Lipidome Alterations Research Articles

Metabolic and Lipidomic Assessment of Kidney Cells Exposed to Nephrotoxic Vancomycin Dosages.

Vancomycin is a glycopeptide antibiotic used against multi-drug resistant gram-positive bacteria such as Staphylococcus aureus (MRSA). Although invaluable against resistant bacteria, vancomycin harbors adverse drug reactions including cytopenia, ototoxicity, as well as nephrotoxicity. Since nephrotoxicity is a rarely occurring side effect, its mechanism is incompletely understood. Only recently, the actual clinically relevant concentration the in kidneys of patients receiving vancomycin was investigated and were found to exceed plasma concentrations by far. We applied these clinically relevant vancomycin concentrations to murine and canine renal epithelial cell lines and assessed metabolic and lipidomic alterations by untargeted and targeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analyses. Despite marked differences in the lipidome, both cell lines increased anabolic glucose reactions, resulting in higher sorbitol and lactate levels. To the best of our knowledge, this is the first endometabolic profiling of kidney cells exposed to clinically relevant vancomycin concentrations. The presented study will provide a valuable dataset to nephrotoxicity researchers and might add to unveiling the nephrotoxic mechanism of vancomycin.

Lipidomic Analysis of Archival Pathology Specimens Identifies Altered Lipid Signatures in Ovarian Clear Cell Carcinoma

Cancer metabolism is associated with the enhanced lipogenesis required for rapid growth and proliferation. However, the magnitude of dysregulation of diverse lipid species still requires significant characterization, particularly in ovarian clear cell carcinoma (OCCC). Here, we have implemented a robust sample preparation workflow together with targeted LC-MS/MS to identify the lipidomic changes in formalin-fixed paraffin-embedded specimens from OCCC compared to tumor-free ovarian tissue. We quantitated 340 lipid species, representing 28 lipid classes. We observed differential regulation of diverse lipid species belonging to several glycerophospholipid classes and trihexosylceramide. A number of unsaturated lipid species were increased in OCCC, whereas saturated lipid species showed a decrease in OCCC compared to the controls. We also carried out total fatty acid analysis and observed an increase in the levels of several unsaturated fatty acids with a concomitant increase in the index of stearoyl-CoA desaturase (SCD) in OCCC. We confirmed the upregulation of SCD (the rate-limiting enzyme for the synthesis of monounsaturated fatty acids) by immunohistochemistry (IHC) assays. Hence, by carrying out a mass spectrometry analysis of archival tissue samples, we were able to provide insights into lipidomic alterations in OCCC.

Heart failure is associated with accumulation of long chain acylcarnitines in children suffering from cardiomyopathy

Cardiac failure in adults is associated with down regulation of fatty acid beta oxidation and accumulation of long chain (LC) fatty acid derivatives such as LC acylcarnitines [1] , [2] . These lipidomic disturbances have been shown to impair cardiac function [3] . No data are available concerning metabolic modification in heart failure in children. We retrospectively collected acylcarnitines profiles, NT pro BNP, clinical and echographical data and MRI performed in children explored for a non-metabolic cardiomyopathy in our centre from 2015 to 2021. Eighteen children aged from 1 month to 16 years old (median 2.7 years old) met the inclusion criteria. Thirteen were diagnosed for a dilated cardiomyopathy (DCM) [with normal left ventricular ejection fraction (LVEF) for 5 of them], 4 had a hypertrophic cardiomyopathy and 1 suffered from a restrictive cardiomyopathy. Seven children had clinical symptoms of cardiac insufficiency, and nine showed elevation of NT pro BNP. Considering first only children with DCM, sum of total acylcarnitines and sum of LC acylcarnitines were significantly enhanced in patients with impaired LVEF compared to those with normal LVEF (40.0 ± 16.8 vs. 16.2 ± 5.7 μM, P < 0.01, and 4.8 ± 1.6 vs. 3.1 ± 0.7 μM, P < 0.05, respectively). Similarly, considering the whole patients with cardiomyopathy, children with an elevation of NT pro BNP level displayed accumulation of total acylcarnitines and LC acylcarnitines compared to those with a normal NT pro BNP level (38.9 ± 16.9 vs. 15.5 ± 8.2 μM, P < 0.01, and 5.2 ± 2.4 vs. 2.8 ± 1.1 μM, P < 0.01, respectively). Our results suggest alteration of fatty acid oxidation in children with cardiomyopathy and impaired LVEF or elevated NT pro BNP. This metabolic modification needs to be confirmed with a larger scale study. Such lipidomic alteration could worsen heart function, and may suggest considering a metabolic treatment of heart failure in children.

Amniotic fluid metabolomic and lipidomic alterations associated with hemoglobin Bart's diseases.

α-Thalassemia is the most common inherited disease in southern China. The severest form is hemoglobin (Hb) Bart's disease, in which the affected fetuses almost always die in utero or shortly after birth, and the mothers are at high risk for severe morbidity. To investigate the changes in all metabolites in fetuses with Hb Bart's disease and to characterize the metabolomic and lipidomic biomarkers in the development of Hb Bart's fetuses. Amniotic fluid (AF) specimens were selected from 34 pregnant women who underwent interventional prenatal diagnosis from June 2017 to June 2018. Gap-PCR analysis was used to diagnose Hb Bart's disease, and untargeted metabolomic and lipidomic analyses were performed. By analyzing AF samples, 935 differential metabolites were selected between Hb Bart's and control fetuses. The metabolites with significant changes mainly involved D-glutamine and D-glutamate metabolism, histidine metabolism, arginine metabolism, beta-alanine metabolism and alanine, aspartate and glutamate metabolism. Further lipidomics analysis revealed 132 differential lipids, mainly involved phosphatidylcholine and triglyceride metabolism. Through the characterized metabolites in AF, a schematic model of Hb Bart's disease was established. Glutamate and glutathione metabolism, aspartate metabolism, urea metabolism and triglyceride metabolism were significantly changed in the Hb Bart's group compared to the control group. The characterized biomarkers were mainly involved in oxidative stress reaction, iron overload and liver dysfunction. This finding may help improve the treatment options for α-thalassemia as well as diagnosing phenotype of patients.

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2±) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2± mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids and that increasing evidence has linked dysregulation of lipid metabolism to ASD, we performed lipidomic analysis and discovered decreased levels of certain species of sphingomyelin, hexosyl ceramide and their common precursor, ceramide, in 16p11.2± striatum, all of which are major myelin components. We further identified lack of ceramide synthase 2 as the possible reason behind the decrease in these lipid species. Taken together, our data suggest a role for myelin and myelin lipids in ASD development.

LINT-Web: A Web-Based Lipidomic Data Mining Tool Using Intra-Omic Integrative Correlation Strategy.

Lipidomics is a younger member of the "omics" family. It aims to profile lipidome alterations occurring in biological systems. Similar to the other "omics", lipidomic data is highly dimensional and contains a massive amount of information awaiting deciphering and data mining. Currently, the available bioinformatic tools targeting lipidomic data processing and lipid pathway analysis are limited. A few tools designed for lipidomic analysis perform only basic statistical analyses, and lipid pathway analyses rely heavily on public databases (KEGG, Reactome, and HMDB). Due to the inadequate understanding of lipid signaling and metabolism, the use of public databases for lipid pathway analysis can be biased and misleading. Instead of using public databases to interpret lipidomic ontology, the authors introduce an intra-omic integrative correlation strategy for lipidomic data mining. Such an intra-omic strategy allows researchers to unscramble and predict lipid biological functions from correlated genomic ontological results using statistical approaches. To simplify and improve the lipidomic data processing experience, they designed an interactive web-based tool: LINT-web (http://www.lintwebomics.info/) to perform the intra-omic analysis strategy, and validated the functions of LINT-web using two biological systems. Users without sophisticated statistical experience can easily process lipidomic datasets and predict the potential lipid biological functions using LINT-web.

Investigating Global Lipidome Alterations with the Lipid Network Explorer.

Lipids play an important role in biological systems and have the potential to serve as biomarkers in medical applications. Advances in lipidomics allow identification of hundreds of lipid species from biological samples. However, a systems biological analysis of the lipidome, by incorporating pathway information remains challenging, leaving lipidomics behind compared to other omics disciplines. An especially uncharted territory is the integration of statistical and network-based approaches for studying global lipidome changes. Here we developed the Lipid Network Explorer (LINEX), a web-tool addressing this gap by providing a way to visualize and analyze functional lipid metabolic networks. It utilizes metabolic rules to match biochemically connected lipids on a species level and combine it with a statistical correlation and testing analysis. Researchers can customize the biochemical rules considered, to their tissue or organism specific analysis and easily share them. We demonstrate the benefits of combining network-based analyses with statistics using publicly available lipidomics data sets. LINEX facilitates a biochemical knowledge-based data analysis for lipidomics. It is availableas a web-application and as a publicly available docker container.

Targeted Lipidomic Analysis of Aqueous Humor Reveals Signaling Lipid-Mediated Pathways in Primary Open-Angle Glaucoma.

Simple SummaryAnalysis of the eye liquids collected from a cohort of primary open-angle glaucoma patients identified signaling lipids, the pattern of which suggests a role of arachidonic acid/platelet activating-factor (PAF)-dependent pathways and oxidative stress in the pathogenesis of the disease and provides novel targets for its diagnostics and treatment.Primary open-angle glaucoma (POAG) is characterized by degeneration of retinal ganglion cells associated with an increase in intraocular pressure (IOP) due to hindered aqueous humor (AH) drainage through the trabecular meshwork and uveoscleral pathway. Polyunsaturated fatty acids and oxylipins are signaling lipids regulating neuroinflammation, neuronal survival and AH outflow. Among them, prostaglandins have been previously implicated in glaucoma and employed for its treatment. This study addressed the role of signaling lipids in glaucoma by determining their changes in AH accompanying IOP growth and progression of the disease. Eye liquids were collected from patients with POAG of different stages and cataract patients without glaucoma. Lipids were identified and quantified by UPLC-MS/MS. The compounds discriminating glaucoma groups were recognized using ANCOVA and PLS-DA statistic approaches and their biosynthetic pathways were predicted by bioinformatics. Among 22 signaling lipids identified in AH, stage/IOP-dependent alterations in glaucoma were provided by a small set of mediators, including 12,13-DiHOME, 9- and 13-HODE/KODE, arachidonic acid and lyso-PAF. These observations correlated with the expression of cytochromes P450 (CYPs) and phospholipases A2 in the ocular tissues. Interestingly, tear fluid exhibited similar lipidomic alterations in POAG. Overall, POAG may involve arachidonic acid/PAF-dependent pathways and oxidative stress as evidenced from an increase in its markers, KODEs and 12,13-DiHOME. The latter is a product of CYPs, one of which, CYP1B1, is known as POAG and primary congenital glaucoma-associated gene. These data provide novel targets for glaucoma treatment. Oxylipin content of tear fluid may have diagnostic value in POAG.

Plasma lipidome profiling of newborns with antenatal exposure to Zika virus.

The 2015-2016 Zika virus (ZIKV) outbreak in Brazil was remarkably linked to the incidence of microcephaly and other deleterious clinical manifestations, including eye abnormalities, in newborns. It is known that ZIKV targets the placenta, triggering an inflammatory profile that may cause placental insufficiency. Transplacental lipid transport is delicately regulated during pregnancy and deficiency on the delivery of lipids such as arachidonic and docosahexaenoic acids may lead to deficits in both brain and retina during fetal development. Here, plasma lipidome profiles of ZIKV exposed microcephalic and normocephalic newborns were compared to non-infected controls. Our results reveal major alterations in circulating lipids from both ZIKV exposed newborns with and without microcephaly relative to controls. In newborns with microcephaly, the plasma concentrations of hydroxyoctadecadienoic acid (HODE), primarily as 13-HODE isomer, derived from linoleic acid were higher as compared to normocephalic ZIKV exposed newborns and controls. Total HODE concentrations were also positively associated with levels of other oxidized lipids and several circulating free fatty acids in newborns, indicating a possible plasma lipidome signature of microcephaly. Moreover, higher concentrations of lysophosphatidylcholine in ZIKV exposed normocephalic newborns relative to controls suggest a potential disruption of polyunsaturated fatty acids transport across the blood-brain barrier of fetuses. The latter data is particularly important given the neurocognitive and neurodevelopmental abnormalities observed in follow-up studies involving children with antenatal ZIKV exposure, but normocephalic at birth. Taken together, our data reveal that plasma lipidome alterations associated with antenatal exposure to ZIKV could contribute to identification and monitoring of the wide spectrum of clinical phenotypes at birth and further, during childhood.

Redox imbalance impedes photosynthetic activity in rice by disrupting cellular membrane integrity and induces programmed cell death under submergence.

Climate change negatively impacts the global hydrological resources leading to detrimental flood events. Submergence impedes the cellular membrane integrity, consequently affecting the membrane fluidity. Different abiotic stresses influence membrane lipid composition. Therefore, the remodeling of membrane lipids plays a major role in stress adaptation. Submergence-induced membrane lipid peroxidation is well established in plants. However, dynamic changes in lipid composition for regulating submergence tolerance in rice remain so far unexplored. The present study explored the effect of submergence on the lipidomic profile of the Sub1 near-isogenic lines (NILs) of rice, viz. Swarna, and Swarna Sub1 with contrasting submergence tolerance. The study also examined the association of lipidomic alteration with the membrane integrity and submergence tolerance. Submergence caused increased accumulation of reactive oxygen species (ROS), which was significantly higher in Swarna than Swarna Sub1. The lipid profile was also considerably altered under submergence. Following submergence, Swarna exhibited a significant decrease in phospholipid content accompanied by increased lipid peroxidation and electrolyte leakage. Furthermore, the disintegration of the thylakoid membrane resulted in a significant decrease in the chlorophyll content and photosynthesis rate under submergence. Submergence-induced hypoxic condition also promoted starch depletion to fulfill the energy requirement. In contrast, submergence acclimation in Swarna Sub1 was associated with the shift to anaerobic respiration mediated by increased alcohol dehydrogenase (ADH) activity. Effective ROS detoxification in Swarna Sub1 facilitated by increased antioxidant enzyme activities contributed to the submergence tolerance by maintaining membrane integrity and photosynthetic activity. The present study established the direct association of lipid remodeling with membrane integrity, cell viability, and photosynthesis and also devised a crop model to reveal the molecular background of submergence tolerance in plants.

Lipidomic alteration of plasma in cured COVID-19 patients using ultra high-performance liquid chromatography with high-resolution mass spectrometry.

Background: The pandemic of novel coronavirus disease 2019 (COVID-19) has become a serious public health crisis worldwide. The symptoms of COVID-19 vary from mild to severe among different age groups, but the physiological changes related to COVID-19 are barely understood.Methods: In the present study, a high-resolution mass spectrometry (HRMS)-based lipidomic strategy was used to characterize the endogenous plasma lipids for cured COVID-19 patients with different ages and symptoms. These patients were further divided into two groups: those with severe symptoms or who were elderly and relatively young patients with mild symptoms. In addition, automated lipidomic identification and alignment was conducted by LipidSearch software. Multivariate and univariate analyses were used for differential comparison.Results: Nearly 500 lipid compounds were identified in each cured COVID-19 group through LipidSearch software. At the level of lipid subclasses, patients with severe symptoms or elderly patients displayed dramatic changes in plasma lipidomic alterations, such as increased triglycerides and decreased cholesteryl esters (ChE). Some of these differential lipids might also have essential biological functions. Furthermore, the differential analysis of plasma lipids among groups was performed to provide potential prognostic indicators, and the change in signaling pathways.Conclusions: Dyslipidemia was observed in cured COVID-19 patients due to the viral infection and medical treatment, and the discharged patients should continue to undergo consolidation therapy. This work provides valuable knowledge about plasma lipid markers and potential therapeutic targets of COVID-19 and essential resources for further research on the pathogenesis of COVID-19.

Identification of a distinct lipidomic profile in the osteoarthritic synovial membrane by mass spectrometry imaging

Synovial inflammation is one of the most characteristic events in different types of arthritis, including Osteoarthritis (OA). Emerging evidence also suggests the involvement of lipids in the regulation of inflammatory processes. The aim of this study was to elucidate the heterogeneity and spatial distribution of lipids in the OA synovial membrane and explore their putative involvement in inflammation. The abundance and distribution of lipids were examined in human synovial membranes. To this end, histological cuts from this tissue were analysed by matrix-assisted laser desorption ionization - mass spectrometry imaging (MALDI-MSI). The lipidomic profile of OA synovium was characterized and compared with healthy and other forms of inflammatory arthropathies as Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) using principal component analysis and discriminant analysis methods. Lipid identification was undertaken by tandem MS analyses and database queries. Our results reveal differential and characteristic lipidomic profiles between OA and control samples. Specifically, we unveiled that OA synovium presents elevated levels of phosphatidylcholines, fatty acids and lysophosphatidic acids and lower levels of lysophosphatidylcholines compared to control tissues. The spatial distribution of particular glycerophospholipids was also correlated with hypertrophic, inflamed or vascularized synovial areas. Compared with other inflammatory arthritis, the OA tissue showed lower amounts of phosphatidylethanolamine-based plasmalogens. This study provides a novel insight into the lipid profiles of synovial membrane and differences in abundance between OA and control tissues. The lipidomic alterations improves understanding of the pathogenic mechanisms of OA and may be important for its diagnosis.

Tissue Lipidomic Alterations Induced by Prolonged Dexamethasone Treatment.

Dexamethasone is a synthetic glucocorticoid medication vastly used to treat abnormal immune responses and inflammation. Although the medication is well-established in the medical community, the prolonged treatment with high dosages of dexamethasone may lead to severe adverse effects through mechanisms that are not yet well-known. Lipids are a large class of hydrophobic molecules involved in energy storage, signaling, modulation of gene expression, and membranes. Hence, untargeted lipidomics may help unravel the biochemical alterations following prolonged treatment with high dosages of dexamethasone. We performed comprehensive lipidomic analyses of brain, heart, kidney, liver, and muscle samples obtained from rats that were treated with intramuscular injections of dexamethasone for 14 weeks compared to healthy controls. The employed methodology and statistical analysis showed that phosphatidic acids, glycerophospholipids, plasmalogens, and fatty acids are deeply affected by prolonged use of the medication. Brain tissue was only mildly affected, but skeletal muscle showed a strong accumulation of lipids that may be correlated with alterations in the energy metabolism, myopathy, and oxidative processes. This work provides new insights into the mechanisms of action and adverse effects for one of the most commonly prescribed class of drugs in the world.

Methylome and transcriptome profiling revealed epigenetic silencing of LPCAT1 and PCYT1A associated with lipidome alterations in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine diseases of fertile women and a major cause of infertility. The regulatory effects of DNA methylation on gene transcription and downstream lipid metabolism have not been explored in PCOS. In this study, MBD-seq and RNA-seq were performed on ovarian granulosa cells of PCOS patients and controls, and methylation specific PCR and quantitative polymerase chain reaction were used to validate the results. Then lipidomic profiling was conducted on serum of PCOS patients and controls using UPLC-MS. We identified 73 genes with differently methylated promoters and 830 differently expressed genes. The promoter regions of LPCAT1 and PCYT1A were hypermethylated, accompanied by downregulation of their messenger RNA expression, which may be involved in the regulation of PCOS through downstream glycerophospholipid metabolism and phosphatidylcholine synthesis. The lipid profiling results showed significant changes in 21 lipids, which demonstrated the disturbance in glycerophospholipid metabolism and glycerolipid metabolism pathways. Furthermore, the metabolites-genes interaction network was constructed to illustrate the association of aberrant methylome and transcriptome with lipidome alterations in glycerolipid and glycerophospholipid metabolism pathways. Our study suggested that the methylation silencing of LPCAT1 and PCYT1A may promote glycerophospholipids metabolism dysregulation, which provided a novel genetic and lipometabolic basis for the pathogenesis of PCOS.

Replication of SARS-CoV-2 in Adipose Tissue Determines Organ and Systemic Lipid Metabolism in Hamsters and Humans

Obesity increases the risk for poor outcome in patients with coronavirus disease-19 (COVID-19). However, the role of adipose tissue for viral propagation and potential metabolic implications are not understood. We detected SARS-CoV-2 in adipose tissue of overweight but not lean male COVID-19 patients. SARS-CoV-2 replicates to high titres in cultured mature adipocytes, a process depending on lipid accumulation and mobilization. After intranasal inoculation, we observed high viral replication in fat depots of Golden Syrian hamsters, demonstrating dissemination from the respiratory tract and subsequent propagation in adipose tissue. Following induction of pro-inflammatory responses, expression of de novo lipogenesis enzymes was suppressed in adipose tissue. This specific down-regulation was reflected by lipidomic alterations in plasma of SARS-CoV-2 infected hamsters as well as in hospitalized COVID-19 patients. Overall, our study highlights that adipose tissue is an important site of SARS-CoV-2 replication, contributing to dysregulation of systemic lipid metabolism.Funding: This study was supported by a rapid response grant from the Federal Ministry of Health (BMG; ZMV I 1-2520COR501 to GG), by DFG grants SCHE522/4-1 (LS) and SFB1328, project- ID:335447727 (JH). As part of the National Network University Medicine (NUM) funded by the Federal Ministry of Education and Research (BMBF, Germany), this work was funded within the research consortium DEFEAT PANDEMIcs, grant number 01KX2021 (FH, PL, KP, BO).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The Ethics Committee of the Hamburg Chamber of Physicians reviewed and approved the studies (PV7311, 2020-10353-BO-ff, WF-051/20, WF-053/20). For the preparation of primary human white adipocytes, biopsies of subcutaneous and visceral adipose tissues were taken during bariatric surgery at the Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf. All participants signed an informed consent and the study was approved by the Ethics Committee of the Hamburg Chamber of Physicians (PV4889).

Lipidomic Alterations and PPARα Activation Induced by Resveratrol Lead to Reduction in Lesion Size in Endometriosis Models

Endometriosis is an estrogen-dependent chronic inflammatory disease that affects approximately 10% of women of reproductive age and up to 50% of women with infertility. The heterogeneity of the disease makes accurate diagnosis and treatment a clinical challenge. In this study, we generated two models of endometriosis: the first in rats and the second using human ectopic endometrial stromal cells (HEcESCs) derived from the lesion tissues of endometriosis patients. We then applied resveratrol to assess its therapeutic potential. Resveratrol intervention had significant efficacy to attenuate lesion size and to rectify aberrant lipid profiles of model rats. Lipidomic analysis revealed significant lipidomic alterations, including notable increases of sphingolipids and decreases of both glycerolipids and most phospholipids. Upon resveratrol application, both proliferation capacity and invasiveness parameters decreased, and the early apoptosis proportion increased for HEcESCs. The activation of PPARα was also noted as a factor potentially contributing to recovery from endometriosis in both models. Our study provides valuable insight into the mechanisms of resveratrol in endometriosis and therefore strengthens the potential for optimizing resveratrol treatment for this disease.

Aerobic exercise effects on the peripheral plasma lipidome in mild cognitive impairment: The influence of prediabetes

AbstractBackgroundSubclinical glucose intolerance (pre‐Type 2 diabetes; pre‐T2D) likely influences cognitive decline in older adults. Disordered glucose metabolism may itself be a feature of early Alzheimer’s disease or mild cognitive impairment (MCI). While aerobic exercise may benefit episodic memory, the plasma lipidomic alterations associated with aerobic exercise in older, at‐risk or cognitively impaired adults remains unclear.MethodWe performed a retrospective analysis of 95 participants randomly assigned to Aerobic Exercise (n = 54) or Stretching (n = 41) arms in the Piedmont Aging, Cognition, and Exercise (PACE) studies. Analysis of blood lipids was conducted using the QTRAP® 5500 LC‐MS/MS (Sciex) targeted mass spectrometry platform. Co‐expressed lipid modules were identified and submitted to differential expression (DE) analysis.ResultsFactorial analysis of co‐expressed lipids revealed a pattern of complex expression heterogeneity. We found a significant metabolic status (pre‐T2D/ MCI/ comorbid) by treatment arm (Aerobic Exercise/ Stretching) by time point (pre/post intervention) interaction (p = 0.02). Specifically, we see a significant reduction of long chain/ very long chain triacylglycerides (TAGs) in the comorbid (pre‐T2D + MCI) group following aerobic exercise (p=0.03).ConclusionThese findings suggest a complex interrelationship between aerobic exercise and peripheral dyslipidemia associated with pre‐T2D in the context of MCI. Specifically, we see reductions in TAGs following exercise only when the two risk factors are comorbid, but not when they occur alone. These findings may be of value as biomarkers of exercise‐intervention response and suggest specific populations that may benefit from aerobic exercise. Future study of these interrelated risk factors modifying exercise benefit is warranted to understand which MCI patients will benefit from aerobic exercise.

APOC3 rs2070667 Associates with Serum Triglyceride Profile and Hepatic Inflammation in Nonalcoholic Fatty Liver Disease

Single-nucleotide polymorphisms (SNPs) of apolipoprotein C3 (APOC3) play important role in lipid metabolism, and dyslipidemia underlies nonalcoholic fatty liver disease (NAFLD). But the correlation of serum lipidomics, APOC3 SNPs, and NAFLD remains limited understood. Enrolling thirty-four biopsy-proven NAFLD patients from Tianjin, Shanghai, Fujian, we investigated their APOC3 genotype and serum lipid profile by DNA sequencing and ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), respectively. Scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was then performed to reveal the role of lipidomics-affecting APOC3 SNPs in NAFLD-specific pathological alterations. Here, we reported that APOC3 SNPs (rs4225, rs4520, rs5128, rs2070666, and rs2070667) intimately correlated to serum lipidomics in NAFLD patients. A allele instead of G allele at rs2070667, which dominated the SNPs underlying lipidomic alteration, exhibited downregulatory effect on triacylglycerols (TGs: TG 54 : 7, TG 54 : 8, and TG 56 : 9) containing polyunsaturated fatty acid (PUFA). Moreover, subjects with low-level PUFA-containing TGs were predisposed to high-grade lobular inflammation (TG 54 : 7, rho = −0.454 and P = 0.007; TG 54 : 8, rho = −0.411 and P =0.016; TG 56 : 9, rho = −0.481 and P = 0.004). The significant correlation of APOC3 rs2070667 and inflammation grading [G/G vs. G/A+A/A: 0.00 (0.00 and 1.00) vs. 1.50 (0.75 and 2.00), P = 0.022] further confirmed its pathological action on the basis of lipidomics-impacting activity. These findings suggest an inhibitory effect of A allele at APOC3 rs2070667 on serum levels of PUFA-containing TGs, which are associated with high-grade lobular inflammation in NAFLD patients.

Photosynthetic pigment production and metabolic and lipidomic alterations in the marine cyanobacteria Synechocystis sp. PCC 7338 under various salinity conditions

Synechocystis sp. PCC 7338 (hereafter referred to as Synechocystis 7338) is a marine cyanobacterium that has the potential to produce photosynthetic pigments. In this study, we investigated the effects of various NaCl concentrations (0, 0.4, 0.8, and 1.2 M) on cell growth, photosynthetic pigments, and metabolites and intact lipid species profiles in Synechocystis 7338. The overall growth pattern of Synechocystis 7338 was similar under 0, 0.4, and 0.8 M NaCl conditions. Cell growth was retarded after reaching the exponential phase under 1.2 M NaCl; however, a similar growth pattern was observed after the exponential phase under 0.4 M NaCl (control group). The highest production of chlorophyll a (4.18 mg L−1), allophycocyanin (4.08 mg L−1), and phycoerythrin (1.70 mg L−1) were achieved under 1.2 M NaCl conditions. Altered metabolic and lipidomic profiles were observed at different NaCl conditions; significantly increased relative yields of glucosylglycerol, one diacylglyceryltrimethylhomoserine, one monogalactosyldiacylglycerol, and four phosphatidylglycerol species were observed under 1.2 M NaCl conditions using gas chromatography–mass spectrometry and direct infusion–mass spectrometry analyses. In addition, it was revealed that the photosynthetic activity recovered under 1.2 M NaCl conditions in long-term culture. Hydrogen peroxide content significantly increased under 1.2 M NaCl conditions. It is believed that glutathione content also significantly increased under high salinity conditions to retain the normal functioning of Synechocystis 7338. These results indicate that high salinity conditions for Synechocystis 7338 culture could be used for the large-scale production of chlorophyll a, allophycocyanin, phycoerythrin, and other bioactive metabolites.

Lipidome Alterations Induced by Cystic Fibrosis, CFTR Mutation, and Lung Function.

Cystic fibrosis is a genetic pathology characterized by abnormal accumulation of mucus in the respiratory, gastrointestinal, and reproductive tracts, caused by mutations in the CFTR gene. Although the classical presentation of the condition is well known, there is still a need for a better characterization of metabolic alterations related to cystic fibrosis and different genotypic mutations. We employed untargeted, comprehensive lipidomics of blood serum samples to investigate alterations in the lipid metabolism related to the pathology, mutation classes, and lung function decline. Six unique biomarker candidates were able to independently differentiate diseased individuals from healthy controls with excellent performance. Cystic fibrosis patients showed dyslipidemia for most lipid subclasses, with significantly elevated odd-chain and polyunsaturated fatty acyl lipids. Phosphatidic acids and diacylglycerols were particularly affected by different genotypic mutation classes. We selected a biomarker panel composed of four lipids, including two ceramides, one sphingomyelin, and one fatty acid, which correctly classified all validation samples from classes III and IV. A biomarker panel of five oxidized lipids was further selected to differentiate patients with reduced lung function, measured as predicted FEV1%. Our results indicate that cystic fibrosis is deeply related to lipid metabolism and provide new clues for the investigation of the disease mechanisms and therapeutic targets.