and PTE levels were associated with BP I, but not with BP II. Moreover, plasma PTE levels differed between patients with BP I and II. Our findings highlight the importance of ethanolamine phospholipids in the pathophysiology of BP, especially BP I.
Topics: Adult; Bipolar Disorder; Endoplasmic Reticulum Stress; Female; Humans; Male; Middle Aged; Mitochondrial Diseases; Phosphatidylethanolamines; Plasmalogens
PubMed: 31841251
DOI: 10.1111/pcn.12967 -
Archives of Biochemistry and Biophysics Mar 2018Myeloperoxidase produces the two-electron oxidant HOCl, which targets plasmalogen phospholipids liberating 2-chlorofatty aldehyde. 2-Chlorofatty aldehyde has four known... (Review)
Review
Myeloperoxidase produces the two-electron oxidant HOCl, which targets plasmalogen phospholipids liberating 2-chlorofatty aldehyde. 2-Chlorofatty aldehyde has four known fates: 1) oxidation to 2-chlorofatty acid; 2) reduction to 2-chlorofatty alcohol; 3) Schiff base adduct formation with proteins and amines; and 4) reactivity with glutathione through nucleophilic attack of the α-chlorinated carbon. 2-Chlorofatty acid does not undergo conventional fatty acid β-oxidation due to the presence of the α-chlorinated carbon; however, 2-chlorofatty acid does undergo sequential ω-oxidation and β-oxidation from the ω-end, ultimately resulting in 2-chloroadipic acid urinary excretion. Recent studies have demonstrated that 2-chlorofatty acid clearance is increased by treatment with the PPAR-α agonist WY14643, which increases the enzymatic machinery responsible for hepatic ω-oxidation. Furthermore, 2-chlorofatty acid has been shown to be a PPAR-α agonist, and thus accelerates its own clearance. The roles of 2-chlorofatty aldehyde and 2-chlorofatty acid on leukocyte and endothelial function have been explored by several groups, suggesting that chlorinated lipids induce endothelial cell dysfunction, neutrophil chemotaxis, monocyte apoptosis, and alterations in vascular tone. Thus, the chlorinated lipidome, produced in response to leukocyte activation, is a potential biomarker and therapeutic target to modulate host response in inflammatory diseases.
Topics: Aldehydes; Animals; Biomarkers; Chlorine; Disease; Esterification; Fatty Acids, Nonesterified; Halogenation; Humans; Hypochlorous Acid; Lipid Metabolism; Neutrophils; Oxidation-Reduction; PPAR alpha; Peroxidase; Plasmalogens
PubMed: 29378164
DOI: 10.1016/j.abb.2018.01.010 -
EBioMedicine Mar 2017Plasmalogens (Pls) reportedly decreased in postmortem brain and in the blood of patients with Alzheimer's disease (AD). Recently we showed that intraperitoneal... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and Blood Plasmalogen Changes by Oral Administration of Plasmalogen in Patients with Mild Alzheimer's Disease and Mild Cognitive Impairment: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial.
BACKGROUND
Plasmalogens (Pls) reportedly decreased in postmortem brain and in the blood of patients with Alzheimer's disease (AD). Recently we showed that intraperitoneal administration of Pls improved cognitive function in experimental animals. In the present trial, we tested the efficacy of oral administration of scallop-derived purified Pls with respect to cognitive function and blood Pls changes in patients with mild AD and mild cognitive impairment (MCI).
METHODS
The study was a multicenter, randomized, double-blind, placebo-controlled trial of 24weeks. Participants were 328 patients aged 60 to 85years who had 20 to 27 points in Mini Mental State Examination-Japanese (MMSE-J) score and five or less points in Geriatric Depression Scale-Short Version-Japanese (GDS-S-J). They were randomized to receive either 1mg/day of Pls purified from scallop or placebo. The patients and study physicians were masked to the assignment. The primary outcome was MMSE-J. The secondary outcomes included Wechsler Memory Scale-Revised (WMS-R), GDS-S-J and concentration of phosphatidyl ethanolamine plasmalogens (PlsPE) in erythrocyte membrane and plasma. This trial is registered with the University Hospital Medical Information Network, number UMIN000014945.
FINDINGS
Of 328 patients enrolled, 276 patients completed the trial (140 in the treatment group and 136 in the placebo group). In an intention-to-treat analysis including both mild AD (20≤MMSE-J≤23) and MCI (24≤MMSE-J≤27), no significant difference was shown between the treatment and placebo groups in the primary and secondary outcomes, with no severe adverse events in either group. In mild AD patients, WMS-R improved significantly in the treatment group, and the between group difference was nearly significant (P=0.067). In a subgroup analysis of mild AD patients, WMS-R significantly improved among females and those aged below 77years in the treatment group, and the between-group differences were statistically significant in females (P=0.017) and in those aged below 77years (P=0.029). Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group.
INTERPRETATION
Oral administration of scallop-derived purified Pls may improve cognitive functions of mild AD.
FUNDING
The Japanese Plasmalogen Society.
Topics: Administration, Oral; Aged; Aged, 80 and over; Alzheimer Disease; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Plasmalogens
PubMed: 28259590
DOI: 10.1016/j.ebiom.2017.02.012 -
Frontiers in Immunology 2018Macrophages, as professional phagocytes of the immune system, possess the ability to detect and clear invading pathogens and apoptotic cells through phagocytosis....
Macrophages, as professional phagocytes of the immune system, possess the ability to detect and clear invading pathogens and apoptotic cells through phagocytosis. Phagocytosis involves membrane reorganization and remodeling events on the cell surface, which play an essential role in innate immunity and tissue homeostasis and the control of inflammation. In this work, we report that cells deficient in membrane ethanolamine plasmalogen demonstrate a reduced capacity to phagocytize opsonized zymosan particles. Amelioration of plasmalogen deficiency in these cells by incubation with lysoplasmalogen results in a significant augmentation of the phagocytic capacity of the cells. In parallel with these increases, restoration of plasmalogen levels in the cells also increases the number and size of lipid rafts in the membrane, reduces membrane fluidity down to levels found in cells containing normal plasmalogen levels, and improves receptor-mediated signaling. Collectively, these results suggest that membrane plasmalogen level determines characteristics of the plasma membrane such as fluidity and the formation of microdomains that are necessary for efficient signal transduction leading to optimal phagocytosis by macrophages.
PubMed: 30087680
DOI: 10.3389/fimmu.2018.01723 -
Brain Pathology (Zurich, Switzerland) Sep 2019Plasmalogens are the most abundant form of ether phospholipids in myelin and their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP), a severe developmental...
Plasmalogens are the most abundant form of ether phospholipids in myelin and their deficiency causes Rhizomelic Chondrodysplasia Punctata (RCDP), a severe developmental disorder. Using the Gnpat-knockout (KO) mouse as a model of RCDP, we determined the consequences of a plasmalogen deficiency during myelination and myelin homeostasis in the central nervous system (CNS). We unraveled that the lack of plasmalogens causes a generalized hypomyelination in several CNS regions including the optic nerve, corpus callosum and spinal cord. The defect in myelin content evolved to a progressive demyelination concomitant with generalized astrocytosis and white matter-selective microgliosis. Oligodendrocyte precursor cells (OPC) and mature oligodendrocytes were abundant in the CNS of Gnpat KO mice during the active period of demyelination. Axonal loss was minimal in plasmalogen-deficient mice, although axonal damage was observed in spinal cords from aged Gnpat KO mice. Characterization of the plasmalogen-deficient myelin identified myelin basic protein and septin 7 as early markers of dysmyelination, whereas myelin-associated glycoprotein was associated with the active demyelination phase. Using in vitro myelination assays, we unraveled that the intrinsic capacity of oligodendrocytes to ensheath and initiate membrane wrapping requires plasmalogens. The defect in plasmalogens was rescued with glyceryl 1-myristyl ether [1-O-tetradecyl glycerol (1-O-TDG)], a novel alternative precursor in the plasmalogen biosynthesis pathway. 1-O-TDG treatment rescued myelination in plasmalogen-deficient oligodendrocytes and in mutant mice. Our results demonstrate the importance of plasmalogens for oligodendrocyte function and myelin assembly, and identified a novel strategy to promote myelination in nervous tissue.
Topics: Animals; Axons; Central Nervous System; Chondrodysplasia Punctata, Rhizomelic; Demyelinating Diseases; Disease Models, Animal; Glyceryl Ethers; Leukodystrophy, Metachromatic; Mice; Mice, Knockout; Myelin Sheath; Oligodendroglia; Peroxisomes; Plasmalogens; Spinal Cord
PubMed: 30667116
DOI: 10.1111/bpa.12710