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Biology Direct Feb 2024Peroxisomes are primarily studied in the brain, kidney, and liver due to the conspicuous tissue-specific pathology of peroxisomal biogenesis disorders. In contrast,... (Meta-Analysis)
Meta-Analysis
Peroxisomes are primarily studied in the brain, kidney, and liver due to the conspicuous tissue-specific pathology of peroxisomal biogenesis disorders. In contrast, little is known about the role of peroxisomes in other tissues such as the heart. In this meta-analysis, we explore mitochondrial and peroxisomal gene expression on RNA and protein levels in the brain, heart, kidney, and liver, focusing on lipid metabolism. Further, we evaluate a potential developmental and heart region-dependent specificity of our gene set. We find marginal expression of the enzymes for peroxisomal fatty acid oxidation in cardiac tissue in comparison to the liver or cardiac mitochondrial β-oxidation. However, the expression of peroxisome biogenesis proteins in the heart is similar to other tissues despite low levels of peroxisomal fatty acid oxidation. Strikingly, peroxisomal targeting signal type 2-containing factors and plasmalogen biosynthesis appear to play a fundamental role in explaining the essential protective and supporting functions of cardiac peroxisomes.
Topics: Humans; Peroxisomes; Fatty Acids; Peroxisomal Disorders; Mitochondria; Oxidation-Reduction
PubMed: 38365851
DOI: 10.1186/s13062-024-00458-1 -
Metabolites Aug 2023Physical activity (PA) is known to have beneficial effects on health, primarily through its antioxidative stress properties. However, the specific metabolic pathways...
Physical activity (PA) is known to have beneficial effects on health, primarily through its antioxidative stress properties. However, the specific metabolic pathways that underlie these effects are not fully understood. This study aimed to investigate the metabolic pathways that are involved in the protective effects of moderate PA in non-obese and healthy individuals. Data on 305 young, non-obese participants were obtained from the Qatar Biobank. The participants were classified as active or sedentary based on their self-reported PA levels. Plasma metabolomics data were collected and analyzed to identify differences in metabolic pathways between the two groups. The results showed that active participants had increased activation of antioxidative, stress-related pathways, including lysoplasmalogen, plasmalogen, phosphatidylcholine, vitamin A, and glutathione. Additionally, there were significant associations between glutathione metabolites and certain clinical traits, including bilirubin, uric acid, hemoglobin, and iron. This study provides new insights into the metabolic pathways that are involved in the protective effects of moderate PA in non-obese and healthy individuals. The findings may have implications for the development of new therapeutic strategies that target these pathways.
PubMed: 37755253
DOI: 10.3390/metabo13090973 -
International Journal of Molecular... Jul 2023Parkinson's-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although...
Parkinson's-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient's quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD; however, its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine are the metabolites that significantly discriminate parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, the biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, the glucose-alanine cycle, glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation.
Topics: Rats; Animals; Parkinson Disease; Oxidopamine; Neurodegenerative Diseases; Quality of Life; Alanine
PubMed: 37569578
DOI: 10.3390/ijms241512202 -
Aging and Disease Oct 2023Aberrant lipid metabolism has been strongly linked to Alzheimer's disease (AD) pathogenesis. However, the role of lipids in the pathophysiological processes of AD and...
Aberrant lipid metabolism has been strongly linked to Alzheimer's disease (AD) pathogenesis. However, the role of lipids in the pathophysiological processes of AD and their clinical progression is unclear. We hypothesized that plasma lipids are associated with the pathological hallmarks of AD, progression from mild cognitive impairment (MCI) to AD, and the rate of cognitive decline in MCI patients. To evaluate our hypotheses, we analysed the plasma lipidome profile by liquid chromatography coupled to mass spectrometry in an LC-ESI-QTOF-MS/MS platform for 213 subjects recruited consecutively: 104 AD, 89 MCI, and 20 control subjects. Forty-seven (52.8%) MCI patients progressed to AD during follow-up (58 ± 12.5 months). We found that higher plasma levels of sphingomyelin SM(36:0) and diglyceride DG(44:3) were associated with an increased risk of amyloid beta 42 (Aβ42) positivity in CSF, while levels of SM(40:1) were associated with a reduced risk. Higher plasma levels of ether-linked triglyceride TG(O-60:10) were negatively associated with pathological levels of phosphorylated tau in CSF. Plasma levels of fatty acid ester of hydroxy fatty acid FAHFA(34:0) and ether-linked phosphatidylcholine PC(O-36:1) were positively associated with pathological levels of total tau in CSF. Regarding the plasma lipids most associated with progression from MCI to AD, our analysis detected phosphatidyl-ethanolamine plasmalogen PE(P-36:4), TG(59:12), TG(46:0), and TG(O-62:7). Furthermore, TG(O-62:7) was the lipid that was most strongly associated with the rate of progression. In conclusion, our results indicate that neutral and ether-linked lipids are involved in the pathophysiological processes of AD and the progression from MCI to AD dementia, suggesting the involvement of lipid-mediated antioxidant mechanisms in AD.
PubMed: 37196122
DOI: 10.14336/AD.2023.0221 -
Molecular Metabolism Apr 2024Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting...
OBJECTIVE
Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here we investigated the effect of adipose-specific inactivation of the peroxisomal lipid synthetic protein PexRAP on fatty acid synthase (FASN)-mediated lipogenesis and its impact on adiposity and metabolic homeostasis.
METHODS
To explore the role of PexRAP in adipose tissue, we metabolically phenotyped mice with adipose-specific knockout of PexRAP. Bulk RNA sequencing was used to determine transcriptomic responses to PexRAP deletion and C-malonyl CoA allowed us to measure de novo lipogenic activity in adipose tissue of these mice. In vitro cell culture models were used to elucidate the mechanism of cellular responses to PexRAP deletion.
RESULTS
Adipose-specific PexRAP deletion promoted diet-induced obesity and insulin resistance through activation of de novo lipogenesis. Mechanistically, PexRAP inactivation inhibited the flux of carbons to ethanolamine plasmalogens. This increased the nuclear PC/PE ratio and promoted cholesterol mislocalization, resulting in activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation led to increased expression of the phospholipid remodeling enzyme LPCAT3 and induced FASN-mediated lipogenesis, which promoted diet-induced obesity and insulin resistance.
CONCLUSIONS
These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.
Topics: Animals; Mice; 1-Acylglycerophosphocholine O-Acyltransferase; Adipose Tissue; Cholesterol; Dietary Fats; Insulin Resistance; Lipogenesis; Liver X Receptors; Mice, Knockout; Obesity
PubMed: 38458567
DOI: 10.1016/j.molmet.2024.101913 -
Redox Biochemistry and Chemistry Dec 2023Myeloperoxidase and eosinophil peroxidase exert their antimicrobial functions through the oxidative actions of their hypohalous acid products. Plasmalogen phospholipids...
Myeloperoxidase and eosinophil peroxidase exert their antimicrobial functions through the oxidative actions of their hypohalous acid products. Plasmalogen phospholipids are particularly susceptible to oxidation of their vinyl ether functional group by hypohalous acids. This produces a family of halogenated lipid products with pro-inflammatory roles and potential biomarker utility. The initial product of plasmalogen oxidation by HOCl is 2-chlorofatty aldehyde, which has been shown to play a key role at the blood-endothelium interface. and studies indicate increased endothelial barrier permeability, neutrophil chemotaxis, neutrophil and platelet adherence to endothelium, and promotion of erythrocyte lysis as some of its effects. These effects may be due to protein modification by 2-chlorofatty aldehyde. 2-Chlorofatty aldehyde is metabolized by host dehydrogenases to 2-chlorofatty acid. While it is less chemically reactive, 2-chlorofatty acid has partial overlap of pro-inflammatory effects with 2-chlorofatty aldehyde and unique actions such as induction of neutrophil extracellular trap formation. The stability of 2-chlorofatty acid in plasma also makes it well-suited as a biomarker of HOCl generation, and its plasma levels may be predictive of disease outcomes. 2-Bromofatty aldehydes and acids are produced analogously from HOBr reaction with plasmalogens. Their functions have yet to be well-elucidated, though similarities with chlorolipids have been observed, and increased reactivity with proteins is expected through enhanced electrophilicity of the alpha carbon. Altogether, these halogenated lipids represent underexplored mediators of diseases involving excess hypohalous acid production.
PubMed: 38073668
DOI: 10.1016/j.rbc.2023.100011 -
Inflammation Aug 2023Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and...
Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools.
Topics: Humans; Synovial Fluid; Synovial Membrane; Arthritis, Rheumatoid; Osteoarthritis; Anti-Inflammatory Agents; Fatty Acids; Fatty Acids, Unsaturated
PubMed: 37140681
DOI: 10.1007/s10753-023-01816-3 -
International Journal of Biochemistry... 2023Phospholipids are highly diverse molecules with pleiotropic biological roles, from membrane components and signaling molecules, whose composition can change in response...
BACKGROUND
Phospholipids are highly diverse molecules with pleiotropic biological roles, from membrane components and signaling molecules, whose composition can change in response to both endogenous and external stimuli. Recent lipidomic studies on edible bivalve mollusks were focused on lipid nutritional value and growth requirements. However, no data are available on phospholipid profiles during bivalve larval development. In the model marine bivalve , early larvae (up to 48 hours post fertilization-hpf) undergo dramatic molecular and functional changes, including shell biogenesis and neurogenesis, that are sustained by egg lipid reserves. Changes in phospholipid composition may also occur participating in the complex processes of early development.
OBJECTIVE
The lipidome of eggs and early larval stages (24 and 48 hpf) was investigated in order to identify possible changes in phospholipid classes and related metabolic pathways that may play a role in key steps of development.
MATERIALS AND METHODS
Lipidomic analysis were performed by NMR spectroscopy and liquid chromatography-mass spectrometry (LC-MS), with focus on phospholipids. Shifts in relative species composition of phosphatidylcholine, phosphatidylethanolamine, plasmalogen, and ceramide aminoethylphosphonate-CAEP, the bivalve analogue of the main mammalian ceramide sphingomyelin, were observed. Expression of genes involved in ceramide homeostasis was also modulated from eggs to early larval stages.
RESULTS
The results represent the first data on changes in phospholipid composition in bivalve larvae and suggest a functional role of phospholipids in mussel early development.
CONCLUSION
The results underline the importance of lipidomic studies in bivalve larvae, in both physiological conditions and in response to environmental stress.
PubMed: 38020445
DOI: No ID Found -
Molecules (Basel, Switzerland) Jan 2024Brain-derived neurotrophic factor (BDNF) plays an important role in neurogenesis, synaptic plasticity, and cognition. BDNF is a neurotrophin that binds to tropomyosin...
Brain-derived neurotrophic factor (BDNF) plays an important role in neurogenesis, synaptic plasticity, and cognition. BDNF is a neurotrophin that binds to tropomyosin receptor kinase B (TrkB), a specific receptor on target cell surfaces; it acts on neuronal formation, development, growth, and repair via transcription factors, such as cAMP response element-binding protein (CREB), and it is involved in learning and memory. BDNF expression is decreased in patients with Alzheimer's disease (AD). Exercise and the intake of several different foods or ingredients can increase BDNF expression, as confirmed with lutein, xanthophylls (polar carotenoids), and ethanolamine plasmalogen (PlsEtn), which are present at high levels in the brain. This study examined the effects of combining lutein and PlsEtn using lutein-rich Chlorella and ascidian extracts containing high levels of PlsEtn bearing docosahexaenoic acid, which is abundant in the human brain, on the activation of the BDNF-TrkB-CREB signaling pathway in the hippocampus of Sprague-Dawley rats. Although activation of the BDNF-TrkB-CREB signaling pathway in the hippocampus was not observed in Chlorella or ascidian PlsEtn monotherapy, activation was observed with combination therapy at an equal dose. The results of this study suggest that the combination of Chlorella and ascidian PlsEtn may have a preventive effect against dementia, including AD.
Topics: Humans; Rats; Animals; Chlorella; Brain-Derived Neurotrophic Factor; Lutein; Rats, Sprague-Dawley; Signal Transduction; Brain; Alzheimer Disease; Plasmalogens
PubMed: 38257270
DOI: 10.3390/molecules29020357 -
Frontiers in Microbiology 2023SARS-CoV-2 subverts host cell processes to facilitate rapid replication and dissemination, and this leads to pathological inflammation.
INTRODUCTION
SARS-CoV-2 subverts host cell processes to facilitate rapid replication and dissemination, and this leads to pathological inflammation.
METHODS
We used niclosamide (NIC), a poorly soluble anti-helminth drug identified initially for repurposed treatment of COVID-19, which activates the cells' autophagic and lipophagic processes as a chemical probe to determine if it can modulate the host cell's total lipid profile that would otherwise be either amplified or reduced during SARS-CoV-2 infection.
RESULTS
Through parallel lipidomic and transcriptomic analyses we observed massive reorganization of lipid profiles of SARS-CoV-2 infected Vero E6 cells, especially with triglycerides, which were elevated early during virus replication, but decreased thereafter, as well as plasmalogens, which were elevated at later timepoints during virus replication, but were also elevated under normal cell growth. These findings suggested a complex interplay of lipid profile reorganization involving plasmalogen metabolism. We also observed that NIC treatment of both low and high viral loads does not affect virus entry. Instead, NIC treatment reduced the abundance of plasmalogens, diacylglycerides, and ceramides, which we found elevated during virus infection in the absence of NIC, resulting in a significant reduction in the production of infectious virions. Unexpectedly, at higher viral loads, NIC treatment also resulted in elevated triglyceride levels, and induced significant changes in phospholipid metabolism.
DISCUSSION
We posit that future screens of approved or new partner drugs should prioritize compounds that effectively counter SARS-CoV-2 subversion of lipid metabolism, thereby reducing virus replication, egress, and the subsequent regulation of key lipid mediators of pathological inflammation.
PubMed: 37901834
DOI: 10.3389/fmicb.2023.1251065