-
Biochimica Et Biophysica Acta Dec 2006Peroxisomal disorders are a group of inherited diseases in man in which either peroxisome biogenesis or one or more peroxisomal functions are impaired. The peroxisomal... (Review)
Review
Peroxisomal disorders are a group of inherited diseases in man in which either peroxisome biogenesis or one or more peroxisomal functions are impaired. The peroxisomal disorders identified to date are usually classified in two groups including: (1) the disorders of peroxisome biogenesis, and (2) the single peroxisomal enzyme deficiencies. This review is focused on the second group of disorders, which currently includes ten different diseases in which the mutant gene affects a protein involved in one of the following peroxisomal functions: (1) ether phospholipid (plasmalogen) biosynthesis; (2) fatty acid beta-oxidation; (3) peroxisomal alpha-oxidation; (4) glyoxylate detoxification, and (5) H2O2 metabolism.
Topics: Fatty Acids; Glyoxylates; Humans; Hydrogen Peroxide; Oxidation-Reduction; Peroxisomal Disorders; Peroxisomes; Plasmalogens
PubMed: 17055078
DOI: 10.1016/j.bbamcr.2006.08.010 -
Nutrients Jul 2022Plasmalogens (Pls) are glycerophospholipids that play critical roles in the brain. Evidence supports the role of diet and that of the gut microbiota in regulating brain...
Plasmalogens (Pls) are glycerophospholipids that play critical roles in the brain. Evidence supports the role of diet and that of the gut microbiota in regulating brain lipids. We investigated the impact of dietary intake of inulin-a soluble fiber used as prebiotic-on the Pl content of the cortex in mice. No global modification in the Pl amounts was observed when evaluated by gas chromatographic analysis of dimethyl acetals (DMAs). However, the analysis of individual molecular species of Pls by liquid chromatography revealed a reduced abundance of major species of ethanolamine Pls (PlsEtn)-PE(P-18:0/22:6) and PE(P-34:1)-in the cortex of mice fed a diet supplemented with inulin. DMA and expression levels of genes (, , and ) encoding key enzymes of Pl biosynthesis or degradation were not altered in the liver and in the cortex of mice exposed to inulin. In addition, the fatty acid profile and the amount of lyso forms derived from PlsEtn were not modified in the cortex by inulin consumption. To conclude, inulin affects the brain levels of major PlsEtn and further investigation is needed to determine the exact molecular mechanisms involved.
Topics: Animals; Brain; Dietary Supplements; Group VI Phospholipases A2; Inulin; Liver; Mice; Plasmalogens
PubMed: 35956273
DOI: 10.3390/nu14153097 -
The Journal of Neuroscience : the... Sep 2019Epidemiological studies suggest that poor nutrition during pregnancy influences offspring predisposition to experience developmental and psychiatric disorders. Animal...
Epidemiological studies suggest that poor nutrition during pregnancy influences offspring predisposition to experience developmental and psychiatric disorders. Animal studies have shown that maternal undernutrition leads to behavioral impairment, which is linked to alterations in monoaminergic systems and inflammation in the brain. In this study, we focused on the ethanolamine plasmalogen of the brain as a possible contributor to behavioral disturbances observed in offspring exposed to maternal undernutrition. Maternal food or protein restriction between gestational day (GD) 5.5 and GD 10.5 resulted in hyperactivity of rat male adult offspring. Genes related to the phospholipid biosynthesis were found to be activated in the PFC, but not in the NAcc or striatum, in the offspring exposed to prenatal undernutrition. Corresponding to these gene activations, increased ethanolamine plasmalogen (18:0p-22:6) was observed in the PFC using mass spectrometry imaging. A high number of crossings and the long time spent in the center area were observed in the offspring exposed to prenatal undernutrition and were mimicked in adult rats via the intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome. Additionally, plasmalogen (18:0p-22:6) increased only in the PFC, and not in the NAcc or striatum. These results suggest that brain plasmalogen is one of the key molecules to control behavior, and its injection using liposome is a potential therapeutic approach for cognitive impairment. Maternal undernutrition correlates to developmental and psychiatric disorders. Here, we found that maternal undernutrition in early pregnancy led to hyperactivity in rat male offspring and induced gene activation of phospholipid-synthesizing enzyme and elevation of ethanolamine plasmalogen (18:0p-22:6) level in the PFC. Intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome maintained crossing activity and the activity was circumscribed to the center area for a long time period, as in prenatally undernourished offspring with aberrant behavior. Furthermore, the amount of ethanolamine plasmalogen (18:0p-22:6) increased in the PFC of the rat after injection. Our result suggests that brain plasmalogen is one of the key molecules to control behavior and that its injection using liposome is a potential therapeutic approach for cognitive impairment.
Topics: Animals; Behavior, Animal; Female; Male; Malnutrition; Plasmalogens; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar
PubMed: 31391260
DOI: 10.1523/JNEUROSCI.2721-18.2019 -
EBioMedicine Sep 2021HIV infection and normal aging share immune and inflammatory changes that result in premature aging and non-communicable diseases (NCDs), but the exact pathophysiology...
BACKGROUND
HIV infection and normal aging share immune and inflammatory changes that result in premature aging and non-communicable diseases (NCDs), but the exact pathophysiology is not yet uncovered. We identified the common metabolic pathways underlying various NCDs in treated HIV infection.
METHODS
We performed untargeted metabolomics including 87 HIV-negative (-) normal controls (NCs), 87 HIV-positive (+) NCs, and 148 HIV+ subjects with only one type of NCDs, namely, subclinical carotid atherosclerosis, neurocognitive impairment (NCI), liver fibrosis (LF) and renal impairment. All HIV+ subjects were virally suppressed.
RESULTS
HIV+ patients presented widespread alterations in cellular metabolism compared to HIV- NCs. Glycerophospholipid (GPL) metabolism was the only one disturbed pathway presented in comparisons including HIV- NCs across age groups, HIV+ NCs across age groups, HIV+ NCs vs HIV- NCs and each of HIV+ NCDs vs HIV+ NCs. D-glutamine and D-glutamate metabolism and alanine-aspartate-glutamate metabolism were presented in comparisons between HIV+ NCs vs HIV- NCs, HIV+ LF or HIV+ NCI vs HIV+ NCs. Consistently, subsequent analysis identified a metabolomic fingerprint specific for HIV+ NCDs, containing 42 metabolites whose relative abundance showed either an upward (mainly GPL-derived lipid mediators) or a downward trend (mainly plasmalogen phosphatidylcholines, plasmalogen phosphatidylethanolamines, and glutamine) from HIV- NCs to HIV+ NCs and then HIV+ NCDs, reflecting a trend of increased oxidative stress.
INTERPRETATION
GPL metabolism emerges as the common metabolic disturbance linking HIV to NCDs, followed by glutamine and glutamate metabolism. Together, our data point to the aforementioned metabolisms and related metabolites as potential key targets in studying pathophysiology of NCDs in HIV infection and developing therapeutic interventions.
FUNDING
China National Science and Technology Major Projects on Infectious Diseases, National Natural Science Foundation of China, Yi-wu Institute of Fudan University, and Shanghai Municipal Health and Family Planning Commission.
Topics: Adolescent; Adult; Aged; Alanine; Aspartic Acid; Atherosclerosis; Cognitive Dysfunction; Female; Glutamic Acid; Glutamine; Glycerophospholipids; HIV Infections; Humans; Liver Cirrhosis; Male; Metabolome; Middle Aged; Plasmalogens; Renal Insufficiency
PubMed: 34419928
DOI: 10.1016/j.ebiom.2021.103548 -
Lipids in Health and Disease May 2020Glycerophospholipids were the main components of cerebral cortex lipids, and there was a close association between lipid homeostasis and human health. It has been...
Recovery of brain DHA-containing phosphatidylserine and ethanolamine plasmalogen after dietary DHA-enriched phosphatidylcholine and phosphatidylserine in SAMP8 mice fed with high-fat diet.
BACKGROUND
Glycerophospholipids were the main components of cerebral cortex lipids, and there was a close association between lipid homeostasis and human health. It has been reported that dietary DHA-enriched phosphatidylcholine (DHA-PC) and phosphatidylserine (DHA-PS) could improve brain function. However, it was unclear that whether supplementation of DHA-PC and DHA-PS could change lipid profiles in the brain of dementia animals.
METHODS
SAMP8 mice was fed with different diet patterns for 2 months, including high-fat diet and low-fat diet. After intervention with DHA-PC and DHA-PS for another 2 months, the lipid profile in cerebral cortex was determined by lipidomics in dementia mice.
RESULTS
High-fat diet could significantly decrease the levels of DHA-containing PS/pPE, DPA-containing PS, and AA-containing PE, which might exhibit the potential of lipid biomarkers for the prevention and diagnosis of AD. Notably, DHA-PC and DHA-PS remarkably recovered the lipid homeostasis in dementia mice. These might provide a potential novel therapy strategy and direction of dietary intervention for patients with cognitive decline.
CONCLUSIONS
DHA-PC and DHA-PS could recover the content of brain DHA-containing PS and pPE in SAMP8 mice fed with high-fat diet.
Topics: Alzheimer Disease; Animals; Cerebral Cortex; Diet, High-Fat; Disease Models, Animal; Docosahexaenoic Acids; Lipidomics; Male; Mice; Phosphatidylcholines; Phosphatidylserines; Plasmalogens
PubMed: 32450867
DOI: 10.1186/s12944-020-01253-3 -
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 -
Biomolecules Nov 2021Vitamin D hypovitaminosis is associated with several neurological diseases such as Alzheimer's disease, Parkinson's disease or multiple sclerosis but also with other...
Impact of Vitamin D Deficiency on Phosphatidylcholine-/Ethanolamine, Plasmalogen-, Lyso-Phosphatidylcholine-/Ethanolamine, Carnitine- and Triacyl Glyceride-Homeostasis in Neuroblastoma Cells and Murine Brain.
Vitamin D hypovitaminosis is associated with several neurological diseases such as Alzheimer's disease, Parkinson's disease or multiple sclerosis but also with other diseases such as cancer, diabetes or diseases linked to inflammatory processes. Importantly, in all of these diseases lipids have at least a disease modifying effect. Besides its well-known property to modulate gene-expression via the VDR-receptor, less is known if vitamin D hypovitaminosis influences lipid homeostasis and if these potential changes contribute to the pathology of the diseases themselves. Therefore, we analyzed mouse brain with a mild vitamin D hypovitaminosis via a targeted shotgun lipidomic approach, including phosphatidylcholine, plasmalogens, lyso-phosphatidylcholine, (acyl-/acetyl-) carnitines and triglycerides. Alterations were compared with neuroblastoma cells cultivated in the presence and with decreased levels of vitamin D. Both in cell culture and in vivo, decreased vitamin D level resulted in changed lipid levels. While triglycerides were decreased, carnitines were increased under vitamin D hypovitaminosis suggesting an impact of vitamin D on energy metabolism. Additionally, lyso-phosphatidylcholines in particular saturated phosphatidylcholine (e.g., PC aa 48:0) and plasmalogen species (e.g., PC ae 42:0) tended to be increased. Our results suggest that vitamin D hypovitaminosis not only may affect gene expression but also may directly influence cellular lipid homeostasis and affect lipid turnover in disease states that are known for vitamin D hypovitaminosis.
Topics: Animals; Carnitine; Cholecalciferol; Ethanolamine; Mice; Plasmalogens
PubMed: 34827697
DOI: 10.3390/biom11111699 -
Frontiers in Cell and Developmental... 2022Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisome biogenesis disorder caused by defects in leading to impairment in plasmalogen (Pls) biosynthesis and...
A Deficient Mouse Series Correlates Biochemical and Neurobehavioral Markers to Genotype Severity-Implications for the Disease Spectrum of Rhizomelic Chondrodysplasia Punctata Type 1.
Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisome biogenesis disorder caused by defects in leading to impairment in plasmalogen (Pls) biosynthesis and phytanic acid (PA) oxidation. Pls deficiency is the main pathogenic factor that determines the severity of RCDP. Severe (classic) RCDP patients have negligible Pls levels, congenital cataracts, skeletal dysplasia, growth and neurodevelopmental deficits, and cerebral hypomyelination and cerebellar atrophy on brain MRI. Individuals with milder or nonclassic RCDP have higher Pls levels, better growth and cognitive outcomes. To better understand the pathophysiology of RCDP disorders, we generated an allelic series of mice either homozygous for the hypomorphic allele, compound heterozygous for the hypomorphic and null alleles or homozygous for the null allele. Pex7 transcript and protein were almost undetectable in the hypomorphic model, and negligible in the compound heterozygous and null mice. deficient mice showed a graded reduction in Pls and increases in C26:0-LPC and PA in plasma and brain according to genotype. Neuropathological evaluation showed significant loss of cerebellar Purkinje cells over time and a decrease in brain myelin basic protein (MBP) content in deficient models, with more severe effects correlating with genotype. All deficient mice exhibited a hyperactive behavior in the open field environment. Brain neurotransmitters analysis of deficient mice showed a significant reduction in levels of dopamine, norepinephrine, serotonin and GABA. Also, a significant correlation was found between brain neurotransmitter levels, the hyperactivity phenotype, Pls level and the severity of genotype. In conclusion, our study showed evidence of a genotype-phenotype correlation between the severity of deficiency and several clinical and neurobiochemical phenotypes in RCDP1 mouse models. We propose that PA accumulation may underlie the cerebellar atrophy seen in older RCDP1 patients, as even relatively low tissue levels were strongly associated with Purkinje cells loss over time in the murine models. Also, our data demonstrate the interrelation between Pls, brain neurotransmitter deficiencies and the neurobehavioral phenotype, which could be further used as a valuable clinical endpoint for therapeutic interventions. Finally, these models show that incremental increases in levels result in dramatic improvements in phenotype.
PubMed: 35898397
DOI: 10.3389/fcell.2022.886316 -
The Biochemical Journal Jan 1991Studies with mammalian cell lines have led to suggestions that mammalian tissues may derive all of their phosphatidylethanolamine (PE) from the decarboxylation of...
Studies with mammalian cell lines have led to suggestions that mammalian tissues may derive all of their phosphatidylethanolamine (PE) from the decarboxylation of phosphatidylserine (PS), and also that the physiological significance of the CDP-ethanolamine pathway was the synthesis of ethanolamine plasmalogen. We have therefore investigated the biosynthesis of PE and ethanolamine plasmalogen via the CDP-ethanolamine and decarboxylation pathways in vivo in three rat tissues (heart, kidney and liver), which differ in ethanolamine plasmalogen content. In all three tissues [14C]ethanolamine was incorporated into both PE and ethanolamine plasmalogen, whereas [3H]serine was incorporated into only PS and PE fractions. When [14C]ethanolamine was introduced into the animals, the specific radioactivity of ethanolamine plasmalogen in the kidney was always greater than that of the PE fraction; in the heart the specific radioactivity of the ethanolamine plasmalogen fraction was similar to that of the PE fraction, whereas in the liver the specific radioactivity of the PE fraction was always greater than that of the ethanolamine plasmalogen fraction. The results obtained in this study indicate that: (1) the CDP-ethanolamine pathway is utilized for the synthesis of both PE and ethanolamine plasmalogen in all three tissues; (2) the decarboxylation pathway is utilized solely for the synthesis of PE; (3) serine plasmalogens are not formed by base-exchange reactions; (4) the relative utilization of the CDP-ethanolamine pathway for the synthesis of PE and ethanolamine plasmalogen varies among tissues. Our studies also revealed that the hypolipidaemic drug MDL 29350 is a potent inhibitor of PE N-methyltransferase activity in vitro and in vivo.
Topics: Animals; Caproates; Carboxy-Lyases; Cytidine Diphosphate; Ethanolamines; Hydrolysis; Kidney; Methyltransferases; Microsomes, Liver; Myocardium; Phosphatidylethanolamine N-Methyltransferase; Phosphatidylethanolamines; Plasmalogens; Rats; Type C Phospholipases
PubMed: 1989575
DOI: 10.1042/bj2730121 -
PloS One 2016Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased plasmalogens are reported in the brain and...
Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased plasmalogens are reported in the brain and blood of Parkinson's disease (PD) patients. The present study investigated the hypothesis that augmenting plasmalogens could protect striatal dopamine neurons that degenerate in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice, a PD model. First, in a pre-treatment experiment male mice were treated for 10 days with the docosahexaenoic acid (DHA)-plasmalogen precursor PPI-1011 (10, 50 and 200 mg/kg). On day 5 mice received MPTP and were killed on day 11. Next, in a post-treatment study, male mice were treated with MPTP and then received daily for 5 days PPI-1011 (5, 10 and 50 mg/kg). MPTP treatment reduced serum plasmalogen levels, striatal contents of dopamine (DA) and its metabolites, serotonin, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). Pre-treatment with PPI-1011 (10 and 50 mg/kg) prevented all MPTP-induced effects. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding. Post-treatment with PPI-1011 prevented all MPTP-induced effects at 50 mg/kg but not at lower doses. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding in the post-treatment experiment. PPI-1011 treatment (10 days at 5, 10 and 50 mg/kg) of intact mice left unchanged striatal biogenic amine contents. These data demonstrate that treatment with a plasmalogen precursor is capable of protecting striatal dopamine markers in an animal model of PD.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Disease Models, Animal; Docosahexaenoic Acids; Dopamine; Dopamine Plasma Membrane Transport Proteins; Male; Mice; Mice, Inbred C57BL; Parkinson Disease; Plasmalogens; Vesicular Monoamine Transport Proteins
PubMed: 26959819
DOI: 10.1371/journal.pone.0151020