Lysophosphatidylcholines Promote Influenza Virus Reproduction through the MAPK/JNK Pathway in PMA-Differentiated THP-1 Macrophages.

Obesity and metabolic syndrome alter serum lipid profiles. They also increase vulnerability to viral infections and worsen the survival rate and symptoms after infection. How serum lipids affect influenza virus proliferation is unclear. Here, we investigated the effects of lysophosphatidylcholines on influenza A virus (IAV) proliferation. IAV particles in the culture medium were titrated using extraction-free quantitative PCR, and viral RNA and protein levels were assessed using real-time PCR and Western blot, respectively. RNA sequencing data were analyzed using PCA and heatmap analysis, and pathway analysis was performed using the KEGG mapper and PathIN tools. Statistical analysis was conducted using SPSS21.0. LPC treatment of THP-1 cells significantly increased IAV proliferation and IAV RNA and protein levels, and saturated LPC was more active in IAV RNA expression than unsaturated LPC was. The functional analysis of genes affected by LPCs showed that the expression of genes involved in IAV signaling, such as suppressor of cytokine signaling 3 (SOCS3), phosphoinositide-3-kinase regulatory subunit 3 (PI3K) and AKT serine/threonine kinase 3 (AKT3), Toll-like receptor 7 (TKR7), and interferon gamma receptor 1 (IFNGR1), was changed by LPC. Altered influenza A pathways were linked with MAPK and PI3K/AKT signaling. Treatment with inhibitors of MAPK or PI3K attenuated viral gene expression changes induced by LPCs. The present study shows that LPCs stimulated virus reproduction by modifying the cellular environment to one in which viruses proliferated better. This was mediated by the MAPK, JNK, and PI3K/AKT pathways. Further animal studies are needed to confirm the link between LPCs from serum or the respiratory system and IAV proliferation.

Essential trace element and phosphatidylcholine remodeling: Implications for body composition and insulin resistance.

BACKGROUND: Recent studies indicated that bioactive lipids of phosphatidylcholines (PCs) and lysophosphatidylcholines (LysoPCs) predict unhealthy metabolic phenotypes, but results remain inconsistent. To fill this knowledge gap, we investigated whether essential trace elements affect PC-Lyso PC remodeling pathways and the risk of insulin resistance (IR). METHODS: Anthropometric and blood biochemical data (glucose, insulin, and lipoprotein-associated phospholipase A2 (Lp-PLA2)) were obtained from 99 adults. Blood essential/probably essential trace elements and lipid metabolites were respectively measured by inductively coupled plasma mass spectrometry (ICP-MS), and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). RESULT AND CONCLUSION: Except for LysoPC (O-18:0/0:0), an inverse V shape was observed between body weight and PC and LysoPC species. A Pearson correlation analysis showed that essential/probably-essential metals (Se, Cu, and Ni: r=-0.4∼-0.7) were negatively correlated with PC metabolites but positively correlated with LysoPC (O-18:0/0:0) (Se, Cu, and Ni: r=0.85-0.64). Quantile-g computation showed that one quantile increase in essential metals was associated with a 2.16-fold increase in serum Lp-PLA2 (ß=2.16 (95 % confidence interval (CI): 0.34, 3.98), p=0.023), which are key enzymes involved in PC/Lyso PC metabolism. An interactive analysis showed that compared to those with the lowest levels (reference), individuals with the highest levels of serum PCs (pooled, M2) and the lowest essential/probably essential metals (M1) were associated with a healthier body composition and had a 76 % decreased risk of IR (odds ratio (OR)=0.24 (95 % CI: 0.06, 0.90), p<0.05). In contrast, increased exposure to LysoPC(O-18:0/0:0) (M2) and essential metals (M2) exhibited an 8.22-times highest risk of IR (OR= 8.22 (2.07, 32.57), p<0.05) as well as an altered body composition. In conclusion, overexposure to essential/probably essential trace elements may promote an unhealthy body weight and IR through modulating PC/LysoPC remodeling pathways.

Distinctly altered lipid components in hepatocellular carcinoma relate to impaired T cell-dependent antitumor immunity.

BACKGROUND AND AIMS: T cells are master effectors of anti-tumor immunity in cancer. Recent studies suggest that altered lipid metabolism imposed by the tumor microenvironment constrains anti-tumor immunity. However, the tumor-associated lipid species changes that dampen T cell ability to control tumor progression are not fully understood. Here, we plan to clarify the influences of distinctly altered lipid components in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) on T-cell function, aiming to seek lipid metabolic targets for improving T cell anti-tumor effects. METHODS: Tumor tissues and non-tumor liver from HCC patients were collected for RNA-sequencing, lipid profiling and T cell characterizing, followed by correlation analysis. Additionally, the effects of significantly changed lipid components on anti-tumor potential of T cells were tested by in vitro cell experiments and/or in vivo tumor inoculated model. RESULTS: Altered lipid metabolism coincides with impaired T cell response in HBV-related HCC. Characteristic lipid composition, significantly marked by accumulation of long-chain acylcarnitines (LCACs) and reduction of lysophosphatidylcholines (LPCs), are found in the tumor tissue. Notably, LCACs accumulated are associated with T cells exhaustion and deficient functionality, while LPCs correlate to anti-tumor effects of T cells. In particular, supplement of LPCs, including LPC (20:0) and LPC (22:0), directly promote the activation and IFN-γ secretion of T cells in vitro, and suppress tumor growth in vivo. CONCLUSIONS: Our study highlights the distinctly changed lipid components closely related to T cell dysregulation in HCC, and suggests a promising strategy by decreasing LCACs and increasing LPCs for anti-tumor immunotherapy.

The Relationship of Circulating Choline and Choline-Related Metabolite Levels with Health Outcomes: A Scoping Review of Genome-Wide Association Studies and Mendelian Randomization Studies.

Choline is essential for proper liver, muscle, brain, lipid metabolism, cellular membrane composition, and repair. Understanding genetic determinants of circulating choline metabolites can help identify new determinants of choline metabolism, requirements, and their link to disease endpoints. We conducted a scoping review to identify studies assessing the association of genetic polymorphisms on circulating choline and choline-related metabolite concentrations and subsequent associations with health outcomes. This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement scoping review extension. Literature was searched to September 28, 2022, in 4 databases: Embase, MEDLINE, Web of Science, and the Biological Science Index. Studies of any duration in humans were considered. Any genome-wide association study (GWAS) investigating genetic variant associations with circulating choline and/or choline-related metabolites and any Mendelian randomization (MR) study investigating the association of genetically predicted circulating choline and/or choline-related metabolites with any health outcome were considered. Qualitative evidence is presented in summary tables. From 1248 total reviewed articles, 53 were included (GWAS = 27; MR = 26). Forty-two circulating choline-related metabolites were tested in association with genetic variants in GWAS studies, primarily trimethylamine N-oxide, betaine, sphingomyelins, lysophosphatidylcholines, and phosphatidylcholines. MR studies investigated associations between 52 total unique choline metabolites and 66 unique health outcomes. Of these, 47 significant associations were reported between 16 metabolites (primarily choline, lysophosphatidylcholines, phosphatidylcholines, betaine, and sphingomyelins) and 27 health outcomes including cancer, cardiovascular, metabolic, bone, and brain-related outcomes. Some articles reported significant associations between multiple choline types and the same health outcome. Genetically predicted circulating choline and choline-related metabolite concentrations are associated with a wide variety of health outcomes. Further research is needed to assess how genetic variability influences choline metabolism and whether individuals with lower genetically predicted circulating choline and choline-related metabolite concentrations would benefit from a dietary intervention or supplementation.

Serum mannan-binding lectin-associated serine proteases in early pregnancy for gestational diabetes in Chinese pregnant women.

Aims: This study aimed to explore associations of mannan-binding lectin-associated serine protease (MASP) levels in early pregnancy with gestational diabetes mellitus (GDM). We also examined interactions of MASPs and deoxycholic acid (DCA)/glycoursodeoxycholic acid (GUDCA) for the GDM risk and whether the interactive effects if any on the GDM risk were mediated via lysophosphatidylcholine (LPC) 18:0. Materials and methods: A 1:1 case-control study (n = 414) nested in a prospective cohort of pregnant women was conducted in Tianjin, China. Binary conditional logistic regressions were performed to examine associations of MASPs with the GDM risk. Additive interaction measures were used to examine interactions between MASPs and DCA/GUDCA for the GDM risk. Mediation analyses and Sobel tests were used to examine mediation effects of LPC18:0 between the copresence of MASPs and DCA/GUDCA on the GDM risk. Results: High MASP-2 was independently associated with GDM [odds ratio (OR): 2.62, 95% confidence interval (CI): 1.44-4.77], while the effect of high MASP-1 on GDM was attributable to high MASP-2 (P for Sobel test: 0.003). Low DCA markedly increased the OR of high MASP-2 alone from 2.53 (1.10-5.85) up to 10.6 (4.22-26.4), with a significant additive interaction. In addition, high LPC18:0 played a significant mediating role in the links from low DCA to GDM and from the copresence of high MASP-2 and low DCA to GDM (P for Sobel test <0.001) but not in the link from high MASP-2 to GDM. Conclusions: High MASP-1 and MASP-2 in early pregnancy were associated with GDM in Chinese pregnant women. MASP-2 amplifies the risk of low DCA for GDM, which is mediated via LPC18:0.

TiO2@COF-based solid-phase microextraction combined with UHPLC-MS/MS for the rapid determination of potential biomarkers of phosphatidylcholines and lysophosphatidylcholines in head and neck cancers.

Phosphatidylcholine (PC) and lysophosphatidylcholine (LPC), two types of phospholipids (PLs), have been reported to be closely correlated with head and neck cancers of laryngeal cancer (LC) and thyroid cancer (TC), which make their analysis crucial. TiO2@COF-based solid-phase microextraction (SPME) coupled to UHPLC-MS/MS was developed for the rapid and accurate detection of seven potential PL biomarkers from small amounts of serum in this work. The combination of TiO2 and COF proves to be effective for the extraction of the target analytes. Under optimal conditions, the developed TiO2@COF-based SPME-UHPLC-MS/MS method revealed good linearity (R2 ≥ 0.997) with LODs ranging from 0.05 to 0.38 ng/mL for PLs, the extraction recoveries and matrix effects ranging from 83.09-112.03% and 85.38-113.67%, respectively. As a high-throughput pretreatment method, satisfactory probe-to-probe reproducibility rates of 2.7-10.1% were obtained. Finally, the TiO2@COF-based SPME-UHPLC-MS/MS method was applied to analyze LPC 14:0, LPC 16:0, LPC 18:0, LPC 18:1, LPC 19:0, PC 16:0/18:1, and PC 18:0 in serum samples from early LC patients (n = 15), early TC patients (n = 15), and healthy volunteers (n = 15). The results indicated that cancer patients could be effectively differentiated from healthy controls using orthogonal partial least squares discriminant analysis (OPLS-DA). In conclusion, the established TiO2@COF-based SPME-UHPLC-MS/MS method is reliable for the rapid determination of the seven PLs in serum samples, which is promising for early diagnosis of head and neck cancers.

Effects of RIPC on the Metabolomical Profile during Lower Limb Digital Subtraction Angiography: A Randomized Controlled Trial.

Remote ischemic preconditioning (RIPC) has demonstrated protective effects in patients with lower extremity arterial disease (LEAD) undergoing digital subtraction angiography (DSA) and/or percutaneous transluminal angioplasty (PTA). This study aimed to investigate the impact of RIPC on the metabolomical profile of LEAD patients undergoing these procedures and to elucidate its potential underlying mechanisms. A total of 100 LEAD patients were enrolled and randomly assigned to either the RIPC group (n = 46) or the sham group (n = 54). Blood samples were drawn before and 24 h after intervention. Targeted metabolomics analysis was performed using the AbsoluteIDQ p180 Kit, and changes in metabolite concentrations were compared between the groups. The RIPC group demonstrated significantly different dynamics in nine metabolites compared to the sham group, which generally showed a decrease in metabolite concentrations. The impacted metabolites included glutamate, taurine, the arginine-dimethyl-amide-to-arginine ratio, lysoPC a C24:0, lysoPC a C28:0, lysoPC a C26:1, PC aa C38:1, PC ae C30:2, and PC ae C44:3. RIPC exhibited a 'stabilization' effect, maintaining metabolite levels amidst ischemia-reperfusion injuries, suggesting its role in enhancing metabolic control. This may improve outcomes for LEAD patients. However, additional studies are needed to definitively establish causal relationships among these metabolic changes.

Identification of candidate metabolite biomarkers for metabolic syndrome and its five components in population-based human cohorts.

BACKGROUND: Metabolic Syndrome (MetS) is characterized by risk factors such as abdominal obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension, and hyperglycemia, which contribute to the development of cardiovascular disease and type 2 diabetes. Here, we aim to identify candidate metabolite biomarkers of MetS and its associated risk factors to better understand the complex interplay of underlying signaling pathways. METHODS: We quantified serum samples of the KORA F4 study participants (N = 2815) and analyzed 121 metabolites. Multiple regression models adjusted for clinical and lifestyle covariates were used to identify metabolites that were Bonferroni significantly associated with MetS. These findings were replicated in the SHIP-TREND-0 study (N = 988) and further analyzed for the association of replicated metabolites with the five components of MetS. Database-driven networks of the identified metabolites and their interacting enzymes were also constructed. RESULTS: We identified and replicated 56 MetS-specific metabolites: 13 were positively associated (e.g., Val, Leu/Ile, Phe, and Tyr), and 43 were negatively associated (e.g., Gly, Ser, and 40 lipids). Moreover, the majority (89%) and minority (23%) of MetS-specific metabolites were associated with low HDL-C and hypertension, respectively. One lipid, lysoPC a C18:2, was negatively associated with MetS and all of its five components, indicating that individuals with MetS and each of the risk factors had lower concentrations of lysoPC a C18:2 compared to corresponding controls. Our metabolic networks elucidated these observations by revealing impaired catabolism of branched-chain and aromatic amino acids, as well as accelerated Gly catabolism. CONCLUSION: Our identified candidate metabolite biomarkers are associated with the pathophysiology of MetS and its risk factors. They could facilitate the development of therapeutic strategies to prevent type 2 diabetes and cardiovascular disease. For instance, elevated levels of lysoPC a C18:2 may protect MetS and its five risk components. More in-depth studies are necessary to determine the mechanism of key metabolites in the MetS pathophysiology.

Precise Metabolomics Defines Systemic Metabolic Dysregulation Distinct to Acute Myocardial Infarction Associated With Diabetes.

BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of death and disability. Diabetes is an important risk factor and a common comorbidity in AMI patients. The higher mortality risk of diabetes-AMI relative to nondiabetes-AMI indicates a need for specific treatment to improve clinical outcome. However, the global metabolic dysregulation of AMI complicated with diabetes is still unclear. We aim to systematically interrogate changes in the metabolic microenvironment immediate to AMI episodes in the absence or presence of diabetes. METHODS: In this work, quantitative metabolomics was used to investigate plasma metabolic differences between diabetes-AMI (n=59) and nondiabetes-AMI (n=59) patients. A diverse array of perturbed metabolic pathways involving carbohydrate metabolism, lipid metabolism, glycolysis, tricarboxylic acid cycle, and amino acid metabolism emerged. RESULTS: In all, our omics-oriented approach defined a metabolic signature of afflicted mitochondrial function aggravated by concurrent diabetes in AMI patients. In particular, our analyses uncovered N-lactoyl-phenylalanine and lysophosphatidylcholines as key functional metabolites that skewed the metabolic picture of diabetes-AMI relative to nondiabetes-AMI. N-lactoyl-phenylalanine was strongly associated with metabolic indicators reflective of mitochondrial overload and negatively correlated with HbA1c (glycosylated hemoglobin, type A1C) specifically in hyperglycemic AMI, suggestive of its central role in glucose utilization and mitochondrial energy production instrumental to the clinical outcome of diabetes-AMI. Reductions in lysophosphatidylcholines, which were negatively correlated with blood glucose and inflammatory markers, might further compromise glucose expenditure and aggravate inflammation leading to poorer prognosis in diabetes-AMI. CONCLUSIONS: As circulating metabolite levels are amenable to therapeutic intervention, such shifts in metabolic signatures provide new clues and potential therapeutic targets specific to the treatment of diabetes-AMI.

Age and gender-specific reference intervals for a panel of lysophosphatidylcholines estimated by tandem mass spectrometry in dried blood spots.

Background and objectives: Very long-chain fatty acyl-lysophosphatidylcholines (VLCFA-LysoPCs) are measured in dried blood spots (DBS) for identifying X-linked adrenoleukodystrophy (X-ALD) and other inherited peroxisomal disorders. Our study aimed to establish age- and gender-specific reference intervals for a panel of LysoPCs measured by tandem mass spectrometry in DBS. Methods: LysoPCs (26:0-, 24:0-, 22:0- and 20:0-LysoPCs) were estimated by flow injection analysis-tandem mass spectrometry (FIA-MS/MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods in 3.2 mm blood spots of 2689 anonymized, putative normal subjects (1375 males, and 1314 females) aged between 2 days and 65 years. Samples were divided into groups: Neonates (0-1month), Infants (>1m-1year), Children and Adolescents (>1-18years), and Adults (>18years). Reference intervals were determined using the percentile approach and represented as the median with the 1st and 99th percentile lower and upper limits. Results: The percentage coefficient of variation (CV) for repeatability assays of internal and external quality control samples were within acceptable limits. Significant differences (P <0.0001, P <0.01) were observed in the concentrations of 26:0-, 24:0-, 22:0- and 20:0-LysoPCs and their ratios, 26:0/22:0-, 24:0/22:0-, 26:0/20:0-and 24:0/20:0-LysoPC in neonates and infants when compared to children, adolescents, and adults. Levels of 26:0-, 24:0- and 22:0-LysoPCs decreased, whereas 20:0-LysoPC increased with age. There were no significant gender-based differences in the concentration of LysoPCs. Conclusion: We established age- and gender-specific reference intervals for a panel of LysoPCs in DBS. These reference values would be helpful when interpreting LysoPC values in DBS during screening for X-ALD and other peroxisomal disorders.

Are Phosphatidylcholine and Lysophosphatidylcholine Body Levels Potentially Reliable Biomarkers in Obesity? A Review of Human Studies.

Phosphatidylcholines (PCs) are the major components of biological membranes in animals and are a class of phospholipids that incorporate choline as a headgroup. Lysophosphatidylcholines (LPCs) are a class of lipid biomolecules derived from the cleavage of PCs, and are the main components of oxidized low-density lipoproteins (oxLDLs) that are involved in the pathogenesis of atherosclerosis. Since obesity is associated with a state of chronic low-grade inflammation, one can anticipate that the lipidomic profile changes in this context and both PCs and LPCs are gaining attention as hypothetically reliable biomarkers of obesity. Thus, a literature search is performed on PubMed, Latin American and Caribbean Health Science Literature (LILACS), and Excerpta Medica DataBASE (Embase) to obtain the findings of population studies to clarify this hypothesis. The search strategy resulted in a total of 2403 reports and 21 studies were included according to the eligibility criteria. Controversial data on the associations of PCs and LPCs with body mass index (BMI) and body fat parameters have been identified. There is an inverse relationship between BMI and most species of PCs, and a majority of studies exhibited negative associations between BMI and LPCs. Other findings regarding the differences between PCs and LPCs in obesity are presented, and the associated uncertainties are discussed in detail.

Different Profiles of the Triad of Lysophosphatidylcholine, Lysophosphatidic Acid, and Autotaxin in Patients with Neuropathic Pain Diseases: a Preliminary Observational Study.

The mechanisms underlying neuropathic pain remain unclear. Lysophosphatidic acid (LPA) is a bioactive phospholipid derived mainly from lysophosphatidylcholine (LPC) by extracellular autotaxin (ATX), and has attracted attention as a candidate biomarker of neuropathic pain. We aimed to investigate the levels of LPA, LPC, and ATX in patients with lumbar spinal canal stenosis (LSCS) or other neuropathic pain diseases, and to distinguish the underlying mechanism of LSCS from other neuropathic pain conditions. Furthermore, the levels of phosphorylated neurofilament heavy chain (pNF-H), an objective surrogate marker of axonal damage, were also measured. Cerebrospinal fluid (CSF) samples were obtained from 56 patients with LSCS (n = 31) and various etiologies other than LSCS (n = 25). Patients with LSCS complained of pain intensity comparable to that of patients without LSCS. The LPA levels were significantly higher in patients with LSCS than in non-LSCS patients, while the ATX levels were significantly lower. However, the differences in LPC and pNF-H levels between the two patient groups were not significant. The LPA/LPC ratio was significantly higher in the LSCS group. Notably, the difference in LPA between the two groups diminished in the analysis of covariance (ANCOVA) with ATX as a covariate. Thus, it helped to reveal that LPA synthesis in patients with LSCS depends more efficiently on ATX than in non-LSCS neuropathic pain patients with other etiologies. Our findings further suggest that the triad of LPA, LPC, and ATX in LSCS may contribute to the development and maintenance of neuropathic pain in a manner different from non-LSCS neuropathic conditions.

Spectrum of Clinical and Imaging Characteristics of 48 X-Linked Adrenoleukodystrophy Patients: Our Experience from a University Hospital.

Background and Objectives: X-linked adrenoleukodystrophy (X-ALD) occurs due to the mutation in the ABCD1-gene. Our study was to correlate the clinical, radiological, and biochemical features in a cohort of X-ALD patients. Methods: We retrospectively analyzed 48 (M: F: 47:1) biochemically confirmed cases of X-ALD, classified them as cerebral ALD (childhood, adolescent, and adult), adrenomyeloneuropathy, Addisonian only. The Magnetic Resonance Imaging (MRI) of the radiological patterns was classified based on Loes classification. Results: The various clinical phenotypes were childhood cerebral X-ALD (58.3%), adolescent cerebral X-ALD (14.6%), adult-cerebral X-ALD (20.8%), Addisonian variant (4.2%), and adrenomyeloneuropathy (AMN) (2.1%). The imaging features were posterior white matter (Pattern-1) observed in 33 (68.75%) patients, cerebellar white matter (Pattern-4) noted in 5 subjects, anterior white matter (Pattern-2) observed in 3 patients, combined parieto-occipital and frontal white matter (Pattern-5) observed in 3 patients, isolated projection fiber (Pattern-3) observed in 1 patient. Rare features of the involvement of optic tract, anterior and lateral columns of cervicodorsal cord, bilateral central tegmental tracts, basal ganglia, and tigroid appearance were observed. Interpretation: This is a comprehensive clinical, biochemical, and imaging analysis with follow-up information of one of the largest series of X-ALD patients. The knowledge regarding the clinical features, typical and atypical imaging patterns is of vital importance for early diagnosis and treatment.

Longitudinal associations between blood lysophosphatidylcholines and skeletal muscle mitochondrial function.

Lysophosphatidylcholines (LPCs) are phospholipids critical in the synthesis of cardiolipin, an essential component of mitochondrial membranes. Lower plasma LPCs have been cross-sectionally associated with lower skeletal muscle mitochondrial function, but whether lower LPCs and their decline over time are longitudinally associated with an accelerated decline of mitochondria function is unknown. We analyzed data from 184 participants in the Baltimore Longitudinal Study of Aging (mean age: 74.5 years, 57% women, 25% black) who had repeated measures of plasma LPCs (16:0, 16:1, 17:0, 18:0, 18:1, 18:2, 20:3, 20:4, 24:0, and 28:1) by liquid chromatography-tandem mass spectrometry and repeated measures of skeletal muscle oxidative capacity (kPCr) assessed by 31P magnetic resonance spectroscopy over an average of 2.4 years. Rates of change in kPCr and each LPC were first estimated using simple linear regression. In multivariable linear regression models adjusted for baseline demographics and PCr % depletion, lower baseline LPC 16:1 and faster rates of decline in LPC 16:1 and 18:1 were significantly associated with a faster rate of decline in kPCr (B = - 0.169, 95% CI: - 0.328, - 0.010, p = 0.038; B = 0.209, 95% CI: 0.065, 0.352, p = 0.005; B = 0.156, 95% CI: 0.011, 0.301, p = 0.035, respectively). Rates of change in other LPCs were not significantly associated with change in kPCr (all p > 0.05). Lower baseline concentrations and faster decline in selected plasma lysophosphatidylcholines over time are associated with faster decline in skeletal muscle mitochondrial function. Strategies to prevent the decline of plasma LPCs at an early stage may slow down mitochondrial function decline and impairment during aging.

Circulating Metabolome and White Matter Hyperintensities in Women and Men.

BACKGROUND: White matter hyperintensities (WMH), identified on T2-weighted magnetic resonance images of the human brain as areas of enhanced brightness, are a major risk factor of stroke, dementia, and death. There are no large-scale studies testing associations between WMH and circulating metabolites. METHODS: We studied up to 9290 individuals (50.7% female, average age 61 years) from 15 populations of 8 community-based cohorts. WMH volume was quantified from T2-weighted or fluid-attenuated inversion recovery images or as hypointensities on T1-weighted images. Circulating metabolomic measures were assessed with mass spectrometry and nuclear magnetic resonance spectroscopy. Associations between WMH and metabolomic measures were tested by fitting linear regression models in the pooled sample and in sex-stratified and statin treatment-stratified subsamples. Our basic models were adjusted for age, sex, age×sex, and technical covariates, and our fully adjusted models were also adjusted for statin treatment, hypertension, type 2 diabetes, smoking, body mass index, and estimated glomerular filtration rate. Population-specific results were meta-analyzed using the fixed-effect inverse variance-weighted method. Associations with false discovery rate (FDR)-adjusted P values (PFDR)<0.05 were considered significant. RESULTS: In the meta-analysis of results from the basic models, we identified 30 metabolomic measures associated with WMH (PFDR<0.05), 7 of which remained significant in the fully adjusted models. The most significant association was with higher level of hydroxyphenylpyruvate in men (PFDR.full.adj=1.40×10-7) and in both the pooled sample (PFDR.full.adj=1.66×10-4) and statin-untreated (PFDR.full.adj=1.65×10-6) subsample. In men, hydroxyphenylpyruvate explained 3% to 14% of variance in WMH. In men and the pooled sample, WMH were also associated with lower levels of lysophosphatidylcholines and hydroxysphingomyelins and a larger diameter of low-density lipoprotein particles, likely arising from higher triglyceride to total lipids and lower cholesteryl ester to total lipids ratios within these particles. In women, the only significant association was with higher level of glucuronate (PFDR=0.047). CONCLUSIONS: Circulating metabolomic measures, including multiple lipid measures (eg, lysophosphatidylcholines, hydroxysphingomyelins, low-density lipoprotein size and composition) and nonlipid metabolites (eg, hydroxyphenylpyruvate, glucuronate), associate with WMH in a general population of middle-aged and older adults. Some metabolomic measures show marked sex specificities and explain a sizable proportion of WMH variance.

Serum lysophospholipidome of dietary origin as a suitable susceptibility/risk biomarker of human hypercholesterolemia: A cross-sectional study.

BACKGROUND & AIMS: Whether bioactive lysophospholipids (lyso-PLs) and trimethylamine-N-oxide (TMAO) serve as non-invasive biomarkers in early human hypercholesterolemia (HC) is unknown. This study aimed to assess whether serum lyso-PLs and plasma TMAO may be suitable susceptibility/risk biomarkers of HC in humans. Secondarily, we aimed to evaluate the relationships between targeted metabolites, diet composition and circulating liver transaminases, and verify these results in hamsters. METHODS: A targeted metabolomics and lipidomics approach determined plasma TMAO and serum lysophosphatidylcholines (lyso-PCs) and lysophosphatidylethanolamines (lyso-PEs) in low (L-LDL-c) and moderate to high (MH-LDL-c) LDL-cholesterol subjects. Additionally, the relationships between targeted metabolites, liver transaminases and diet, particularly fatty acid intake, were tested. In parallel, plasma and liver lyso-PL profiles were studied in 16 hamsters fed a moderate high-fat (HFD) or low-fat (LFD) diet for 30 days. RESULTS: Predictive models identified lyso-PC15:0 and lyso-PE18:2 as the most discriminant lyso-PLs among groups. In MH-LDL-c (n = 48), LDL-cholesterol and saturated FAs were positively associated with lyso-PC15:0, whereas in L-LDL-c (n = 70), LDL-cholesterol and polyunsaturated fatty acids (PUFAs) were negatively and positively related to lyso-PE18:2, respectively. Interestingly, in MH-LDL-c, the lower lyso-PE 18:2 concentrations were indicative of higher LDL-cholesterol levels. Intrahepatic accumulation of lyso-PLs-containing essential n-6 PUFAs, including lyso-PE18:2, were higher in HFD-fed hamsters than LFD-fed hamsters. CONCLUSIONS: Overall, results revealed a possible hepatic adaptive mechanism to counteract diet-induced steatosis in animal and hypercholesterolemia progression in humans. In particular, low serum lyso-PE18:2 suggests a suitable susceptibility/risk biomarker of HC in humans.

Development, validation, and clinical application of an FIA-MS/MS method for the quantification of lysophosphatidylcholines in dried blood spots.

BACKGROUND: Lysophosphatidylcholine (LPC) plays pivotal roles in several physiological processes and their disturbances are closely associated with various disorders. In this study, we described the development and validation of a reliable and simple flow injection analysis-tandem mass spectrometry (FIA-MS/MS)-based method using dried blood spots (DBS) for quantification of four individual LPC (C20:0, C22:0, C24:0, and C26:0). METHODS: Lysophosphatidylcholines were extracted from 3.2 mm DBS with 85% methanol containing 60 ng/ml internal standard using a rapid (30 min) and simple procedure. The analytes and the internal standard were directly measured by triple quadrupole tandem mass spectrometry in multiple reactions monitoring mode via positive electrospray ionization. RESULTS: Method validation results showed good linearity ranging from 50 to 2000 ng/ml for each LPC. Intra- and inter-day precision and accuracy were within the acceptable limits at four quality control levels. Recovery was from 70.5% to 107.0%, and all analytes in DBS were stable under assay conditions (24 h at room temperature and 72 h in autosampler). The validated method was successfully applied to assessment of C20:0-C26:0LPCs in 1900 Chinese neonates. C26:0-LPC levels in this study were consistent with previously published values. CONCLUSION: We propose a simple FIA-MS/MS method for analyzing C20:0-C26:0LPCs in DBS, which can be used for first-tier screening.

Lysophosphatidylcholines and phosphatidylcholines as biomarkers for stroke recovery.

Stroke is a serious global public health issue, associated with severe disability and high mortality rates. Its early detection is challenging, and no effective biomarkers are available. To obtain a better understanding of stroke prevention, management, and recovery, we conducted lipidomic analyses to characterize plasma metabolic features. Lipid species were measured using an untargeted lipidomic analysis with liquid chromatography-tandem mass spectrometry. Sixty participants were recruited in this cohort study, including 20 healthy individuals and 40 patients with stroke. To investigate the association between lipids related to long-term functional recovery in stroke patients. The primary independent variable was activities of daily living (ADL) dependency upon admission to the stroke unit and at the 3-month follow-up appointment. ADL dependency was assessed using the Barthel Index. Eleven significantly altered lipid species between the stroke and healthy groups were detected and displayed in a hierarchically clustered heatmap. Acyl carnitine, triacylglycerol, and ceramides were detected as potential lipid markers. Regarding the association between lipid profiles and functional status of patients with stroke the results indicated, lysophosphatidylcholines (LPC) and phosphatidylcholines were closely associated with stroke recovery. LPC may contribute positively role in patient's rehabilitation process via an anti-inflammatory mechanism. Appropriate management or intervention for lipid levels is expected to lead to better clinical outcomes.

Metabolomic and lipidomic characterization of an X-chromosome deletion disorder in neural progenitor cells by UHPLC-HRMS.

INTRODUCTION: Intellectual disorders involving deletions of the X chromosome present a difficult task in the determination of a connection between symptoms and metabolites that could lead to treatment options. One specific disorder of X-chromosomal deletion, Fragile X syndrome, is the most frequently occurring of intellectual disabilities. Previous metabolomic studies have been limited to mouse models that may not have sufficiently revealed the full biochemical diversity of the disease in humans. OBJECTIVES: The primary objective of this study was to elucidate the human biochemistry in X-chromosomal deletion disorders through metabolomic and lipidomic profiling, using cells from a X-deletion patient as a representative case. METHODS: Metabolomic and lipidomic analysis was performed by UHPLC-HRMS on neural progenitor (NP) cells isolated from an afflicted female patient versus normal neural progenitor cells. RESULTS: Results showed perturbations in several metabolic pathways, including those of arginine and proline, that significantly impact both neurotransmitter generation and overall brain function. Coincidently, dysregulation was observed for lipids involved in both cellular structure and membrane integrity. The trends of observed metabolomic changes, as well as lipidomic profiling from identified features, are discussed. CONCLUSION: The lipidomic and metabolomic profiles of NP cell samples exhibited significant differentiation associated with partial deletion of the X chromosome. These findings suggest that rare X-chromosomal deletion disorders are not only a mental disorder limited to alterations in local neuronal functions, but are also metabolic diseases.