Lipidomic Profiling Research Articles

Changes in lipid abundance are associated with disease progression and treatment response in chronic Trypanosoma cruzi infection

BackgroundChagas disease, caused by the parasite Trypanosoma cruzi, is a zoonosis that affects more than seven million people. Current limitations on the diagnosis of the disease hinder the prognosis of patients and the evaluation of treatment efficacy, slowing the development of new therapeutic options. The infection is known to disrupt several host metabolic pathways, providing an opportunity for the identification of biomarkers.MethodsThe metabolomic and lipidomic profiles of a cohort of symptomatic and asymptomatic patients with T. cruzi infection and a group of uninfected controls were analysed using liquid chromatography/mass spectrometry. Differences among all groups and changes before and after receiving anti-parasitic treatment across those with T. cruzi infection were explored.ResultsThree lipids were found to differentiate between symptomatic and asymptomatic participants: 10-hydroxydecanoic acid and phosphatidylethanolamines PE(18:0/20:4) and PE(18:1/20:4). Additionally, sphinganine, 4-hydroxysphinganine, hexadecasphinganine, and other sphingolipids showed post-treatment abundance similar to that in non-infected controls.ConclusionsThese molecules hold promise as potentially useful biomarkers for monitoring disease progression and treatment response in patients with chronic T. cruzi infection.Graphical

Untargeted Lipidomic Profiling of Amniotic Fluid Reveals Dysregulated Lipid Metabolism in Healthy Normal-Weight Mothers with Fetal Macrosomia

Background: Alterations in maternal lipid metabolism have been elucidated by several studies in relation to macrosomia. However, the lipidome of the intrauterine compartment associated with macrosomia, particularly in early pregnancy, remains largely unknown. Objectives: (1) To compare the lipidomic profile of early 2nd trimester amniotic fluid (AF) of healthy mothers with normal body mass index who gave birth to large-for-gestational age (LGA) versus appropriate-for-gestational age (AGA) infants; and (2) to examine if insulin and glucose concentrations in AF were associated with the AF lipidomic profile. Methods: In this nested case–control study, bio-banked AF samples were collected from pregnant women undergoing routine amniocentesis at 12–22 weeks of gestation. A subsample of 15 LGA infants (cases) were contrasted with 15 AGA infants (controls). An untargeted lipidomics analysis using liquid chromatography quadrupole time-of-flight mass spectrometry was conducted. Univariate and multivariate statistical analyses (principal component analysis and partial least-squares discriminant analysis) were used to extract differentially abundant (DA) features with high variable importance in projection (VIP) scores. Results: LGA AF was characterized by elevations of 30 phosphatidic acid species. Among other DA features, sphingomyelin (SM 14:0;O2/20:1) had the highest VIP score and was markedly elevated in LGA AF. Neither insulin nor glucose was associated with 2nd trimester AF lipidomic profiles in these healthy, normal-weight mothers. Conclusion: These findings provide evidence of early dysregulated lipid metabolism in healthy, normal-weight mothers with LGA infants.

The CSF lipid profile in patients with probable idiopathic normal pressure hydrocephalus differs from control but does not differ between shunt responders and non-responders

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a common form of hydrocephalus in the elderly, characterized by enlarged ventricles combined with clinical symptoms presenting as gait impairment, urinary incontinence, and dementia. iNPH may be difficult to differentiate clinically from other neurodegenerative disorders, and up to 80% of cases may remain unrecognized and thus untreated. Consequently, there is a pressing demand for biomarkers that can confirm the diagnosis of iNPH. In this exploratory study, CSF was sampled from the lumbar compartment of 21 control individuals and 19 probable iNPH patients and analysed by an untargeted mass spectroscopy-based platform to reveal a complete CSF lipid profile in these samples. 244 lipids from 17 lipid classes were detected in CSF. Various lipid classes, and select individual lipids, were reduced in the CSF obtained from patients with probable iNPH, whereas a range of lipids belonging to the class of triacylglycerols was elevated. We detected no difference in the CSF lipid profile between probable iNPH patients with and without clinical improvement following CSF shunting. In conclusion, the lipidomic profile of the CSF in patients with probable iNPH therefore may serve as a thought after biomarker of the pathology, which may be employed to complement the clinical diagnosis.

Lipidomic Profiling of Common Wheat Flours from 1891-2010.

Wheat lipids are a minor constituent of wheat, with an important influence on its processing properties. While breeding aimed to improve the protein composition of wheat flour, its influence on the lipid composition remains unknown. We therefore analyzed the lipidome of 60 different common wheat (Triticum aestivum) flours representing cultivars registered and grown in Germany from 1891 to 2010. Four different extraction techniques were tested before the application of a semiquantitative, untargeted UHPLC-MS/MS method. The measurements included 16 different lipid classes and 102 different lipid species. Based on the lipid profile, discrimination between old (registered between 1891 to 1950) and modern (1951 to 2010) cultivars was possible. While the lipid class composition remained constant, differences were due to variations within the class of triacylglycerols, with modern cultivars containing less unsaturated fatty acids than the older ones. Our results imply that improving the lipid class composition of common wheat is a promising target for further breeding.

Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts

Background/Objectives: Breast cancer (BC) is the second most commonly diagnosed cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle. Methods: The pioglitazone and vehicle groups were treated orally for 4 weeks upon reaching a tumor volume of 600 mm3. Whole-animal indirect calorimetry was used to evaluate systemic metabolic states. The transcriptome was profiled using short-read bulk RNA sequencing (RNA-seq). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to profile the metabolome and lipidome. Fast and slow skeletal muscle function were evaluated using isolated ex vivo testing. Results: Pioglitazone was associated with a 16.634% lower average O2 consumption (mL∙h−1, p = 0.035), 16.309% lower average CO2 production (mL∙h−1, p = 0.022), and 16.4% lower cumulative energy expenditure (EE) (kcal∙h−1, p = 0.035), with no changes in substrate utilization. RNA-seq supported the downstream effects of pioglitazone on target genes and displayed considerable upregulation of mitochondrial bioenergetic pathways. K-means cluster 5 showed enrichment of the PPAR signaling pathway (adj. p < 0.05, Log2FC = 2.58). Skeletal muscle metabolomic and lipidomic profiles exhibited dysregulation in response to BC, which was partially restored in pioglitazone-treated mice compared to vehicle-treated BC-PDOX mice. In particular, the overall abundance of total ceramide levels was significantly lower in the PioTx group (−46.327%, p = 0.048). Despite molecular support for pioglitazone’s efficacy, isolated muscle function was not affected by pioglitazone treatment. No significant difference in the area under the fatigue curve (AUC) was found between the pioglitazone and vehicle groups (p = 0.596). Conclusions: BC induces multi-omic dysregulation in skeletal muscle, which pioglitazone partially ameliorates. Future research should focus on profiling systemic metabolic dysfunction, identifying molecular biomarkers of fatigue, and testing alternative pioglitazone treatment regimens.

Association of serum lipidomic profiles with risk of intracranial aneurysm: A Mendelian randomization study.

A two-sample Mendelian randomization (MR) analysis was utilized to assess the causal relationship between lipidomic profiles and the risk of intracranial aneurysms (IAs). Genetic variants related to lipidomic profiles (227 components) and IA [IA, aneurysmal subarachnoid hemorrhage (aSAH) only, unruptured IA (uIA) only] were obtained from published genome-wide association studies (GWASs) or the IEU Open GWAS project and used as instrumental variables for MR analysis. The inverse-variance weighted method was used in the primary analyses to derive causality estimates and was expressed as odds ratio (OR) with 95% confidence interval (CI). Of these 227 lipidomic profiles, only genetically predicted high levels of cholesterol to total lipids ratio in very small very-low-density lipoproteins (VLDL) [OR = 0.629 (95% CI, 0.504-0.786)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.637 (95% CI, 0.509-0.797)], ratio of docosahexaenoic acid to total fatty acids [OR = 0.691 (95% CI, 0.582-0.820)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.630 (95% CI, 0.522-0.760)] reduced the risk of aSAH, whereas genetically predicted high ratio of monounsaturated fatty acids to total fatty acids [OR = 1.471 (95% CI, 1.215-1.781)] increased the risk of aSAH. Moreover, genetically predicted high levels of cholesterol to total lipids ratio in very small VLDL [OR = 0.657 (95% CI, 0.542-0.798)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.663 (95% CI, 0.548-0.803)], free cholesterol to total lipids ratio in small VLDL [OR = 0.682 (95% CI, 0.560-0.832)], phospholipids to total lipids ratio in small VLDL [OR = 0.674 (95% CI, 0.548-0.830)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.678 (95% CI, 0.569-0.808)] reduced the risk of IA. The results of multivariable MR demonstrated that these causal associations persisted after adjusting for systolic blood pressure and cigarettes smoked per day. The effect of serum lipids on IA and aSAH may be mainly caused by subclasses of lipids such as VLDL.

Plasma Lipidomic Profiles Improve upon Traditional Risk Factors for the Prediction of Arterial Stiffness Among Patients with Type 2 Diabetes Mellitum: A Randomized, Placebo-Controlled Trial

Background: Exercise or vitamin D intervention can reduce the risk of arterial stiffness; however, the underlying mechanisms of lipid metabolism remain unexplored. To examine the effects of a 12-week moderate and vigorous exercise program (65–80% maximal heart rate, 60 min/time, 2~3 times/week) with or without vitamin D supplementation (1000 IU/day) on the reduction in arterial stiffness and further explore whether the effects of interventions could be associated with the basal lipidome among patients with Type 2 diabetes mellitum (T2DM). Method: 61 patients with T2DM were randomly assigned to the following groups: control (CON, n = 15), exercise (EX, n = 14), vitamin D (VD, n = 16), and exercise + vitamin D (EX + VD, n = 16). Arterial stiffness risk factors (ankle–brachial index (ABI); brachial–ankle pulse wave velocity (baPWV), systolic blood pressure (SBP), and diastolic blood pressure (DBP)) were evaluated before and after the intervention. The plasma lipidome was determined using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Machine learning was applied to establish prediction models for the responsiveness to arterial stiffness. Result: Vitamin D supplementation could inhibit the decrease in the ankle–brachial index (mean ± SD: EX + VD and VD, −0.001 ± 0.058; EX + CON, −0.047 ± −0.089; p = 0.03). We observed high inter-individual variability in the arterial stiffness risk factors in response to the interventions. We also found that optimally selecting the lipid predictors at baseline, such as SM d44:6, LPE 18:2, and Hex2Cer 29:0, could enhance the predictive power by 100% for arm SBP changes in the exercise group. Basal levels of Cer (33:1) and GM3 (44:4) could enhance the predictive power by 100% for changes in baPWV in the vitamin D group. Conclusions: A 12-week vitamin D supplementation was beneficial in preventing arterial stiffness. Compared with traditional clinical risk factors, specific lipids at baseline could significantly improve the ability to predict intervention-induced changes in the reduction of arterial stiffness.

PTPRZ1 dephosphorylates and stabilizes RNF26 to reduce the efficacy of TKIs and PD-1 blockade in ccRCC.

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often exhibits resistance to tyrosine kinase inhibitors (TKIs) when used as monotherapy. However, the integration of PD-1 blockade with TKIs has significantly improved patient survival, making it a leading therapeutic strategy for ccRCC. Despite these advancements, the efficacy of this combined therapy remains suboptimal, necessitating a deeper understanding of the underlying regulatory mechanisms. Through comprehensive analyses, including mass spectrometry, RNA sequencing, lipidomic profiling, immunohistochemical staining, and ex vivo experiments, we explored the interaction between PTPRZ1 and RNF26 and its impact on ccRCC cell behavior. Our results revealed a unique interaction where PTPRZ1 stabilized RNF26 protein expression by dephosphorylating it at the Y432 site. The modulation of RNF26 levels by PTPRZ1 was found to be mediated through the proteasome pathway. Additionally, PTPRZ1, via its interaction with RNF26, activated the TNF/NF-κB signaling pathway, thereby promoting cell proliferation, angiogenesis, and lipid metabolism in ccRCC cells. Importantly, inhibiting PTPRZ1 enhanced the sensitivity of ccRCC to TKIs and PD-1 blockade, an effect that was attenuated when RNF26 was simultaneously knocked down. These findings highlight the critical role of the PTPRZ1-RNF26 axis in ccRCC and suggest that combining PTPRZ1 inhibitors with current TKIs and PD-1 blockade therapies could significantly improve treatment outcomes for ccRCC patients.

Lipidomic profiling of serum and liver tissue reveals hepatoprotective mechanism of taxifolin in rats with CCl4-induced subacute hepatic injury based on LC-MS/MS

Currently, the hepatoprotective activity of taxifolin, a flavonoid isolated from Pseudotsuga taxifolia, has been reported in many animal models. However, whether the protective effect of taxifolin on the liver is related to its effect on lipidomics is unclear. Based on the significant therapeutic effect of taxifolin on CCl4 induced subacute hepatic injury, we observed the intervention of taxifolin by lipidomics. The results demonstrate that taxifolin can effectively reverse the damage caused by CCl4, which including hepatocyte vacuolization and necrosis. Lipomic profiling based on liquid chromatography-mass spectrometry showed that taxifolin was able to restore lipidomic changes caused by CCl4, including the levels of lysophosphatidylserine (LPS), phosphatidylcholine (PC), coenzyme (Co), phosphatidylglyceride (PG), phosphatidylserine (PS), dimethylphosphatidylethanolamine (dMePE), ceramide (Cer), sphingosine (So), triglycerides (TG), and monogalactosyl diacylglycerol (MGDG) in the rat liver, and phosphatidylcarbinol (PMe) and phosphatidylethanolamine (PE), plant sphingosine (phSM), glucose ceramide (CerG1), TG, and diglycerides (DG) in serum. Spearman's correlation analysis showed that CerG1, phSM, PE, and PMe in serum, and Cer, dMePE, PG, PS, So, TG, and MGDG in liver were positively correlated with serum levels of aspartate transaminase, alanine transaminase, and liver index; while TG, DG in serum, and Co, LPS, PC in liver were negatively correlated with the parameters. In total, 43 and 34 lipid molecules were altered by taxifolin treatment in the liver and serum, respectively, mainly including glycerophosphoglycerols, glycerophosphocholines, glycerophosphoethanolamines, and linoleic acids and derivatives. Our findings help to provide novel insights into the mechanism of the hepatoprotective effect of taxifolin from a lipidomics approach.

Healthy plasma lipidomic signatures depend on sex, age, body mass index, and contraceptives but not perceived stress.

Perceived stress is thought to contribute to the pathogenesis of metabolic, vascular, mental, and immune diseases, with different susceptibilities in women and men. The present study investigated if and how perceived stress and/or demographic variables including sex, age, body mass index, regular prescription drugs, occasional analgesics, or dietary supplements manifested in plasma lipidomic profiles, obtained by targeted and untargeted mass spectrometry analyses. The study included 217 healthy women and 108 healthy men, aged 18-68 years, who were recruited in a 2:1 female:male ratio to account for women with/without contraceptives. As expected, dehydroepiandrosterone sulfate (DHEAS) and ceramides were higher in men than women, and DHEAS decreased with age, while ceramides increased. Contrary to expectations, neither DHEAS nor ceramides were associated with perceived stress (PSQ30 questionnaire), which was however, associated with BMI in men, but not in women. None of the lipid species or classes showed a similar "age X sex X BMI" interaction, but the endocannabinoid palmitoylethanolamide (PEA) correlated with BMI and hypertension. Independent of perceived stress, lysophosphatidylcholines (LPCs) were lower in women than men, whereas LPC metabolites, lysophosphatidic acids (LPAs), were higher in women. The LPA:LPC ratio was particularly high in women using oral contraceptives suggesting a strong hormone-induced extracellular conversion of LPCs to LPAs, which is catalyzed by the phospholipase D, autotaxin. The results reveal complex sex differences in perceived stress and lipidomic profiles, the latter being exacerbated by contraceptive use, but perceived stress and lipids were not directly correlated.

Bioactive Lipids in Dunaliella salina: Implications for Functional Foods and Health.

Dunaliella salina is a green microalga extensively explored for β-carotene production, while knowledge of its lipid composition is still limited and poorly investigated. Among lipids, polar lipids have been highlighted as bioactive phytochemicals with health-promoting properties. This research aimed to provide an in-depth lipidome profiling of D. salina using liquid and gas chromatography coupled with mass spectrometry. The lipid content was 6.8%, including phospholipids, glycolipids, betaine lipids, sphingolipids, triglycerides, diglycerides, and pigments. Among the total esterified fatty acids, 13.6% were 18:3 omega-3 and 14.7% were 18:1 omega-9. The lipid extract of D. salina showed anti-inflammatory activity by inhibiting cyclooxygenase-2 activity at 100 µg/mL, dose-dependent antioxidant scavenging activity, and antidiabetic activity by inhibiting α-glucosidase activity at 25 and 125 µg/mL. In conclusion, the lipid extract of D. salina has the potential to be used as a functional food ingredient or in the nutraceutical and cosmeceutical industries.

MASLD in persons with HIV is associated with high cardiometabolic risk as evidenced by altered advanced lipoprotein profiles and targeted metabolomics

BackgroundMetabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles.MethodsThis is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters.ResultsOf 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m2. Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use.ConclusionsMASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population.

Impact of soluble epoxide hydrolase inhibition on silica-induced pulmonary fibrosis, ectopic lymphoid neogenesis, and autoantibody production in lupus-prone mice

Objective Acute intranasal (IN) instillation of lupus-prone NZBWF1 mice with crystalline silica (cSiO2) triggers robust lung inflammation that drives autoimmunity. Prior studies in other preclinical models show that soluble epoxide hydrolase (sEH) inhibition upregulates pro-resolving lipid metabolites that are protective against pulmonary inflammation. Herein, we assessed in NZBWF1 mice how acute IN cSiO2 exposure with or without the selective sEH inhibitor TPPU influences lipidomic, transcriptomic, proteomic, and histopathological biomarkers of inflammation, fibrosis, and autoimmunity. Methods Female 6-week-old NZBWF1 mice were fed control or TPPU-supplemented diets for 2 weeks then IN instilled with 2.5 mg cSiO2 or saline vehicle. Cohorts were terminated at 7 or 28 days post-cSiO2 instillation (PI) and lungs analyzed for prostaglandins, cytokines/chemokines, gene expression, differential cell counts, histopathology, and autoantibodies. Results cSiO2-treatment induced prostaglandins, cytokines/chemokine, proinflammatory gene expression, CD206+ monocytes, Ly6B.2+ neutrophils, CD3+ T cells, CD45R+ B cells, centriacinar inflammation, collagen deposition, ectopic lymphoid structure neogenesis, and autoantibodies. While TPPU effectively inhibited sEH as reflected by skewed lipidomic profile in lung and decreased cSiO2-induced monocytes, neutrophils, and lymphocytes in lung lavage fluid, it did not significantly impact other biomarkers. Discussion cSiO2 evoked robust pulmonary inflammation and fibrosis in NZBWF1 mice that was evident at 7 days PI and progressed to ELS development and autoimmunity by 28 days PI. sEH inhibition by TPPU modestly suppressed cSiO2-induced cellularity changes and pulmonary fibrosis. However, TPPU did not affect ELS formation or autoantibody responses, suggesting sEH minimally impacts cSiO2-triggered lung inflammation, fibrosis, and early autoimmunity in our model.

Plasma lipidomic signatures of dementia with Lewy bodies revealed by machine learning, and compared to Alzheimer's disease

BackgroundDementia with Lewy Bodies (DLB) is a complex neurodegenerative disorder that often overlaps clinically with Alzheimer’s disease (AD), presenting challenges in accurate diagnosis and underscoring the need for novel biomarkers. Lipidomic emerges as a promising avenue for uncovering disease-specific metabolic alterations and potential biomarkers, particularly as the lipidomics landscape of DLB has not been previously explored. We aim to identify potential diagnostic biomarkers and elucidate the disease's pathophysiological mechanisms.MethodsThis study conducted a lipidomic analysis of plasma samples from patients with DLB, AD, and healthy controls (HCs) at Xuanwu Hospital. Untargeted plasma lipidomic profiling was conducted via liquid chromatography coupled with mass spectrometry. Machine learning methods were employed to discern lipidomic signatures specific to DLB and to differentiate it from AD.ResultsThe study enrolled 159 participants, including 57 with AD, 48 with DLB, and 54 HCs. Significant differences in lipid profiles were observed between the DLB and HC groups, particularly in the classes of sphingolipids and phospholipids. A total of 55 differentially expressed lipid species were identified between DLB and HCs, and 17 between DLB and AD. Correlations were observed linking these lipidomic profiles to clinical parameters like Unified Parkinson’s Disease Rating Scale III (UPDRS III) and cognitive scores. Machine learning models demonstrated to be highly effective in distinguishing DLB from both HCs and AD, achieving substantial accuracy through the utilization of specific lipidomic signatures. These include PC(15:0_18:2), PC(15:0_20:5), and SPH(d16:0) for differentiation between DLB and HCs; and a panel includes 13 lipid molecules: four PCs, two PEs, three SPHs, two Cers, and two Hex1Cers for distinguishing DLB from AD.ConclusionsThis study presents a novel and comprehensive lipidomic profile of DLB, distinguishing it from AD and HCs. Predominantly, sphingolipids (e.g., ceramides and SPHs) and phospholipids (e.g., PE and PC) were the most dysregulated lipids in relation to DLB patients. The lipidomics panels identified through machine learning may serve as effective plasma biomarkers for diagnosing DLB and differentiating it from AD dementia.

Longitudinal lipidomic profiles of left ventricular mass and hypertrophy in American Indians.

Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.

Serum lipidome reveals lipid metabolic dysregulation in severe fever with thrombocytopenia syndrome

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients.MethodsThis study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals.ResultsOur findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing “dual changes” including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection.ConclusionsOur study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease.

Blood plasma lipid profile in glial tumors

Introduction. In glial tumors, lipid metabolism becomes abnormal. Analysis of lipid metabolism components can be an important characteristic of molecular and genetic profile of gliomas.Aim. To determine the correlation between plasma lipidome profile and immunohistochemical characteristics of glial tumors and to evaluate clinical significance of blood lipid spectrum analysis in preoperative assessment of molecular profile of gliomas.Materials and methods. Immunohistochemical measurement of O-6-methylguanine-DNA-methyl transferase (MGMT), Ki-67, p53, IDH1 tumor markers was performed using the corresponding antibody clones. Composition of plasma lipids was assessed using thin layer chromatography.Results. Even at the early stages of gliomagenesis, significant differences in cholesterol ethers, lysophosphatidylcholines, phosphatidylcholine (PC)/ lysophosphatidylcholine (LPC) ratio, neutral lipids (NL)/phospholipids (PL) in the blood were observed. Significant correlations between Ki-67, MGMT tumor markers and the above-mentioned lipidome parameters were found. The PC/LPC, NL/PL ratios in the blood of the patients from the groups with higher (above 10 %) and lower (below 10 %) Ki-67 mitotic indexes compared to healthy individuals were significantly lower. Therefore, the values of lipidome parameters allow to indirectly assess proliferative activity of gliomas which can be used for preoperative diagnosis of these tumors. No significant differences in the plasma PC/LPC and NL/PL ratios were found between the groups with MGMT promoter methylation and without it. No indirect predictor criteria for MGMT were found.Conclusion. It is impossible to determine decreased epigenetic activity of corresponding transcripts and preoperative prognosis for alkylating agent therapy based on the parameters of plasma lipid metabolism.

Exposure to PFOA, PFOS, and PFHxS induces Alzheimer's disease-like neuropathology in cerebral organoids

Per- and polyfluoroalkyl substances (PFASs), a class of ubiquitous synthetic organic chemicals, are widely utilized across various industrial applications. However, the long-term neurological health effects of PFAS mixture exposure in humans remain poorly understood. To address this gap, we have designed a comprehensive study to predict and validate cell-type-specific neurotoxicity of PFASs using single-cell RNA sequencing (scRNA-seq) and cerebral organoids. Cerebral organoids were exposed to a PFAS mixture at concentrations of 1 × (10 ng/ml PFOS and PFOA, and 1 ng/ml PFHxS), 30 × , and 900 × over 35 days, with a follow-up analysis at day 70. Pathological alterations and lipidomic profiles were analyzed to identify disrupted molecular pathways and mechanisms. The scRNA-seq data revealed a significant impact of PFASs on neurons, suggesting a potential role in Alzheimer's Disease (AD) pathology, as well as intellectual and cognitive impairments. PFAS-treated cerebral organoids exhibited Aβ accumulation and tau phosphorylation. Lipidomic analyses further revealed lipid disturbances in response to PFAS mixture exposure, linking PFAS-induced AD-like neuropathology to sphingolipid metabolism disruption. Collectively, our findings provide novel insights into the PFAS-induced neurotoxicity, highlighting the significance of sphingolipid metabolism in the development of AD-like neuropathology. The use of cerebral organoids and scRNA-seq offers a powerful methodology for evaluating the health risks associated with environmental contaminants, particularly those with neurotoxic potential.

Exploring the circulating metabolome of sepsis: metabolomic and lipidomic profiles sampled in the ambulance

BackgroundSepsis is defined as a dysfunctional host response to infection. The diverse clinical presentations of sepsis pose diagnostic challenges and there is a demand for enhanced diagnostic markers for sepsis as well as an understanding of the underlying pathological mechanisms involved in sepsis. From this perspective, metabolomics has emerged as a potentially valuable tool for aiding in the early identification of sepsis that could highlight key metabolic pathways and underlying pathological mechanisms.ObjectiveThe aim of this investigation is to explore the early metabolomic and lipidomic profiles in a prospective cohort where plasma samples (n = 138) were obtained during ambulance transport among patients with infection according to clinical judgement who subsequently developed sepsis, patients who developed non-septic infection, and symptomatic controls without an infection.MethodsMultiplatform metabolomics and lipidomics were performed using UHPLC–MS/MS and UHPLC–QTOFMS. Uni- and multivariable analysis were used to identify metabolite profiles in sepsis vs symptomatic control and sepsis vs non-septic infection.ResultsUnivariable analysis disclosed that out of the 457 annotated metabolites measured across three different platforms, 23 polar, 27 semipolar metabolites and 133 molecular lipids exhibited significant differences between patients who developed sepsis and symptomatic controls following correction for multiple testing. Furthermore, 84 metabolites remained significantly different between sepsis and symptomatic controls following adjustment for age, sex, and Charlson comorbidity score. Notably, no significant differences were identified in metabolites levels when comparing patients with sepsis and non-septic infection in univariable and multivariable analyses.ConclusionOverall, we found that the metabolome, including the lipidome, was decreased in patients experiencing infection and sepsis, with no significant differences between the two conditions. This finding indicates that the observed metabolic profiles are shared between both infection and sepsis, rather than being exclusive to sepsis alone.

8182 New Mouse Model Mirrors Human MODY8: Opening Doors to Understanding Exocrine-Endocrine Crosstalk in the Diabetic Pancreas

Abstract Disclosure: K. El Jellas: None. V. Salerno: None. L.S. Katz: None. J. Hu: None. G. Fogarty: None. A. Mandal: None. A. DiStefano-Forti: None. D. Scott: None. M. Lowe: None. A. Molven: None. R.N. Kulkarni: None. Maturity-onset diabetes of the young, type 8 (MODY8) is a dominantly inherited form of monogenic diabetes, caused by heterozygous mutations in the carboxyl ester lipase (CEL) gene expressed in pancreatic acinar cells. MODY8 is characterized by chronic pancreatitis and exocrine dysfunction. Despite the intimate anatomical relationship between the endocrine and exocrine pancreas, little is known about the biological components mediating exocrine-endocrine communication in regulating glucose homeostasis. Here, we report a refined mouse model that bears the mutation present in MODY8 patients on one allele, and the humanized normal variable number of tandem repeat (VNTR) of CEL with 16 repeats (16R) on the other, mimicking the genetic make-up seen in MODY8 patients. Examination of glucose homeostasis revealed that inducing stress (e.g. by high-fat diet) leads to glucose intolerance in MODY8/16R mice and a blunted glucose-stimulated insulin-secretion compared to their control littermates. Histopathological analyses demonstrated features of chronic pancreatitis in some pancreatic lobes, including inflammation, acinar atrophy, acinar-to-ductal metaplasia, fibrosis and fat infiltration, mirroring the morphology of the human disease. Moreover, we applied immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) to intact pancreata and found that beta-cell mass was significantly decreased in the MODY8/16R mice, with a large number of islets located within fatty lobes. These results are coupled with comparative proteomics and lipidomic profiling with the aim of understanding the molecular signatures of exocrine and endocrine cells during pathogenesis. In conclusion, we have generated a mouse that recapitulates several features of the exocrine and endocrine phenotype characteristic of human MODY8. This novel model provides a unique opportunity, not possible in humans, to characterize pancreatic endocrine-exocrine communication in a longitudinal manner as a response to diverse environmental stressors. Presentation: 6/2/2024