Plasma Lipidomic Profiles Research Articles

Relationships between plasma lipidomic profiles and brown adipose tissue density in humans

Background/objectivesThe thermogenic function of brown adipose tissue (BAT) is generally activated in winter and tightly regulated through various metabolic processes. However, the mechanisms mediating these changes have not been elucidated in humans. Here, we investigated the relationships between BAT density (BAT-d) and lipid metabolites in plasma from men and women in the winter and summer.Subjects/methodsIn total, 92 plasma samples were obtained from 23 men and 23 women, aged 21–55 years, on two different occasions (summer and winter). Lipid metabolites were comprehensively quantified using liquid chromatography-time-of-flight-mass spectrometry. BAT-d was evaluated by measuring total hemoglobin concentrations in the supraclavicular region using near-infrared time-resolved spectroscopy. Anthropometric parameters, such as the percentage of whole body fat and visceral fat area (VFA), were evaluated. Factors influencing BAT-d were investigated by univariate and multivariate regression analyses.ResultsA variety of metabolite peaks, such as glycerophospholipids (168 peaks), steroids and derivatives (78 peaks), fatty acyls (62 peaks), and glycerolipids (31 peaks), were detected. Univariate regression analysis, corrected by false discovery rate to yield Q values, revealed significant correlations in BAT-d and phosphatidylethanolamine (PE(46:2), r = 0.62, Q = 4.9 × 10−2) in the summer, androgens (r = 0.75, Q = 7.0 × 10−3) in the winter, and diacylglycerol (DG(36:1), r = −0.68, Q = 4.9 × 10−2) in the summer in men, but not in women. Multivariate regression analysis in the winter revealed a significant correlation between BAT-d and plasma androgens (P = 5.3 × 10−5) in men and between BAT-d and VFA (P = 2.2 × 10−3) in women.ConclusionsCertain lipids in plasma showed unique correlations with BAT-d depending on sex and season. BAT-d showed a specific correlation with plasma androgens in men in the winter.

Current metabolic perspective on malnutrition in obesity: towards more subgroup-based nutritional approaches?

Lifestyle intervention may be effective in reducing type 2 diabetes mellitus incidence and cardiometabolic risk. A more personalised nutritional approach based on an individual or subgroup-based metabolic profile may optimise intervention outcome. Whole body insulin resistance (IR) reflects defective insulin action in tissues such as muscle, liver, adipose tissue, gut and brain, which may precede the development of cardiometabolic diseases. IR may develop in different organs but the severity may vary between organs. Individuals with more pronounced hepatic IR have a distinct plasma metabolome and lipidome profile as compared with individuals with more pronounced muscle IR. Additionally, genes related to extracellular modelling were upregulated in abdominal subcutaneous adipose tissue in individuals with more pronounced hepatic IR, whilst genes related to inflammation as well as systemic low-grade inflammation were upregulated in individuals with primarily muscle IR. There are indications that these distinct IR phenotypes may also respond differentially to dietary macronutrient composition. Besides metabolic phenotype, microbial phenotype may be of importance in personalising the response to diet. In particular fibres or fibre mixtures, leading to a high distal acetate and SCFA production may have more pronounced effects on metabolic health. Notably, individuals with prediabetes may have a reduced response to diet-induced microbiota modulation with respect to host insulin sensitivity and metabolic health outcomes. Overall, we need more research to relate metabolic subphenotypes to intervention outcomes to define more optimal diets for individuals with or predisposed to chronic metabolic diseases.

Lipidomic identification of plasma lipids associated with pain behaviour and pathology in a mouse model of osteoarthritis

IntroductionOsteoarthritis (OA) is the most common form of joint disease, causing pain and disability. Previous studies have demonstrated the role of lipid mediators in OA pathogenesis.ObjectivesTo explore potential alterations in the plasma lipidomic profile in an established mouse model of OA, with a view to identification of potential biomarkers of pain and/or pathology.MethodsPain behaviour was assessed following destabilisation of the medial meniscus (DMM) model of OA (n = 8 mice) and compared to sham controls (n = 7). Plasma and knee joints were collected at 16 weeks post-surgery. Plasma samples were analysed using ultra-high performance liquid chromatography accurate mass high resolution mass spectrometry (UHPLC-HR-MS) to identify potential differences in the lipidome, using multivariate and univariate statistical analyses. Correlations between pain behaviour, joint pathology and levels of lipids were investigated.Results24 lipids, predominantly from the lipid classes of cholesterol esters (CE), fatty acids (FA), phosphatidylcholines (PC), N-acylethanolamines (NAE) and sphingomyelins (SM), were differentially expressed in DMM plasma compared to sham plasma. Six of these lipids which were increased in the DMM model were identified as CE(18:2), CE(20:4), CE(22:6), PC(18:0/18:2), PC(38:7) and SM(d34:1). CEs were positively correlated with pain behaviour and all six lipid species were positively correlated with cartilage damage. Pathways shown to be involved in altered lipid homeostasis in OA were steroid biosynthesis and sphingolipid metabolism.ConclusionWe identify plasma lipid species associated with pain and/or pathology in a DMM model of OA.

Plasma lipidomic profiling identifies a novel complex lipid signature associated with ischemic stroke in chronic kidney disease

Despite contribution of dyslipidemia to ischemic stroke, plasma lipidomic correlates of stroke in CKD is not studied. This study is aimed to identify plasma lipid alterations associated with stroke. Cross sectional. 214 participants of Clinical Phenotyping and Resource Biobank Core (CPROBE). Clinical data and plasma samples at the time of recruitment were obtained and used to generate lipidomic data by liquid chromatography/mass-spectrometry-based untargeted platform. Various levels of free fatty acids, acylcarnitines and complex lipids. Stroke. includes compound by compound comparison of lipids using t-test adjusted by false discovery rate in patients with and without stroke, and application of logistic regression analysis to identify independent lipid predictors of stroke and to estimate the odds associated with their various levels. Overall, we identified 330 compounds. Enrichment analysis revealed overrepresentation of differentially regulated phosphatidylcholines (PC)s and phosphatidylethanolamines (PE)s were overrepresented in stroke (P<0.001). Abundance of PC38:4, PE36:4, PC34:0, and palmitate were significantly higher, but those of plasmenyl-PE (pPE)38:2, and PE 32:2 was significantly lower in patients with stroke (p≤0.0014). After adjusting, each 1-SD increase in palmitate and PC38:4 was independently associated with 1.84 fold (95% CI: 1.06-3.20, p=0.031) and 1.84 fold (1.11-3.05, p=0.018) higher risk of stroke, respectively. We observed a significant trend toward higher abundance of PCs, PEs, pPEs, and sphingomyelins in stroke (p≤0.046). Small sample size; unclear, if similar changes in the same or opposite direction preceded stroke, as the cross-sectional nature of the observation does not allow determining the effect of time course on lipid alterations. Differential regulation of palmitate, PCs, and PEs in patients with CKD and a history of stroke may represent a previously unrecognized risk factor and might be a target of risk stratification and modification.

Lipidomic Profile Revealed the Association of Plasma Lysophosphatidylcholines with Adolescent Obesity.

Objective The human lipidomic profile reflects lipid metabolism, including the early phase of pathophysiological changes associated with diseases. An investigation of the association between the plasma lipidomic profile and adolescent obesity might provide new insights into the biological mechanisms of obesity. Therefore, we aimed to investigate the association of the plasma lipidome with obesity in Chinese adolescents using lipidomics. Methods Using a combination of liquid chromatography and electrospray ionization tandem mass spectrometry, we quantified 328 lipid species from 24 lipid classes and subclasses in 100 male adolescents aged 14–16 years who were categorized into four groups: (1) normal weight with traditional normal clinical plasma lipid levels (NN); (2) normal weight with traditional abnormal clinical plasma lipid levels (NA); (3) obese with traditional normal clinical plasma lipid levels (ON); and (4) obese with traditional abnormal clinical plasma lipid levels (OA). The concentrations of all the lipid species were compared between obese and normal-weight adolescents at different traditional clinical plasma lipid levels using the Kruskal–Wallis test followed by the Mann–Whitney U test. A partial least squares discriminant analysis (PLS-DA) was applied to select lipids with a significant ability to discriminate adolescent obesity. Results The lipidomic profile distinguished obese adolescents from normal-weight subjects. Regardless of whether traditional clinical plasma lipid levels were normal or abnormal, we observed a significant reduction in the levels of five lysophosphatidylcholines (LPC) species (LPC18:2, LPC18:1, LPC20:2, LPC20:1, and LPC20:0) in the obese group compared with the normal-weight group (difference = −31.29% to −13.19%; P=9.91 × 10−5 to 2.28 × 10−2). The ability of these five LPC species to discriminate adolescent obesity was confirmed in the PLS-DA model. Conclusions The findings provided evidence for the association of some LPC species with adolescent obesity. The discriminatory effects of five LPC species were identified between normal-weight and obese adolescents, independent of traditional clinical plasma lipid levels. These results will provide a basis for validation in subsequent studies.

Similar plasma lipidomic profile in people living with HIV treated with a darunavir-based or an integrase inhibitor-based antiretroviral therapy

Cardiovascular disease is an important cause of morbidity and mortality in people living with HIV (PLWH), who commonly experience lipid disturbances. The aim of this study was to determine whether the plasma lipidomic profile differs between PLWH receiving a darunavir-based ART and those receiving integrase inhibitor-based ART. This was a cross-sectional study of unselected patients for whom metabolomic analysis was performed using ultra-high-performance liquid chromatography coupled to mass spectrometry. Data for the two subgroups were compared by calculating the log2 of the fold change for each metabolite and then grouping these into the main lipid families. Sixty-two PLWH aged 49.3 ± 8.6 years (82% men) were included: 12 patients (19.4%) had hypertension, 8 (12.9%) had type 2 diabetes, 25 (41.0%) had dyslipidaemia and 9 (14.5%) were taking statins, without significant differences in all these variables between the two groups. Twenty-five (40.3%) received darunavir-based ART and 37 (59.7%) integrase inhibitor-based ART. Although the differences were not statistically significant, patients treated with darunavir-based ART had higher concentrations of total cholesterol (211 mg/dL vs 194 mg/dL), LDL-cholesterol (132 mg/dL vs 117 mg/dL) and triglycerides (155 mg/dL vs 122 mg/dL), and lower HDL-cholesterol concentration (50 mg/dL vs 52 mg/dL). The main lipid families and metabolites differed slightly between groups (log2-fold change; P-value): ceramides (−0.07; 0.49), phosphatidylinositols (−0.05; 0.63), diacylglycerols (0.10; 0.64), phosphatidylethanolamines (0.03; 0.78), triacylglycerols (0.27; 0.18) and lysophosphatidylethanolamines (0.03; 0.83). In the integrase inhibitor-based group, the use of tenofovir alafenamide fumarate significantly increases the majority of lipid fractions, when compared with tenofovir disoproxil fumarate. The lipidomic profile did not differ between PLWH treated with darunavir-based or integrase inhibitor-based ART. This was especially true for ceramides, which are involved in cardiovascular disease. Further studies are needed to study the impact of ART in lipidomic profile.

Association of Lipidomic Profiles With Progression of Carotid Artery Atherosclerosis in HIV Infection

Lipid metabolism disruption and excess risk of cardiovascular disease (CVD) have been observed in HIV-infected individuals, but the associations among HIV infection, plasma lipidome, and CVD risk have not been well understood. To evaluate plasma lipidomic profiles and their associations with carotid artery atherosclerosis in individuals with HIV and individuals without HIV. Prospective analysis in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study during a 7-year follow-up (from 2004-2006 to 2011-2013) at multicenter HIV cohorts in the United States. The study included 737 participants aged 35 to 55 years (520 with HIV and 217 without HIV) without CVD or carotid artery plaque at baseline. Data were analyzed between April 2017 and July 2019. Two hundred eleven plasma lipid species. Poisson regression was used to examine the associations of baseline lipid species with risk of plaque measured by repeated B-mode carotid artery ultrasonography imaging. Of the 737 included participants, 398 (54%) were women, 351 (48%) were African American (non-Hispanic), 156 of 737 (21%) were nonwhite Hispanic, and the mean (SD) age was 45 (6) years. After adjusting for demographic and behavioral factors, we identified 12 lipid species, representing independent signals for 10 lipid classes, associated with risk of plaque. Nine lipid species remained significant after further adjusting for conventional CVD risk factors, although many of them showed moderate to high association with conventional blood lipids (eg, total and low-density lipoprotein cholesterols and triglycerides). Cholesteryl ester (16:1) (risk ratio [RR] per standard deviation, 1.28; 95% CI, 1.08-1.52), ceramide (16:0) (RR, 1.29; 95% CI, 1.02-1.63), lysophosphatidylcholine (20:4) (RR, 1.28; 95% CI, 1.05-1.58), lysophosphatidylethanolamine (16:0) (RR, 1.28; 95% CI, 1.05-1.57), phosphatidylethanolamine (38:6) (RR, 1.33; 95% CI, 1.08-1.64), phosphatidylethanolamine-plasmalogen (36:2) (RR, 1.25; 95% CI, 1.04-1.52), phosphatidylserine-plasmalogen (36:3) (RR, 1.19; 95% CI, 1.00-1.43), and triacylglycerol (54:6) (RR, 1.26; 95% CI, 1.04-1.54) were associated with increased risk of plaque, while phosphatidylcholine (36:4) (RR, 0.65; 95% CI, 0.54-0.77) was associated with decreased risk of plaque. Most of these plaque-increased lipid species showed higher levels in individuals with HIV, particularly among individuals with HIV using antiretroviral therapy compared with individuals without HIV. Network analysis identified 9 lipid modules, and 2 modules composed of triacylglycerols and phosphatidylcholines with long and unsaturated acyl chains, respectively, showed the strongest associations with increased risk of plaque. This study identified multiple plasma lipid species associated with carotid artery atherosclerosis, and alterations in these lipid species might be associated with HIV infection and antiretroviral therapy. Our data suggest unfavorable associations of long-chain and unsaturated triacylglycerols and phosphatidylcholines with carotid artery plaque formation.

Plasma Lipidomics Profiles After a Diet Characterized by Whole Grains Compared to a Diet High in Refined Grains and Added Sugars (FS03-07-19)

ObjectivesDietary patterns high in fiber from sources including whole grains, legumes, fruits, vegetables, nuts and seeds, are associated with lower risk of chronic disease, such as cardiovascular disease and cancer. We investigated how plasma lipidomics profiles differed between a diet high in whole grains (WG) versus a diet high in refined grains and added sugars (RG). MethodsUsing a randomized, crossover, controlled feeding study, 80 healthy participants (n = 40 men, n = 40 women, 40 normal weight, 40 overweight/obese), 18–45 y, were randomized to receive either a WG or RG diet for 28 days. After a 28-day washout period where participants resumed their habitual diet, they crossed over to the other diet. Targeted, differential mobility mass spectrometry was performed on fasting plasma samples collected at the baseline and end of each diet period and quantified the concentrations of 863 lipids from 13 classes. Paired t-tests and pairwise partial least squares-discriminant analysis (PLS-DA) were used to evaluate differences in lipid profiles between the two diets. ResultsAt a class level, only ceramides were significantly different when comparing the two diets. After removing lipid species with > 20% missing values or CVs < 25%, 606 were retained for species analysis. Sixty-seven lipid species were significantly different between diets at day 28 (FDR < 0.05): 38 of 414 detected triglycerides, 9 of 59 phosphatidylethanolamines, 9 of 63 phosphatidylcholines, 4 of 22 cholesterol esters, 3 of 11 sphingomyelins, 2 of 13 lysophosphatidylcholines, and 1 of 5 ceramides. The majority of significant lipids were higher in plasma after the WG diet. PLSDA analysis showed the first and second components explaining 49% and 8.4%, respectively. Based on the selected components, lipidomic profiles showed fair separation for the two groups of diet. R2 values were 0.07 and 0.43, and Q2 values were -0.03 and 0.04 for components 1 and 2, respectively. ConclusionsHigher concentrations of some lipid species such as cholesterol ester 12:0, a carrier of high-density lipoprotein, could indicate a favorable shift in lipid profiles. Further investigation using more complex models are being conducted. Funding SourcesNational Cancer Institute - National Institutes of Health.

Values of integration between lipidomics and clinical phenomes in patients with acute lung infection, pulmonary embolism, or acute exacerbation of chronic pulmonary diseases: a preliminary study

BackgroundThe morbidity and mortality of patients with critical illnesses remain high in pulmonary critical care units and a poorly understood correlation between alterations of lipid elements and clinical phenomes remain unelucidated.MethodsIn the present study, we investigated plasma lipidomic profiles of 30 patients with severe acute pneumonia (SAP), acute pulmonary embolism (APE), and acute exacerbation of chronic pulmonary diseases (AECOPD) or 15 healthy with the aim to compare disease specificity of lipidomic patterns. We defined the specificity of lipidomic profiles in SAP by comparing it to both APE and AECOPD. Analysis of the correlation between altered lipid elements and clinical phenotypes using the lipid-QTL model was then carried out.ResultsWe integrated lipidomic profiles with clinical phenomes measured by score values from the digital evaluation score system and found phenome-associated lipid elements to identify disease-specific lipidomic profiling. The present study demonstrates that lipidomic profiles of patients with acute lung diseases are different from healthy lungs, and there are also disease-specific portions of lipidomics among SAP, APE, or AECOPD. The comprehensive profiles of clinical phenomes or lipidomics are valuable in describing the disease specificity of patient phenomes and lipid elements. The combination of clinical phenomes with lipidomic profiles provides more detailed disease-specific information on panels of lipid elements When compared to the use of each separately.ConclusionsIntegrating biological functions with disease specificity, we believe that clinical lipidomics may create a new alternative way to understand lipid-associated mechanisms of critical illnesses and develop a new category of disease-specific biomarkers and therapeutic targets.

Body Mass Index in Multiple Sclerosis modulates ceramide-induced DNA methylation and disease course.

BackgroundMultiple Sclerosis (MS) results from genetic predisposition and environmental variables, including elevated Body Mass Index (BMI) in early life. This study addresses the effect of BMI on the epigenome of monocytes and disease course in MS.MethodsFifty-four therapy-naive Relapsing Remitting (RR) MS patients with high and normal BMI received clinical and MRI evaluation. Blood samples were immunophenotyped, and processed for unbiased plasma lipidomic profiling and genome-wide DNA methylation analysis of circulating monocytes. The main findings at baseline were validated in an independent cohort of 91 therapy-naïve RRMS patients. Disease course was evaluated by a two-year longitudinal follow up and mechanistic hypotheses tested in human cell cultures and in animal models of MS.FindingsHigher monocytic counts and plasma ceramides, and hypermethylation of genes involved in negative regulation of cell proliferation were detected in the high BMI group of MS patients compared to normal BMI. Ceramide treatment of monocytic cell cultures increased proliferation in a dose-dependent manner and was prevented by DNA methylation inhibitors. The high BMI group of MS patients showed a negative correlation between monocytic counts and brain volume. Those subjects at a two-year follow-up showed increased T1 lesion load, increased disease activity, and worsened clinical disability. Lastly, the relationship between body weight, monocytic infiltration, DNA methylation and disease course was validated in mouse models of MS.InterpretationHigh BMI negatively impacts disease course in Multiple Sclerosis by modulating monocyte cell number through ceramide-induced DNA methylation of anti-proliferative genes.FundThis work was supported by funds from the Friedman Brain Institute, NIH, and Multiple Sclerosis Society.

Lipidomics Profiles are Related to Preterm Birth and Depressive Symptoms in Pregnant African American Women

African American women have a higher preterm birth rate (PTB, birth before 37 weeks) compared to non‐Hispanic white women. Exposure to chronic stressors has been related to higher rates of PTB (Latendresse et al. 2009 &amp; Misra et al. 2010). This project is a part of a larger research study to investigate the social and biological mechanisms responsible for higher PTB and other pregnancy complications in African American women. We hypothesized that the lipidomic profiles will be related to gestational age at birth and depressive symptoms among pregnant African American women. Thirty women were recruited at the prenatal clinic site in Metropolitan Detroit. Women completed the questionnaires and plasma samples were collected between 8 to 16 weeks of gestation. The lipidomic profiles were determined by “shotgun” Orbitrap high resolution/accurate mass spectrometry. Plasma triglycerides, glycerolipids, phospholipids, sphingolipids, sterols, fatty acids, and signaling lipids were measured. The data were analyzed by multivariate analysis, Principal Component Analysis (PCA), Orthogonal Projections to Latent Structures (OPLS), and OPLS Discriminant Analysis (OPLS‐DA) using SIMCA P+ software. PCA was used to identify the outliers and patterns in the data. OPLS DA score plot showed good separation and groupings of PTB and full‐term birth. The corresponding S‐plot, loading plot, and Variable Importance for the Projection (VIP) plot/list were used to identify the lipids responsible for the groupings. We identified a panel of lipid markers of PTB. Higher levels of triglycerides species TG (53:5), TG (53:4), TG (54:5), TG (54:6), TG (52:6) and TG (52:4) and lower levels of phospholipid species PC (37:1), PC (41:6) and PC (39:3) were associated with PTB. Plasma lipidomics profiles showed a good correlation with the Center for Epidemiologic Studies Depression Scale (CES‐D) scores in the OPLS model. There was a clear separation in the OPLS DA score plot between women with CES‐D scores ≥ 23 compared to women with CES‐D scores &lt; 23. Phosphatidylcholine PC (37:1) levels were also lower among women with CES‐D scores ≥ 23 compared to women with CES‐D scores &lt; 23 pointing toward a possible connection between depressive symptoms and PTB. We also investigated the differences in lipidomics profiles based on Body Mass Index (BMI). Although the overweight pregnant women group (pre‐pregnancy BMI &gt;25 kg/m2) showed higher levels of triglycerides, there was no clear overlap with the PTB model. Our data suggest the role of specific triglycerides and phosphatidylcholines in PTB. Further investigation of the association of PTB and depressive symptoms with lipidomics profiles and phospholipid metabolism in a larger sample of pregnant African American women may lead to the identification of non‐invasive lipid biomarkers of PTB and intervention strategies for these women.Support or Funding InformationR01 MD011575, Social Stressors and Inflammation: A Mixed Methods Approach to Preterm Birth. National Institute on Minority Health and Health DisparitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Modulation of plasma lipidomic signature in metastatic castration-resistant prostate cancer (mCRPC).

TPS331 Background: Altered lipid metabolism and its impact on prostate cancer (PC) is increasingly recognised, in light of the association between obesity and worse PC outcomes. Our exploratory study was the first to identify baseline plasma lipidomic profiles in men with mCRPC commencing docetaxel that were associated with survival. A prognostic three-lipid signature was derived, consisting of ceramide, sphingomyelin and phosphatidylcholine (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). This signature was independently prognostic when modelled with clinicopathological factors and metabolic characteristics. A key question is whether therapeutic modulation of a patient’s lipid profile is possible. Statins significantly reduce the plasma levels of ceramides, sphingomyelin and cholesterol in cardiovascular disease, suggesting that this therapy could change the poor prognostic lipid profile of mCRPC patients. This trial assesses whether addition of simvastatin to docetaxel for mCRPC can reverse the poor prognostic lipid signature with the aim of developing a precision medicine strategy for metabolic targeting. Methods: This investigator-initiated, multi-centre, open-label, single arm, pilot study enrols patients with mCRPC commencing docetaxel for disease progression, not already receiving a lipid-lowering agent. Patients are treated with simvastatin 40mg orally once daily for 12 weeks, commencing on day 1 of the first cycle of docetaxel. Blood is taken at baseline and after 12 weeks of simvastatin and the plasma lipidomic profile is determined using liquid chromatography and electrospray ionisation-tandem mass spectrometry. The lipidomic profile is classified as either good or poor prognostic as per our three-lipid signature model derived by logistic regression. The primary objective is to assess the rates of conversion from a poor prognostic lipid signature to good prognostic after simvastatin. A sample size of 60 men provides over 90% power, with a 1-sided type 1 error of 10%, to detect conversion to the good prognostic signature in 50% of patients, assuming 25% of patients have the poor prognostic signature at baseline as previously detected. To date, 6 patients have been enrolled to the trial. Clinical trial information: ACTRN12617000965303.

Evaluation of lipid markers in surfactant obtained from asthmatic horses exposed to hay.

OBJECTIVE To evaluate the lipidomic profile of surfactant obtained from horses with asthma at various clinical stages and to compare results with findings for healthy horses exposed to the same conditions. SAMPLE Surfactant samples obtained from 6 horses with severe asthma and 7 healthy horses. PROCEDURES Clinical evaluation of horses and surfactant analysis were performed. Samples obtained from horses with severe asthma and healthy horses before (baseline), during, and after exposure to hay were analyzed. Crude surfactant pellets were dried prior to dissolution in a solution of isopropanol:methanol:chloroform (4:2:1) containing 7.5mM ammonium acetate. Shotgun lipidomics were performed by use of high-resolution data acquisition on an ion-trap mass spectrometer. Findings were analyzed by use of an ANOVA with a Tukey-Kramer post hoc test. RESULTS Results of lipidomic analysis were evaluated to detect significant differences between groups of horses and among exposure statuses within groups of horses. Significantly increased amounts of cyclic phosphatidic acid (cPA) and diacylglycerol (DAG) were detected in surfactant from severely asthmatic horses during exposure to hay, compared with baseline and postexposure concentrations. Concentrations of cPA and DAG did not change significantly in healthy horses regardless of exposure status. CONCLUSIONS AND CLINICAL RELEVANCE cPA 16:0 and DAG 36:2 were 2 novel lipid mediators identified in surfactant obtained from asthmatic horses with clinical disease. These molecules were likely biomarkers of sustained inflammation. Further studies are needed to evaluate a possible correlation with disease severity and potential alterations in the plasma lipidomic profile of horses with asthma.

Plasma lipidomic profiling in murine mutants of Hermansky-Pudlak syndrome reveals differential changes in pro- and anti-atherosclerotic lipids.

Atherosclerosis is characterized by the accumulation of lipid-rich plaques in the arterial wall. Its pathogenesis is very complicated and has not yet been fully elucidated. It is known that dyslipidemia is a major factor in atherosclerosis. Several different Hermansky–Pudlak syndrome (HPS) mutant mice have been shown either anti-atherosclerotic or atherogenic phenotypes, which may be mainly attributed to corresponding lipid perturbation. To explore the effects of different HPS proteins on lipid metabolism and plasma lipid composition, we analyzed the plasma lipid profiles of three HPS mutant mice, pa (Hps9−/−), ru (Hps6−/−), ep (Hps1−/−), and wild-type (WT) mice. In pa and ru mice, some pro-atherosclerotic lipids, e.g. ceramide (Cer) and diacylglycerol (DAG), were down-regulated whereas triacylglycerol (TAG) containing docosahexaenoic acid (DHA) (22:6) fatty acyl was up-regulated when compared with WT mice. Several pro-atherosclerotic lipids including phosphatidic acid (PA), lysophosphatidylserine (LPS), sphingomyelin (SM), and cholesterol (Cho) were up-regulated in ep mice compared with WT mice. The lipid droplets in hepatocytes showed corresponding changes in these mutants. Our data suggest that the pa mutant resembles the ru mutant in its anti-atherosclerotic effects, but the ep mutant has an atherogenic effect. Our findings may provide clues to explain why different HPS mutant mice exhibit distinct anti-atherosclerotic or atherogenic effects after being exposed to high-cholesterol diets.

Editorial: Blood Tests for Alzheimer's Disease and Related Disorders.

This issue of the Journal of Prevention of Alzheimer’s Disease (AD) includes a timely Clinical Trials on AD Task Force Report on promising blood tests for AD and related disorders (1). It highlights the promise of recently developed plasma amyloid-β42/40 (Aβ42/40) measurements for the assessment of neuritic plaque burden (e.g., reference 2), ultrasensitive neurofilament light (NfL) measurements for the assessment of ongoing neuroaxonal injury in a wide range of neurological disorders (3), and their potential roles in evaluation of interventions to treat and prevent the clinical onset of AD. It also considers recently developed plasma total-tau measurements, an indicator of neuronal injury and/or Aβ-mediated tau secretion (4), plasma phospho-tau measurements, a potential indicator of neurofibrillary tangle burden, and the ongoing effort to develop high-dimensional plasma genomic, transcriptomic, metabolomic, lipidomic, and proteomic profiles.

Plasma Lipidomic Profiling and Risk of Type 2 Diabetes in the PREDIMED Trial.

Specific lipid molecular changes leading to type 2 diabetes (T2D) are largely unknown. We assessed lipidome factors associated with future occurrence of T2D in a population at high cardiovascular risk. We conducted a case-cohort study nested within the PREDIMED trial, with 250 incident T2D cases diagnosed during 3.8 years of median follow-up, and a random sample of 692 participants (639 noncases and 53 overlapping cases) without T2D at baseline. We repeatedly measured 207 plasma known lipid metabolites at baseline and after 1 year of follow-up. We built combined factors of lipid species using principal component analysis and assessed the association between these lipid factors (or their 1-year changes) and T2D incidence. Baseline lysophosphatidylcholines and lysophosphatidylethanolamines (lysophospholipids [LPs]), phosphatidylcholine-plasmalogens (PC-PLs), sphingomyelins (SMs), and cholesterol esters (CEs) were inversely associated with risk of T2D (multivariable-adjusted P for linear trend ≤0.001 for all). Baseline triacylglycerols (TAGs), diacylglycerols (DAGs), and phosphatidylethanolamines (PEs) were positively associated with T2D risk (multivariable-adjusted P for linear trend <0.001 for all). One-year changes in these lipids showed associations in similar directions but were not significant after adjustment for baseline levels. TAGs with odd-chain fatty acids showed inverse associations with T2D after adjusting for total TAGs. Two plasma lipid profiles made up of different lipid classes were found to be associated with T2D in participants at high cardiovascular risk. A profile including LPs, PC-PLs, SMs, and CEs was associated with lower T2D risk. Another profile composed of TAGs, DAGs, and PEs was associated with higher T2D risk.

Large-scale plasma lipidomic profiling identifies lipids that predict cardiovascular events in secondary prevention.

Plasma lipidomic measures may enable improved prediction of cardiovascular outcomes in secondary prevention. The aim of this study is to determine the association of plasma lipidomic measurements with cardiovascular events and assess their potential to predict such events. Plasma lipids (n = 342) were measured in a retrospective subcohort (n = 5,991) of the LIPID study. Proportional hazards regression was used to identify lipids associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and cardiovascular death. Multivariable models adding lipid species to traditional risk factors were created using lipid ranking established from the Akaike information criterion within a 5-fold cross-validation framework. The results were tested on a diabetic case cohort from the ADVANCE study (n = 3,779). Specific ceramide species, sphingolipids, phospholipids, and neutral lipids containing omega-6 fatty acids or odd-chain fatty acids were associated with future cardiovascular events (106 species) and cardiovascular death (139 species). The addition of 7 lipid species to a base model (11 conventional risk factors) resulted in an increase in the C-statistics from 0.629 (95% CI, 0.628-0.630) to 0.654 (95% CI, 0.653-0.656) for prediction of cardiovascular events and from 0.673 (95% CI, 0.671-0.675) to 0.727 (95% CI, 0.725-0.728) for prediction of cardiovascular death. Categorical net reclassification improvements for cardiovascular events and cardiovascular death were 0.083 (95% CI, 0.081-0.086) and 0.166 (95% CI, 0.162-0.170), respectively. Evaluation on the ADVANCE case cohort demonstrated significant improvement on the base models. The improvement in the prediction of cardiovascular outcomes, above conventional risk factors, demonstrates the potential of plasma lipidomic profiles as biomarkers for cardiovascular risk stratification in secondary prevention. Bristol-Myers Squibb, the National Health and Medical Research Council of Australia (grants 211086, 358395, and 1029754), and the Operational Infrastructure Support Program of the Victorian government of Australia.

Plasma Lipidomic Profiles in Relation to Incident Type 2 Diabetes among Women with a History of Gestational Diabetes Mellitus

Background: Dyslipidemia is a risk factor of type 2 diabetes (T2D). Women with a history of gestational diabetes (GDM) have a greater T2D risk; however, whether lipids patterns contribute to risk of progression remains unclear. Methods: We conducted a nested case-control study of incident T2D among women enrolled in the Nurses’ Health Study II reporting a history of GDM prior to the first blood collection (1995-1999) and followed-up through 2013. Plasma lipidomics containing 180 metabolites were measured in a subset of 175 incident cases and 176 age-matched controls by liquid chromatography-mass spectrometry. We constructed lipid networks using a weighted-correlation algorithm, and examined the association of individual lipids and sub-networks with T2D risk using logistic regression, adjusting for established T2D risk factors. Results: We identified 39 lipids species significantly associated with T2D risk (FDR&amp;lt;0.05), and observed different association patterns (in which associations were differed by numbers of carbon and double-bonds) across various lipid classes. We constructed 5 co-regulating lipid sub-networks, one of which (featuring the interactions between diacylglycerol, triacylglycerol, and phosphatidylethanolamine with mid-length carbon and less double-bonds) was significantly associated with incident T2D risk (odds ratio for increasing quartiles was 1 [reference], 2.4, 3.4, and 4.4; P-trend=0.0008). The addition of significant lipid species to a base model (13 traditional risk factors and medications) to predict incident T2D increased the c-statistics from 0.83 to 0.90 (P=0.001) with a corresponding categorical net reclassification index of 0.27 (P&amp;lt;0.001) in cross-validation. Conclusions: The dysregulation of certain lipid specie/class may contribute to a higher risk of incident T2D after a GDM pregnancy. Plasma lipid species and the network signatures may aid future clinical risk assessment and targeted interventions. Disclosure J. Li: None. L. Liang: None. F. Hu: None. C. Zhang: None. D. Tobias: None.

Unbiased lipidomic profiling reveals metabolomic changes during the onset and antipsychotics treatment of schizophrenia disease.

Schizophrenia (SCH) is one of the most common psychiatric disorders, which involves impairments in motivation and cognition. The pathological mechanisms underlying SCH are still unknown, and no effective therapies can prevent or treat perfectly the cognitive impairments and deficit symptoms caused by SCH. We aimed to find the lipid expression change in plasma that underlie SCH onset and antipsychotics treatment. We performed a data independent acquisition-based untargeted lipidomic approach on a quadrupole-time of flight liquid chromatography coupled to mass spectrometry platform. The plasma lipidomic profiles of SCH patients (n = 20) pre- and post-antipsychotics treatment were acquired as well as healthy controls (n = 29). Grouped or paired t-test were used to analyze the data. Over 1000 features were detected by our lipidomic analysis, of which 445 lipids belonging to 17 lipid species were reliably identified by tandem mass spectrometry. After statistical analysis, 47 lipids belonging to 9 lipid species were found to be dysregulated between naive SCH patients and healthy controls, and 50 lipids belonging to 9 lipid species were found to be dysregulated after antipsychotics treatment. These findings include several new SCH-relevant lipid species such as sphingomyelin, acylcarnitine and ceramide. Four types of lipid expression regulative patterns can be concluded from the above mentioned findings, revealing information about mechanism, side-effect and potential target of antipsychotics. The work presented here have revealed several new lipid species which are significantly dysregulated in SCH disease development or antipsychotics treatment. These lipids provide new evidence for the pathological studies of SCH and new antipsychotics development, or can be considered as potentially candidate biomarkers for further validation.

SAT-472 - Impact of short term weight loss (very low calorie diet vs bariatric surgery) on hepatic insulin resistance and plasma lipidomic profile

SAT-472 - Impact of short term weight loss (very low calorie diet vs bariatric surgery) on hepatic insulin resistance and plasma lipidomic profile