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The Journal of Physical Chemistry... May 2024Heart tissue can experience a progressive accumulation of transthyretin (TTR), a small four subunit protein that transports holoretinol binding protein and thyroxine....
Heart tissue can experience a progressive accumulation of transthyretin (TTR), a small four subunit protein that transports holoretinol binding protein and thyroxine. This severe pathology is known as transthyretin amyloid cardiomyopathy. Numerous experimental studies indicated that the aggregation rate and toxicity of TTR fibrils could be altered by the presence of lipids; however, the role of plasmalogens in this process remains unknown. In this study, we investigate the effect of choline plasmalogens (CPs) with different lengths and saturations of fatty acids (FAs) on TTR aggregation. We found that CPs with saturated and unsaturated FAs strongly suppressed TTR aggregation. We also found that CPs with saturated FAs did not change the morphology of TTR fibrils; however, much thicker fibrillar species were formed in the presence of CPs with unsaturated FAs. Finally, we found that CPs with C16:0, C18:0, and C18:1 FAs substantially lowered the cytotoxicity of TTR fibrils that were formed in their presence.
Topics: Prealbumin; Plasmalogens; Humans; Amyloid; Protein Aggregates; Fatty Acids
PubMed: 38661515
DOI: 10.1021/acs.jpclett.4c00868 -
Journal of Agricultural and Food... May 2024The sea cucumber plasmalogen PlsEtn has been shown to be associated with various chronic diseases related to lipid metabolism. However, the mechanism is unclear....
The sea cucumber plasmalogen PlsEtn has been shown to be associated with various chronic diseases related to lipid metabolism. However, the mechanism is unclear. Therefore, the present study used the sea cucumber plasmanylcholine PakCho as a structural contrast to PlsEtn and assessed its effect in 8 week high-fat diet (HFD)-fed mice. The lipidomic approach based on high-resolution mass spectrometry combined with molecular biology techniques was used to evaluate the mechanism of PlsEtn. The results showed that both PlsEtn and PakCho significantly inhibited an increase in mouse body weight and liver total triglyceride and total cholesterol levels caused by HFD. In addition, oil red O staining demonstrated that lipid droplets stored in the liver were degraded. Meanwhile, untargeted lipidomic experiments revealed that total lipids (increased by 42.8 mmol/mg prot; < 0.05), triglycerides (increased by 38.9 mmol/mg prot; < 0.01), sphingolipids (increased by 1.5 mmol/mg prot; < 0.0001), and phospholipids (increased by 2.5 mmol/mg prot; < 0.05) were all significantly elevated under HFD. PlsEtn resolved lipid metabolism disorders by alleviating the abnormal expression of lipid subclasses. In addition, five lipid molecular species, PE (18:1/20:4), PE (18:1/20:3), PE (18:1/18:3), TG (16:0/16:0/17:0), and TG (15:0/16:0/18:1), were identified as the biomarkers of HFD-induced lipid metabolism disorders. Finally, lipophagy-associated protein expression analysis showed that HFD abnormally activated lipophagy via ULK1 phosphorylation and PlsEtn alleviated lipophagy disorder through lysosomal function promotion. In addition, PlsEtn performed better than PakCho. Taken together, the current study results unraveled the mechanism of PlsEtn in alleviating lipid metabolism disorder and offered a new theoretical foundation for the high-value development of sea cucumber.
Topics: Animals; Diet, High-Fat; Mice; Sea Cucumbers; Liver; Male; Lipid Metabolism; Plasmalogens; Mice, Inbred C57BL; Triglycerides; Humans; Lipids
PubMed: 38630981
DOI: 10.1021/acs.jafc.4c00152 -
Biochimica Et Biophysica Acta.... Jun 2024Sea cucumber phospholipids, including the plasmalogen (PlsEtn) and plasmanylcholine (PakCho), have been shown to play a regulatory role in lipid metabolism disorders,...
Sea cucumber phospholipids, including the plasmalogen (PlsEtn) and plasmanylcholine (PakCho), have been shown to play a regulatory role in lipid metabolism disorders, but their mechanism of action remains unclear. Therefore, high-fat diet (HFD) and palmitic acid were used to establish lipid accumulation models in mice and HepG2 cells, respectively. Results showed that PlsEtn can reduce lipid deposition both in vivo and in vitro. HFD stimulation abnormally activated lipophagy through the phosphorylation of the AMPK/ULK1 pathway. The lipophagy flux monitor revealed abnormalities in the fusion stage of lipophagy. Of note, only PlsEtn stimulated the dynamic remodeling of the autophagosome membrane, which was indicated by the significantly decreased LC3 II/I ratio and p62 level. In all experiments, the effect of PlsEtn was significantly higher than that of PakCho. These findings elucidated the mechanism of PlsEtn in alleviating lipid accumulation, showed that it might be a lipophagy enhancer, and provided new insights into the high-value utilization of sea cucumber as an agricultural resource.
Topics: Animals; Diet, High-Fat; Plasmalogens; Sea Cucumbers; Lipid Metabolism; Mice; Humans; Hep G2 Cells; Male; Mice, Inbred C57BL; Autophagy
PubMed: 38609006
DOI: 10.1016/j.bbalip.2024.159495 -
The Journal of Biological Chemistry May 2024Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE)...
Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia, including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.
Topics: Animals; Humans; Mice; Brain; Homeostasis; Lipid Metabolism; Lipid Peroxidation; Mice, Knockout; Myelin Sheath; Oligodendroglia; Phosphatidylethanolamines; Phospholipid Ethers; Plasmalogens; Selenoproteins; Spastic Paraplegia, Hereditary
PubMed: 38582453
DOI: 10.1016/j.jbc.2024.107259 -
Scientific Reports Apr 2024Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain...
Alzheimer's disease (AD) is a neurodegenerative disease that commonly causes dementia. Identifying biomarkers for the early detection of AD is an emerging need, as brain dysfunction begins two decades before the onset of clinical symptoms. To this end, we reanalyzed untargeted metabolomic mass spectrometry data from 905 patients enrolled in the AD Neuroimaging Initiative (ADNI) cohort using MS-DIAL, with 1,304,633 spectra of 39,108 unique biomolecules. Metabolic profiles of 93 hydrophilic metabolites were determined. Additionally, we integrated targeted lipidomic data (4873 samples from 1524 patients) to explore candidate biomarkers for predicting progressive mild cognitive impairment (pMCI) in patients diagnosed with AD within two years using the baseline metabolome. Patients with lower ergothioneine levels had a 12% higher rate of AD progression with the significance of P = 0.012 (Wald test). Furthermore, an increase in ganglioside (GM3) and decrease in plasmalogen lipids, many of which are associated with apolipoprotein E polymorphism, were confirmed in AD patients, and the higher levels of lysophosphatidylcholine (18:1) and GM3 d18:1/20:0 showed 19% and 17% higher rates of AD progression, respectively (Wald test: P = 3.9 × 10 and 4.3 × 10). Palmitoleamide, oleamide, diacylglycerols, and ether lipids were also identified as significantly altered metabolites at baseline in patients with pMCI. The integrated analysis of metabolites and genomics data showed that combining information on metabolites and genotypes enhances the predictive performance of AD progression, suggesting that metabolomics is essential to complement genomic data. In conclusion, the reanalysis of multiomics data provides new insights to detect early development of AD pathology and to partially understand metabolic changes in age-related onset of AD.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; Multiomics; Neuroimaging; Biomarkers; Lipids; Cognitive Dysfunction; Disease Progression
PubMed: 38565541
DOI: 10.1038/s41598-024-56837-1 -
Journal of the American Society For... May 2024The identification and quantitation of plasmalogen glycerophospholipids is challenging due to their isobaric overlap with plasmanyl ether-linked glycerophospholipids,...
The identification and quantitation of plasmalogen glycerophospholipids is challenging due to their isobaric overlap with plasmanyl ether-linked glycerophospholipids, susceptibility to acid degradation, and their typically low abundance in biological samples. Trimethylation enhancement using diazomethane (TrEnDi) can be used to significantly enhance the signal of glycerophospholipids through the creation of quaternary ammonium groups producing fixed positive charges using C-diazomethane in complex lipid extracts. Although TrEnDi requires a strong acid for complete methylation, we report an optimized protocol using 10 mM HBF with the subsequent addition of a buffer solution that prevents acidic hydrolysis of plasmalogen species and enables the benefits of TrEnDi to be realized for this class of lipids. These optimized conditions were applied to aliquots of bovine liver extract (BLE) to achieve permethylation of plasmalogen lipids within a complex mixture. Treating aliquots of unmodified and TrEnDi-derivatized BLE samples with 80% formic acid and comparing their liquid chromatography mass spectrometry (LCMS) results to analogous samples not treated with formic acid, enabled the identification of 29 plasmalogen species. On average, methylated plasmalogen species from BLE demonstrated 2.81-fold and 28.1-fold sensitivity gains over unmodified counterparts for phosphatidylcholine and phosphatidylethanolamine plasmalogen species, respectively. Furthermore, the compatibility of employing C-TrEnDi and a previously reported iodoacetalization strategy was demonstrated to effectively identify plasmenyl-ether lipids in complex biological extracts at greater levels of sensitivity. Overall, we detail an optimized C-TrEnDi derivatization strategy that enables the analysis of plasmalogen glycerophospholipids with no undesired cleavage of radyl groups, boosting their sensitivity in LCMS and LCMS/MS analyses.
Topics: Animals; Cattle; Plasmalogens; Carbon Isotopes; Diazomethane; Liver; Glycerophospholipids; Methylation; Chromatography, Liquid; Tandem Mass Spectrometry
PubMed: 38551491
DOI: 10.1021/jasms.4c00015 -
Molecular Neurobiology Mar 2024Central retinal artery occlusion (CRAO) is a kind of ophthalmic emergency which may cause loss of functional visual acuity. However, the limited treatment options...
Central retinal artery occlusion (CRAO) is a kind of ophthalmic emergency which may cause loss of functional visual acuity. However, the limited treatment options emphasize the significance of early disease prevention. Metabolomics has the potential to be a powerful tool for early identification of individuals at risk of CRAO. The aim of the study was to identify potential biomarkers for CRAO through a comprehensive analysis. We employed metabolomics analysis to compare venous blood samples from CRAO patients with cataract patients for the venous difference, as well as arterial and venous blood from CRAO patients for the arteriovenous difference. The analysis of metabolites showed that PC(P-18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PC(P-18:0/20:4(5Z,8Z,11Z,14Z)) and octanoylcarnitine were strongly correlated with CRAO. We also used univariate logistic regression, random forest (RF), and support vector machine (SVM) to screen clinical parameters of patients and found that HDL-C and ApoA1 showed significant predictive efficacy in CRAO patients. We compared the predictive performance of the clinical parameter model with combined model. The prediction efficiency of the combined model was significantly better with area under the receiver operating characteristic curve (AUROC) of 0.815. Decision curve analysis (DCA) also exhibited a notably higher net benefit rate. These results underscored the potency of these three substances as robust predictors of CRAO occurrence.
PubMed: 38459364
DOI: 10.1007/s12035-024-04093-9 -
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 -
Applied and Environmental Microbiology Apr 2024Plasmalogen is a specific glycerophospholipid present in both animal and bacterial organisms. It plays a crucial function in eukaryotic cellular processes and is closely...
UNLABELLED
Plasmalogen is a specific glycerophospholipid present in both animal and bacterial organisms. It plays a crucial function in eukaryotic cellular processes and is closely related to several human diseases, including neurological disorders and cancers. Nonetheless, the precise biological role of plasmalogen in bacteria is not well understood. In this study, we identified SMU_438c as the enzyme responsible for plasmalogen production in under anaerobic conditions. The heterologous expression of SMU_438c in a plasmalogen-negative strain, , resulted in the production of plasmalogen, indicating that this enzyme is sufficient for plasmalogen production. Additionally, the plasmalogen-deficient exhibited significantly lower acid tolerance and diminished its colonization in flies compared to the wild-type strain and complemented strain. In summary, our data suggest that plasmalogen plays a vital role in bacterial stress tolerance and colonization.
IMPORTANCE
This study sheds light on the biological role of plasmalogen, a specific glycerophospholipid, in bacteria, particularly in . Plasmalogens are known for their significant roles in eukaryotic cells and have been linked to human diseases like neurological disorders and cancers. The enzyme SMU_438c, identified as essential for plasmalogen production under anaerobic conditions, was crucial for acid tolerance and colonization in by , underscoring its importance in bacterial stress response and colonization. These findings bridge the knowledge gap in bacterial physiology, highlighting plasmalogen's role in microbial survival and offering potential insights into microbial pathogenesis and host-microbe interactions.
Topics: Humans; Animals; Bacterial Proteins; Plasmalogens; Streptococcus mutans; Acids; Drosophila; Neoplasms; Nervous System Diseases; Biofilms
PubMed: 38456674
DOI: 10.1128/aem.01500-23 -
International Journal of Biological... Apr 2024Plasmalogens comprise a large fraction of the total phospholipids in plasma membranes. These molecules modulate membrane fluidity, produce inflammatory mediators...
Plasmalogens comprise a large fraction of the total phospholipids in plasma membranes. These molecules modulate membrane fluidity, produce inflammatory mediators mitigating effects of metabolic stresses. A growing body of evidence suggests that an onset of Parkinson's disease (PD), a severe neurodegenerative pathology, can be triggered by metabolic changes in plasma membranes. However, the role of plasmalogens in the aggregation of α-synuclein (α-syn), an expected molecular cause of PD, remains unclear. In this study we examine the effect of choline plasmalogens (CPs), unique phospholipids that have a vinyl ether linkage at the sn-1 position of glycerol, on the aggregation rate of α-syn. We found that the length and saturation of fatty acids (FAs) in CPs change rates of protein aggregation. We also found drastic changes in the morphology of α-syn fibrils formed in the presence of different CPs compared to α-syn fibrils grown in the lipid-free environment. At the same time, we did not observe substantial changes in the secondary structure and toxicity of α-syn fibrils formed in the presence of different CPs. These results indicate that the length and saturation of FAs in CPs present in the plasma membrane can alter α-syn stability and modulate its aggregation properties, which, in turn can accelerate or delay the onset of PD.
Topics: Humans; alpha-Synuclein; Plasmalogens; Amyloid; Parkinson Disease
PubMed: 38447831
DOI: 10.1016/j.ijbiomac.2024.130632