Phospholipid Metabolism Research Articles

External redox couple enhanced anammox sludge activity at low temperature: Insight into intracellular resource synthesis

Anaerobic ammonium oxidation (anammox), an energy-efficient deamination biotechnology, faces operational challenges in low-temperature environments. Enhancing the metabolic activity of anammox bacteria (AnAOB) is pivotal for advancing its application in mainstream municipal wastewater treatment. Inspired by the metabolic adaptability of AnAOB and based on our previous findings, this work investigated the enhancement of intracellular ATP and NADH synthesis through the exogenous supply of reduced humic acid (HAred) and H2O2 redox couple, aiming to augment AnAOB activity under low-temperature conditions. Our experimental setup involved continuous dosing of 0.0067 μmol g-1 volatile suspended solid of H2O2 and 10 mg g-1 volatile suspended solid of HAred into a mainstream anammox reactor operated at 15 °C with an influent TN content of 60 mg/L. The results showed that HAred / H2O2 couple succeeded in maintaining the effluent TN at 10.72 ± 0.91 mg l-1. The specific anammox activity, ATP and NADH synthesis levels of sludge increased by 1.34, 2.33 and 6.50 folds, respectively, over the control setup devoid of the redox couple. High-throughput sequencing analysis revealed that the relative abundance of Candidatus Kuenenia after adding HAred / H2O2 couple reached 3.65 % at the end of operation, which was 5.14 folds higher than that of the control group. Further metabolomics analysis underscored an activation in the metabolism of amino acids, nucleotides, and phospholipids, which collectively enhanced the availability of ATP and NADH for the respiratory processes. These findings may provide guidance on strategy development for improving the electron transfer efficiency of AnAOB and underscore the potential of using redox couples to promote the mainstream application of anammox technology.

Phospholipid metabolism-related genotypes of PLA2R1 and CERS4 contribute to nonobese MASLD.

Abnormal phospholipid metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. We aimed to clarify whether genetic variants of phospholipid metabolism modify these relationships. This case-control study consecutively recruited 600 patients who underwent MRI-based proton density fat fraction examination (240 participants with serum metabonomics analysis, 128 biopsy-proven cases) as 3 groups: healthy control, nonobese MASLD, and obese MASLD, (n = 200 cases each). Ten variants of phospholipid metabolism-related genes [phospholipase A2 Group VII rs1805018, rs76863441, rs1421378, and rs1051931; phospholipase A2 receptor 1 (PLA2R1) rs35771982, rs3828323, and rs3749117; paraoxonase-1 rs662 and rs854560; and ceramide synthase 4 (CERS4) rs17160348)] were genotyped using SNaPshot. The T-allele of CERS4 rs17160348 was associated with a higher risk of both obese and nonobese MASLD (OR: 1.95, 95% CI: 1.20-3.15; OR: 1.76, 95% CI: 1.08-2.86, respectively). PLA2R1 rs35771982-allele is a risk factor for nonobese MASLD (OR: 1.66, 95% CI: 1.11-1.24), moderate-to-severe steatosis (OR: 3.24, 95% CI: 1.96-6.22), and steatohepatitis (OR: 2.61, 95% CI: 1.15-3.87), while the paraoxonase-1 rs854560 T-allele (OR: 0.50, 95% CI: 0.26-0.97) and PLA2R1 rs3749117 C-allele (OR: 1.70, 95% CI: 1.14-2.52) are closely related to obese MASLD. After adjusting for sphingomyelin level, the effect of the PLA2R1 rs35771982CC allele on MASLD was attenuated. Furthermore, similar effects on the association between the CERS4 rs17160348 C allele and MASLD were observed for phosphatidylcholine, phosphatidic acid, sphingomyelin, and phosphatidylinositol. The mutations in PLA2R1 rs35771982 and CERS4 rs17160348 presented detrimental impact on the risk of occurrence and disease severity in nonobese MASLD through altered phospholipid metabolism.

Deciphering the Impact of ZnO Nanoparticles and a Sunscreen Product Containing ZnO on Phosphorus Dynamics and Release in Chlorella pyrenoidosa in Aquatic Systems.

Zinc oxide nanoparticles (ZnO NPs) expedite the conversion of organic phosphorus (OP) into PO4-P (Pi), facilitating phosphorus (P) absorption by algae. Our study explored the mechanisms of converting OP (2-aminoethylphosphonic acid (AEP) and β-glycerol phosphate (β-GP)) into Pi in Chlorella pyrenoidosa under P deficiency with sunscreen and ZnO NPs. Cell density followed the order of K2HPO4 > β-GP+ZnO > β-GP > AEP+ZnO > AEP > P-free. ZnO NPs promoted the conversion of β-GP, containing C-O-P bonds (0.028-0.041 mg/L), into Pi more efficiently than AEP, which possesses C-P bonds (0.022-0.037 mg/L). Transcriptomics revealed Pi transport/metabolism (phoB (3.99-12.01 fold), phoR (2.20-5.50 fold), ppa (4.49-10.40 fold), and ppk (2.50-5.40 fold)) and phospholipid metabolism (SQD1 (1.85-2.79 fold), SQD2 (2.60-6.53 fold), MGD (2.13-3.21 fold), and DGD (4.08-7.56 fold)) were up-regulated compared to K2HPO4. 31P nuclear magnetic resonance spectroscopy identified intracellular P as polyphosphate, orthophosphate, and pyrophosphate. Synchrotron radiation-based X-ray near-edge structure spectroscopy indicated that K2HPO4 and Zn3(PO4)2 in β-GP+ZnO were increased by 8.09% and 7.28% compared to AEP+ZnO, suggesting superior P storage in β-GP+ZnO. Overall, ZnO NPs improved photoinduced electron-hole pair separation and charge separation efficiency and amplified the ·OH and ·O2- levels, promoting OP photoconversion into Pi and algae growth.

Lipidomics study of Liujunzi decoction in hyperlipidemia rats with spleen deficiency based on UPLC-Q-TOF/MS

Hyperlipidemia refers to the abnormal levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) in peripheral blood circulation. It is a predominant risk factor underlying cardiovascular and cerebrovascular diseases, including coronary heart disease and atherosclerosis. Furthermore, it is also one of the most prevalent chronic diseases globally. Liujunzi Decoction is the basic prescription for the treatment of spleen and stomach diseases. It can tonify the spleen and qi, remove dampness, and reduce turbidity. Moreover, it is also clinically used for the treatment of spleen deficiency hyperlipidemia. However, its metabolites and therapeutic effect on spleen deficiency hyperlipidemia have not been comprehensively determined in vitro and in vivo. This study established a rat model of spleen deficiency hyperlipidemia by inducing starvation and satiety disorders, exhaustion swimming, and intragastric administration of the fat emulsion. To identify related metabolite changes and serum lipid composition, UPLC-Q-TOF-MS, PCA, and OPLS-DA lipidological methods were performed. The results demonstrated significant changes in rat's signs during the modeling process, which were consistent with the criteria for the syndrome differentiation of spleen deficiency in traditional Chinese medicine. Furthermore, this study identified 100 potential biomarkers in rat serum, of which 52 were associated with lipid synthesis, such as LPC, PC, PI, PE, PA, Cer, SM, etc. The pathways involved were glycerol phospholipid, sphingomyelin, and glycerol ester metabolisms. After the Liujunzi decoction intervention, 56 potential biomarkers were observed in the high-dose group, alleviating the metabolic spectrum imbalance by reducing metabolite levels. In addition, metabolic pathway disturbances were markedly improved. This study provides references for future studies on Liujunzi decoction and furnishes essential data for assessing the relationships between chemical constituents and pharmacological activities of Liujunzi decoction.

Comprehensive assessment of the anti-obesity effects of highland barley total, insoluble, and soluble dietary fiber through multi-omics analysis

The impact of different forms of dietary fiber (total, insoluble or soluble) derived from the same source on health remains incompletely understood. In this study, the effects of total, insoluble, and soluble dietary fiber extracted from highland barley (HDF, HIDF, and HSDF) on combating obesity were evaluated and compared. A high-fat diet (HFD) was used to induce obesity in a murine model, followed by gavage administration of HDF, HIDF, or HSDF, and a comprehensive multi-omics approach was utilized to assess and compare the effects of these dietary fibers on obesity-related parameters. The results showed that all three dietary fibers significantly reduced body weight, modified blood lipid profiles, and ameliorated tissue damage in HFD-fed mice. Additionally, 16S rRNA sequencing analysis of mice feces showed that three types of dietary fiber exerted varying degrees of impact on the composition and abundance of gut microbiota while simultaneously promoting the biosynthesis of short-chain fatty acids. Specifically, HDF supplementation remarkably enhanced the abundance of Coprococcus, while HIDF and HSDF supplementation elevated the levels of Akkermansia and Allobaculum, respectively. Transcriptomic and proteomic results suggested the PPAR signaling pathway as a central regulatory mechanism influenced by these fibers. HDF and HIDF were particularly effective in modulating biological processes related to triglyceride and fatty acid metabolism, identifying Abcc3 and Dapk1 as potential targets. Conversely, HSDF primarily affected processes related to membrane lipids, ceramides, and phospholipids metabolism, with Pck1 identified as a potential target. Collectively, HDF, HIDF, and HSDF demonstrated distinct mechanisms in exerting exceptional anti-obesity properties. These insights may inform the development of personalized dietary interventions for obesity.

Phosphatidylinositol-specific phospholipase C-associated phospholipid metabolism mediates DcGLRs channel to promote calcium influx under CaCl2 treatment in shredded carrots during storage

The rapid activation of phosphatidylinositol-specific phospholipase C (PI-PLC) occurs early after the stimulation of biotic and abiotic stress in plants, which directly associated with the calcium channel-induced calcium ion (Ca2+) influx. Exogenous calcium chloride (CaCl2) mediates the calcium signaling transduction to promote the γ-aminobutyric acid accumulation and nutritional quality in shredded carrots whereas the generation mechanism remains uncertain. Therefore, the involvement of PI-PLC-associated phospholipid metabolism was investigated in present study. Our result revealed that CaCl2 treatment promoted the expression and activity of PI-PLC and increased the inositol 1,4,5-trisphosphate and hexakisphosphate content in shredded carrots. The transcripts of multi-glutamate receptor-like channels (DcGLRs), the glutamate and γ-aminobutyric acid (GABA) content, and Ca2+ influx were induced by CaCl2 treatment in shredded carrots during storage. However, PI-PLC inhibitor (U73122) treatment inhibited the activation of PI-PLC, the increase of many DcGLRs family genes expression levels, and Ca2+ influx. Moreover, the identification of DcPI-PLC4/6 and DcGLRs proteins, along with the analysis of characteristic domains such as PLCXc, PLCYc, C2 domain, transmembranous regions, and ligand binding domain, suggests their involvement in phospholipid catalysis and calcium transport in carrots. Furthermore, DcPI-PLC4/6 overexpression in tobacco leaves induced the Ca2+ influx by activating the expressions of NtGLRs and the accumulation of glutamate and GABA. These findings collectively indicate that CaCl2 treatment-induced PI-PLC activation influences DcGLRs expression levels to mediate cytosolic Ca2+ influx, thus, highlighting the “PI-PLC-GLRs-Ca2+” pathway in calcium signaling generation and GABA biosynthesis in shredded carrots.

Lipidomics reveals the reshaping of the mitochondrial phospholipid profile in cells lacking OPA1 and mitofusins

Depletion or mutations of key proteins for mitochondrial fusion, like optic atrophy 1 (OPA1) and mitofusins 1 and 2 (Mfn 1 and 2), are known to significantly impact the mitochondrial ultrastructure, suggesting alterations of their membranes’ lipid profiles. In order to make an insight into this issue, we used hydrophilic interaction liquid chromatography coupled with electrospray ionization–high resolution MS to investigate the mitochondrial phospholipid (PL) profile of mouse embryonic fibroblasts knocked out for OPA1 and Mfn1/2 genes. One hundred sixty-seven different sum compositions were recognized for the four major PL classes of mitochondria, namely phosphatidylcholines (PCs, 63), phosphatidylethanolamines (55), phosphatidylinositols (21), and cardiolipins (28). A slight decrease in the cardiolipin/PC ratio was found for Mfn1/2-knockout mitochondria. Principal component analysis and hierarchical cluster analysis were subsequently used to further process hydrophilic interaction liquid chromatography–ESI-MS data. A progressive decrease in the incidence of alk(en)yl/acyl species in PC and phosphatidylethanolamine classes and a general increase in the incidence of unsaturated acyl chains across all the investigated PL classes was inferred in OPA1 and Mfn1/2 knockouts compared to WT mouse embryonic fibroblasts. These findings suggest a reshaping of the PL profile consistent with the changes observed in the mitochondrial ultrastructure when fusion proteins are absent. Based on the existing knowledge on the metabolism of mitochondrial phospholipids, we propose that fusion proteins, especially Mfns, might influence the PL transfer between the mitochondria and the endoplasmic reticulum, likely in the context of mitochondria-associated membranes.

Metabolomics combined with intestinal microbiota analysis to reveal the effects of Inonotus hispidus on chronic kidney disease caused by high-protein diet

In recent years, the global incidence of chronic kidney disease caused by popular high-protein diet is on the rise. As a traditional edible and medicinal fungus in Asian countries, Inonotus hispidus has been proved to have a variety of biological activities. In this study, a mouse model of chronic kidney disease was established, and the effect of Inonotus hispidus on chronic kidney disease induced by high protein diet was clarified by the comprehensive strategy of metabonomics and intestinal microbiota analysis. We found that Inonotus hispidus fermentation broth may alleviate renal damage by regulating glycerol phospholipid metabolism and bile acid metabolism, and its fermentation broth can reverse the intestinal microbiota imbalance caused by high-protein diet. In addition, through analysis, it is found that high-protein diet can down-regulate the level of Farnesoid X receptor in the kidney, resulting in lipid accumulation and a series of pathological changes in the kidney. We believe that Inonotus hispidus has the potential to become a new type of safe and effective functional food for the treatment of chronic kidney disease.

Roles and Mechanisms of Choline Metabolism in Nonalcoholic Fatty Liver Disease and Cancers.

Choline participates in three major metabolic pathways: oxidation, phosphorylation, and acetylation. Through oxidation, choline is converted to betaine and contributes to methyl metabolism and epigenetic regulation. Through phosphorylation, choline participates in phospholipid metabolism, and serves as the precursor of phosphocholine, phosphatidylcholine, glycerophosphocholine, and other essential compounds, thereby modulating lipid metabolism and transport. Through acetylation, choline is transformed into acetylcholine in cholinergic neurons, playing a vital role in neurotransmission. Moreover, gut microbiota can metabolize choline into trimethylamine-N-oxide, and be involved in the pathogenesis of various diseases such as nonalcoholic fatty liver disease (NAFLD), cancer, cardiovascular disease, etc. Since choline metabolism is implicated in the development of NAFLD and diverse cancers, including liver cancer, it may serve as a therapeutic target for these diseases in the future. Currently, there are numerous therapeutic agents targeting choline metabolism to treat NAFLD and cancers, but most of them are ineffective and some even have adverse effects that lead to a series of complications. Therefore, further research and clinical validation are required to obtain safe and efficacious drugs. This review comprehensively summarizes the choline metabolic pathway and its regulatory mechanisms, elucidates the roles and mechanisms of choline metabolism in the aforementioned diseases, and provides a discussion of the current advances and immense potential of this field.

Zinc-associated phospholipid metabolic alterations and their impacts on ALT levels in workers

Zinc (Zn) is an essential trace element that is required for various biological functions, but excessive exposure to Zn is associated with many disorders and even diseases. However, the health effects and underlying mechanisms of long-term and high concentration exposure of Zn remain to be unclear. In the present study, we investigated the association between occupational exposure to Zn and liver function indicators (like alanine aminotransferase (ALT)) in workers. We found a positive association between Zn exposure and ALT level in workers. Workers having higher blood Zn (7735.65 (1159.15) μg/L) shows a 30.4 % increase in ALT level compared to those with lower blood Zn (5969.30 (989.26) μg/L). Furthermore, we explored the effects of phospholipids (PLs) and their metabolism on ALT level and discovered that Zn exposure in workers was associated with changes in PL levels and metabolism, which had further effects on increased ALT levels in workers. The study provides insights into the relationship between occupational Zn exposure and liver function, highlights the risk of long-term exposure to high concentrations of Zn, and paves the way for understanding the underlying mechanisms of Zn exposure on human health.

The Chinese herbal prescription Kang-Gong-Yan alleviates cervicitis by modulating metabolites and gut microbiota

Context Cervicitis is a common gynecological inflammatory disease. The Chinese herbal prescription Kang-Gong-Yan (KGY) is clinically effective against cervicitis; however, the chemical constituents and therapeutic mechanism of KGY remain elusive. Objective To analyze the chemical constituents of KGY and explore the potential mechanism of KGY in treating cervicitis. Materials and methods UHPLC-Q-Exactive Plus Orbitrap MS was used to identify the active compounds of KGY; Sprague-Dawley (SD) female rats were randomly divided into the control, model, and KGY groups. Phenol mucilage (25%) was slowly injected into the vagina and cervix of the rats to establish the cervicitis model. Then, rats in the KGY groups (low dose: 1 g/kg/d; medium dose: 5 g/kg/d; high dose: 10 g/kg/d) were continuously gavaged KGY for one week. HE staining was used to observe the cervical tissues of rats; ELISA was used to detect inflammatory factors in plasma; non-targeted metabolomics was used to analyze metabolites; 16S rRNA sequencing was used to analyze intestinal microorganisms. Results KGY exerted anti-cervicitis effects and decreased the levels of IL-6, IL-1β, and TNF-α. The mechanism of KGY in treating cervicitis is mainly associated with betaine, amino acid, pyrimidine, and phospholipid metabolism by regulating fifteen metabolites. Moreover, KGY reversed cervicitis-induced gut dysbiosis by mediating five bacteria. Discussion and conclusions The Chinese herbal prescription KGY may alleviate cervicitis by modulating metabolites and gut microbiota disorders. These findings provide a scientific basis for the clinical application of KGY and a new strategy for treating cervicitis in Chinese medicine.

Study on the mechanisms by which pumpkin polysaccharides regulate abnormal glucose and lipid metabolism in diabetic mice under oxidative stress

Pumpkin polysaccharide (PPe-H) can perform physiological functions through its antioxidative and hypoglycemic effects; however, the mechanisms through which PPe-H regulates abnormal glucose and lipid metabolism caused by oxidative stress injury remain unclear. In the present study, streptozotocin was used to generate an acute diabetic mouse model, and the effects of PPe-H on glucose and lipid metabolism impaired by oxidative stress in diabetic mice were studied. PPe-H significantly reduced blood glucose levels and enhanced the oral glucose tolerance of diabetic mice under stress injury (p < 0.05). The analysis of liver antioxidant enzymes showed that PPe-H significantly enhanced the activities of SOD and CAT (p < 0.05), increased the GSH level, and decreased the level of MDA (p < 0.05). Transcriptomic and metabolomic analyses of the liver tissues of mice revealed characteristic differences in the genetic and metabolic levels of the samples, which showed that PPe-H treatment may play a positive role in regulating the metabolism of methionine, cysteine, glycerol phospholipid, and linoleic acid. These results indicated that PPe-H alleviated the symptoms of hyperglycemia by regulating metabolites related to oxidative stress and glycolipid metabolism in diabetic mice.

Cotton adapts to Na2SO4 stress by regulating the metabolic intensity and distribution of metabolites in roots and leaves

Significant Na2SO4 stress severely restricts cotton production in Xinjiang. However, the tolerance mechanism of cotton to Na2SO4 stress is not yet fully understood. This study set up two treatments, normal soil (control, CK) and Na2SO4 stress (Na2SO4, SS), to explore the effects of Na2SO4 stress on the physiological metabolism of cotton leaves and roots. Compared with CK, the total biomass and net photosynthetic stress rate decreased significantly (P < 0.05) by 49.0 and 14.7%, respectively. Additionally, the relative conductivity, malondialdehyde content, superoxide dismutase, peroxidase, and catalase activities of leaves increased significantly by 114.5, 99.8, 160, 16.8, and 117%, respectively. A tandem mass tag (TMT) proteomics analysis identified 319 and 583 differentially expressed proteins in roots and leaves, respectively. They mainly participate in amino acid metabolism, such as alanine, aspartic acid, and glutamate metabolism; histidine metabolism; tyrosine metabolism; tryptophan metabolism; energy metabolism, such as glycolysis; the tricarboxylic acid cycle; phosphorus oxide metabolism; lipid metabolism, such as fatty acid biosynthesis; glycerol phospholipid metabolism; steroid biosynthesis; and steroid hormone biosynthesis. Metabolomic data also showed significant changes in amino acid metabolism, organic acid metabolism, and carbohydrate metabolism in the roots and leaves. Na2SO4 stress inhibited metabolism in cotton roots but promoted metabolism in cotton leaves. Under Na2SO4 stress, cotton may prioritize the use of limited photosynthetic products to maintain the health and life activities of its leaves, while also transporting some organic matter from the leaves to the roots to maintain normal metabolic activity of the roots.

Novel putative causal mutations associated with fat traits in Nellore cattle uncovered by eQTLs located in open chromatin regions

Intramuscular fat (IMF) and backfat thickness (BFT) are critical economic traits impacting meat quality. However, the genetic variants controlling these traits need to be better understood. To advance knowledge in this area, we integrated RNA-seq and single nucleotide polymorphisms (SNPs) identified in genomic and transcriptomic data to generate a linkage disequilibrium filtered panel of 553,581 variants. Expression quantitative trait loci (eQTL) analysis revealed 36,916 cis-eQTLs and 14,408 trans-eQTLs. Association analysis resulted in three eQTLs associated with BFT and 24 with IMF. Functional enrichment analysis of genes regulated by these 27 eQTLs revealed noteworthy pathways that can play a fundamental role in lipid metabolism and fat deposition, such as immune response, cytoskeleton remodeling, iron transport, and phospholipid metabolism. We next used ATAC-Seq assay to identify and overlap eQTL and open chromatin regions. Six eQTLs were in regulatory regions, four in predicted insulators and possible CCCTC-binding factor DNA binding sites, one in an active enhancer region, and the last in a low signal region. Our results provided novel insights into the transcriptional regulation of IMF and BFT, unraveling putative regulatory variants.

Exploring Endocrine Signaling between Adipose Tissues and the Heart using Transfer Learning and Induced Pluripotent Stem Cell Models

Background: Because of the amount of evidence pointed toward obesity as a co-morbidity of heart disease, our goal in this study is to use a data-driven method to discover potential cross talk signals between adipose and cardiac tissues, which may reveal a physiological reason for this association. For this study, we hypothesized that adipose-cardiac crosstalk signaling can be found by unexpected co-expression between adipose tissue genes encoding secreted proteins and cardiac tissue genes and vice versa. By discovering new crosstalk signals between these two tissues, we can find new associations between heart disease and obesity. Methods: Cross-tissue correlations of gene expression have been used to identify candidate endocrine signals that mediate tissue crosstalk, which are otherwise diffcult to detect in circulation. However, the identification of significant cross-tissue gene co-expression is hindered by immense multiple-testing burden. Our goal here is to abstract gene expression patterns of tissues into eigengenes and then test their correlation with secreted protein coding genes across tissues in a pairwise fashion. We first used the NIH Common Fund Genotype-Tissue Expression data set (GTEx v8) which contains RNA seq gene expression data from matched tissues of over 17,000 transcriptomes, to learn the latent structure of gene expression across tissues. To do so, we used PLIER (pathway level information extractor), a matrix factorization algorithm to extract the latent targets as eigengenes that map to specific biological pathways in the target tissue (e.g., pathways in the heart in the case of adipose to heart crosstalk). The learned gene expression structure is then transferred to a smaller data set with matching donor adipose and heart transcript expression data, from which a correlation matrix is constructed to find significant relationships between source tissue crosstalk signals and target tissue eigengenes and nominate novel crosstalk signals. Results: Adipose to heart tissue cross talk correlations using PLIER derived latent eigengene targets revealed many adipokines that had strong correlations with pathways found in the heart tissue through similar gene expression. Among these strong correlations were eigengene targets that were wrapped in metabolism pathways particularly those of fatty acid, phospholipid, and protein metabolism. Adipokines that showed high significant and positive correlation with cardiac latent variable expression included Adiponectin (R = 0.32, p = 4.7e−13), Glutathione Peroxidase 3 (R = 0.34, p = 5e−15) and Galectin 9 (R = 0.37, p &lt; 2.2e−16) among others. Based on these results, we nominated new potential relationships between adipose and cardiac tissue. Work is currently under way to validate these candidate crosstalk signals using human induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Future Directions In conclusion, we have found strong evidence in silico to suggest a relationship between known secreted proteins from adipose tissue (adipokine) and the expression of important pathways (such as fatty acid and protein metabolism) in the heart. Based on the findings of these correlations between adipokines and latent eigengene pathways within the heart, our future directions will involved the understanding of potential downstream functional consequences mediated by the adipose secreted proteins in iPSC derived models. This project was supported in part by NIH award R03-OD032666 and the University of Colorado Translational Research Scholar Program to E.L. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Changes in Oxidised Phospholipids in Response to Oxidative Stress in Microtubule-Associated Protein Tau (MAPT) Mutant Dopamine Neurons.

Microtubule-associated protein Tau (MAPT) is strongly associated with the development of neurodegenerative diseases. In addition to driving the formation of neurofibrillary tangles (NFT), mutations in the MAPT gene can also cause oxidative stress through hyperpolarisation of the mitochondria. This study explores the impact that MAPT mutation is having on phospholipid metabolism in iPSC-derived dopamine neurons, and to determine if these effects are exacerbated by mitochondrial and endoplasmic reticulum stress. Neurons that possessed a mutated copy of MAPT were shown to have significantly higher levels of oxo-phospholipids (Oxo-PL) than wild-type neurons. Oxidation of the hydrophobic fatty acid side chains changes the chemistry of the phospholipid leading to disruption of membrane function and potential cell lysis. In wild-type neurons, both mitochondrial and endoplasmic reticulum stress increased Oxo-PL abundance; however, in MAPT mutant neurons mitochondrial stress appeared to have a minimal effect. Endoplasmic reticulum stress, surprisingly, reduced the abundance of Oxo-PL in MAPT mutant dopamine neurons, and we postulate that this reduction could be modulated through hyperactivation of the unfolded protein response and X-box binding protein 1. Overall, the results of this study contribute to furthering our understanding of the regulation and impact of oxidative stress in Parkinson's disease pathology.

Differential impact of intermittent versus continuous treatment with clozapine on fatty acid metabolism in the brain of an MK-801-induced mouse model of schizophrenia

Continuous antipsychotic treatment is often recommended to prevent relapse in schizophrenia. However, the efficacy of antipsychotic treatment appears to diminish in patients with relapsed schizophrenia and the underlying mechanisms are still unknown. Moreover, though the findings are inconclusive, several recent studies suggest that intermittent versus continuous treatment may not significantly differ in recurrence risk and therapeutic efficacy but potentially reduce the drug dose and side effects. Notably, disturbances in fatty acid (FA) metabolism are linked to the onset/relapse of schizophrenia, and patients with multi-episode schizophrenia have been reported to have reduced FA biosynthesis. We thus utilized an MK-801-induced animal model of schizophrenia to evaluate whether two treatment strategies of clozapine would affect drug response and FA metabolism differently in the brain. Schizophrenia-related behaviors were assessed through open field test (OFT) and prepulse inhibition (PPI) test, and FA profiles of prefrontal cortex (PFC) and hippocampus were analyzed by gas chromatography–mass spectrometry. Additionally, we measured gene expression levels of enzymes involved in FA synthesis. Both intermittent and continuous clozapine treatment reversed hypermotion and deficits in PPI in mice. Continuous treatment decreased total polyunsaturated fatty acids (PUFAs), saturated fatty acids (SFAs) and FAs in the PFC, whereas the intermittent administration increased n-6 PUFAs, SFAs and FAs compared to continuous administration. Meanwhile, continuous treatment reduced the expression of Fads1 and Elovl2, while intermittent treatment significantly upregulated them. This study discloses the novel findings that there was no significant difference in clozapine efficacy between continuous and intermittent administration, but intermittent treatment showed certain protective effects on phospholipid metabolism in the PFC.

The Association between the Plasma Phospholipid Profile and Insulin Resistance: A Population-Based Cross-Section Study from the China Adult Chronic Disease and Nutrition Surveillance.

The dysfunction of phospholipid metabolism enzymes and the change in membrane phospholipid composition are associated with insulin resistance, indicating that phospholipids play an important role in the regulation of insulin sensitivity. The reflection of phospholipid changes in blood might provide clues for both mechanism understanding and intervention. Using a targeted phospholipidomic approach, 199 phospholipid molecular species were identified and quantified in the plasma of 1053 middle-aged participants from a national investigation. The associations of the phospholipid matrix, clusters, and molecular species with insulin resistance were investigated. A significant association was confirmed between the phospholipid matrix and the homeostatic-model assessment of insulin resistance (HOMA-IR) by a distance-based linear model. Furthermore, three clustered phospholipid modules and 32 phospholipid molecular species were associated with HOMA-IR with the strict control of demographic and lifestyle parameters, family history of diabetes, BMI, WC, and blood lipid parameters. The overall decline in lysophosphatidylcholines (LPCs), the decrease in saturated lysophosphatidylethanolamines (LPEs), the decrease in polyunsaturated/plasmenyl phosphatidylcholines (PCs), and the increase in polyunsaturated phatidylethanolamines (PEs) were the prominent characters of plasma phospholipid perturbation associated with insulin resistance. This suggested that PC- and PE-related metabolic pathways were widely involved in the process of insulin resistance, especially the disorder of LPC acylation to diacyl-PC.

Serum metabolism alteration behind different etiology, diagnosis, and prognosis of disorders of consciousness

BackgroundPatients with disorders of consciousness (DoC) exhibit varied revival outcomes based on different etiologies and diagnoses, the mechanisms of which remain largely unknown. The fluctuating clinical presentations in DoC pose challenges in accurately assessing consciousness levels and prognoses, often leading to misdiagnoses. There is an urgent need for a deeper understanding of the physiological changes in DoC and the development of objective diagnostic and prognostic biomarkers to improve treatment guidance.MethodsTo explore biomarkers and understand the biological processes, we conducted a comprehensive untargeted metabolomic analysis on serum samples from 48 patients with DoC. Patients were categorized based on etiology (TBI vs. non-TBI), CRS-R scores, and prognosis. Advanced analytical techniques, including PCA and OPLS-DA models, were employed to identify differential metabolites.ResultsOur analysis revealed a distinct separation in metabolomic profiles among the different groups. The primary differential metabolites distinguishing patients with varying etiologies were predominantly phospholipids, with a notable decrease in glycerophospholipids observed in the TBI group. Patients with higher CRS-R scores exhibited a pattern of impaired carbohydrate metabolism coupled with enhanced lipid metabolism. Notably, serum concentrations of both LysoPE and PE were reduced in patients with improved outcomes, suggesting their potential as prognostic biomarkers.ConclusionsOur study underscores the critical role of phospholipid metabolism in the brain’s metabolic alterations in patients with DoC. It identifies key biomarkers for diagnosis and prognosis, offering insights that could lead to novel therapeutic targets. These findings highlight the value of metabolomic profiling in understanding and potentially treating DoC.

Integrated Omics Analysis Uncovers the Culprit behind Exacerbated Atopic Dermatitis in a Diet-Induced Obesity Model.

Atopic dermatitis (AD), a chronic inflammatory skin disease, is exacerbated by obesity, yet the precise linking mechanism remains elusive. This study aimed to elucidate how obesity amplifies AD symptoms. We studied skin samples from three mouse groups: sham control, AD, and high-fat (HF) + AD. The HF + AD mice exhibited more severe AD symptoms than the AD or sham control mice. Skin lipidome analysis revealed noteworthy changes in arachidonic acid (AA) metabolism, including increased expression of pla2g4, a key enzyme in AA generation. Genes for phospholipid transport (Scarb1) and acyltransferase utilizing AA as the acyl donor (Agpat3) were upregulated in HF + AD skin. Associations were observed between AA-containing phospholipids and skin lipids containing AA and its metabolites. Furthermore, imbalanced phospholipid metabolism was identified in the HF + AD mice, marked by excessive activation of the AA and phosphatidic acid (PA)-mediated pathway. This imbalance featured increased expression of Plcb1, Plcg1, and Dgk involved in PA generation, along with a decrease in genes converting PA into diglycerol (DG) and CDP-DG (Lpin1 and cds1). This investigation revealed imbalanced phospholipid metabolism in the skin of HF + AD mice, contributing to the heightened inflammatory response observed in HF + AD, shedding light on potential mechanisms linking obesity to the exacerbation of AD symptoms.