Phosphatidylcholine Plasmalogen Research Articles

Differences in metabolomic profiles between Black and White women in the U.S.: Analyses from two prospective cohorts.

There is growing interest in incorporating metabolomics into public health practice. However, Black women are under-represented in many metabolomics studies. If metabolomic profiles differ between Black and White women, this under-representation may exacerbate existing Black-White health disparities. We therefore aimed to estimate metabolomic differences between Black and White women in the U.S. We leveraged data from two prospective cohorts: the Nurses' Health Study (NHS; n = 2077) and Women's Health Initiative (WHI; n = 2128). The WHI served as the replication cohort. Plasma metabolites (n = 334) were measured via liquid chromatography-tandem mass spectrometry. Observed metabolomic differences were estimated using linear regression and metabolite set enrichment analyses. Residual metabolomic differences in a hypothetical population in which the distributions of 14 risk factors were equalized across racial groups were estimated using inverse odds ratio weighting. In the NHS, Black-White differences were observed for most metabolites (75 metabolites with observed differences |0.50| standard deviations). Black women had lower average levels than White women for most metabolites (e.g., for N6, N6-dimethlylysine, mean Black-White difference = - 0.98 standard deviations; 95% CI: - 1.11, - 0.84). In metabolite set enrichment analyses, Black women had lower levels of triglycerides, phosphatidylcholines, lysophosphatidylethanolamines, phosphatidylethanolamines, and organoheterocyclic compounds, but higher levels of phosphatidylethanolamine plasmalogens, phosphatidylcholine plasmalogens, cholesteryl esters, and carnitines. In a hypothetical population in which distributions of 14 risk factors were equalized, Black-White metabolomic differences persisted. Most results replicated in the WHI (88% of 272 metabolites available for replication). Substantial differences in metabolomic profiles exist between Black and White women. Future studies should prioritize racial representation.

Phospholipid analyses of rabbit ocular surface tissues

The tissues of the integument covering the ocular surface comprise a mucus membrane functioning as a protective physical barrier and has the ability to mount a defensive inflammatory response. Since lipid metabolism has a role in both of these functions, we studied normal membrane phospholipids (PL) of the cornea and bulbar conjunctiva to (1) determine baseline PL profiles of these tissues, (2) compare and contrast these individual PL metabolite profiles as well as groups of metabolites, and (3) describe pathway-specific metabolic interrelations among these tissues. Corneal and conjunctival tissue samples were isolated from rabbit eyes (n = 30) and extracted with chloroform-methanol using a modified Folch procedure. 31P nuclear magnetic resonance spectroscopy was used to qualitatively and quantitatively measure tissue PL profiles. The cornea and conjunctiva, respectively, have the following PL composition (mole % of total detected phospholipid): phosphatidylglycerol (PG) –, 0.4; lysophosphatidylethanolamine 1.2, –; phosphatidic acid –, 0.4; diPG (cardiolipin) 2.1, 3.5; unknown PL at the chemical shift of 0.13 δ 1.5, 0.9; ethanolamine plasmalogen 11.2, 13.0; phosphatidylethanolamine 11.5, 12.8; phosphatidylserine 8.9, 10.1; sphingomyelin 10.2, 10.7; lysophosphatidylcholine 0.9, 1.4; phosphatidylinositol 5.3, 5.3; phosphatidylcholine (PC) plasmalogen or alkylacylPC 2.2, 1.9; PC 45.1, 40.0. In addition, 28 PL metabolic indices were calculated from these data, which permitted pathway-specific lipid analyses. This study (1) establishes PL profiles of the two ocular tissues of the integument that cover the surface of the eye, (2) compares and contrasts indices comprised of ratios and combinations of PL, and (3) describes pathway-specific metabolic interrelations among these tissues to serve as baselines for studies involving the distribution of tissue phospholipids.

Abstract 3682: Pre-surgical blood metabolites associated with ovarian cancer prognosis

Abstract Background: Ovarian cancer has a poor prognosis with a 5-year survival less than 50%, resulting > 14,000 deaths in the US annually and > 150,000 globally. Identifying prognostic biomarkers at time of diagnosis and elucidating the biological dysregulation among those who are more likely to progress after first-line treatment could inform personalized treatment strategies. Thus, we evaluated metabolites and metabolomic profiles in pretreatment blood associated with survival in women with high-grade serous ovarian cancer, the most common and most deadly histologic subtype. Method: We examined plasma metabolites in blood samples collected prior to ovarian cancer treatment in 80 high-grade serous ovarian cancer patients who participated in the PreOperative Pelvic Mass Study, a clinic-based study enrolling women undergoing surgery for a pelvic mass. Liquid chromatography tandem mass spectrometry was used to measure 524 known metabolites. We excluded metabolites with coefficient of variation ≥ 25% (n = 104), then removed metabolites with missing in > 20% of the samples (n = 3). Metabolites missing in < 20% of the samples were imputed to be half the minimum value for that metabolite, resulting in 417 unduplicated metabolites. All metabolite values were transformed to probit scores to achieve normality. Cox proportional hazard models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for age at diagnosis, body mass index (BMI), and stage. False discovery rate (FDR) was used for multiple testing correction. Metabolite set enrichment analysis (MSEA) was used to identify metabolite classes associated with prognosis. Results: Overall, none of the individual metabolites were significantly associated with survival after multiple testing correction (FDR > 0.05). However, 32 metabolites were associated with survival with p< 0.05, with 12 metabolites being associated with worse survival (HR range: 1.38 - 1.98) and 20 metabolites being associated with better survival (HR range: 0.54 - 0.73). MSEA revealed triglycerides (normalized enrichment score (NES) = 3.14), cholesteryl esters (NES = 2.43), and phosphatidylcholines (NES = 2.30) were positively associated with risk of death (FDR < 0.001). Steroids and steroid derivatives (NES = -1.93), sphingomyelins (NES = -2.45), and carnitines (NES = -2.27) were negatively associated with risk of death (FDR < 0.001). Diglycerides (NES = 1.96), lysophosphatidylethanolamines (NES = 1.72), and phosphatidylcholine plasmalogens (NES = 1.58) were positively associated and phosphatidylethanolamines (NES = -1.93) was negatively associated with risk of death with FDR < 0.05. Discussion: In this study, we explored plasma metabolites associated with mortality in high-grade serous ovarian cancer patients and observed multiple classes of lipid-related metabolites being associated with worse prognosis. Citation Format: Nan Lin, Oana A. Zeleznik, Julian Avila-Pacheco, Clary B. Clish, Allison F. Vitonis, Daniel W. Cramer, Kathryn L. Terry, Naoko Sasamoto. Pre-surgical blood metabolites associated with ovarian cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3682.

Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies

A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity. In four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity. The identified healthy lifestyle metabolomic signature was reflective of lipid metabolism pathways. Shorter and more saturated triacylglycerol and diacylglycerol metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were positively associated. Participants with a higher healthy lifestyle metabolomic signature had a 17% lower risk of all-cause mortality, 19% for cardiovascular disease mortality, and 17% for cancer mortality and were 25% more likely to reach longevity. The healthy lifestyle metabolomic signature explained 38% of the association between the self-reported healthy lifestyle score and total mortality risk and 49% of the association with longevity. This study identifies a metabolomic signature that measures adherence to a healthy lifestyle and shows prediction of total and cause-specific mortality and longevity. This work was funded by the NIH, CIHR, AHA, Novo Nordisk Foundation, and SciLifeLab.

The menopause-related gut microbiome: associations with metabolomics, inflammatory protein markers, and cardiometabolic health in women with HIV.

This study aimed to identify menopause-related gut microbial features, as well as their related metabolites and inflammatory protein markers, and link with cardiometabolic risk factors in women with and without HIV. In the Women's Interagency HIV Study, we performed shotgun metagenomic sequencing on 696 stool samples from 446 participants (67% women with HIV), and quantified plasma metabolomics and serum proteomics in a subset (~86%). We examined the associations of menopause (postmenopausal vs premenopausal) with gut microbial features in a cross-sectional repeated-measures design and further evaluated those features in relation to metabolites, proteins, and cardiometabolic risk factors. Different overall gut microbial composition was observed by menopausal status in women with HIV only. We identified a range of gut microbial features that differed between postmenopausal and premenopausal women with HIV (but none in women without HIV), including abundance of 32 species and functional potentials involving 24 enzymatic reactions and lower β-glucuronidase bacterial gene ortholog. Specifically, highly abundant species Faecalibacterium prausnitzii , Bacteroides species CAG:98 , and Bifidobacterium adolescentis were depleted in postmenopausal versus premenopausal women with HIV. Menopause-depleted species (mainly Clostridia ) in women with HIV were positively associated with several glycerophospholipids, while negatively associated with imidazolepropionic acid and fibroblast growth factor 21. Mediation analysis suggested that menopause may decrease plasma phosphatidylcholine plasmalogen C36:1 and C36:2 levels via reducing abundance of species F. prausnitzii and Acetanaerobacterium elongatum in women with HIV. Furthermore, waist-to-hip ratio was associated with menopause-related microbes, metabolites, and fibroblast growth factor 21 in women with HIV. Menopause was associated with a differential gut microbiome in women with HIV, related to metabolite and protein profiles that potentially contribute to elevated cardiometabolic risk.

Fetal sex differences in placental LCPUFA ether and plasmalogen phosphatidylethanolamine and phosphatidylcholine contents in pregnancies complicated by obesity

BackgroundWe have previously reported that maternal obesity reduces placental transport capacity for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA), a preferred form for transfer of DHA (omega 3) to the fetal brain, but only in male fetuses. Phosphatidylethanolamine (PE) and phosphatidylcholine (PC), have either sn-1 ester, ether or vinyl ether (plasmalogen) linkages to primarily unsaturated and monounsaturated fatty acids and DHA or arachidonic acid (ARA, omega 6) in the sn-2 position. Whether ether and plasmalogen PC and PE metabolism in placenta impacts transfer to the fetus is unexplored. We hypothesized that ether and plasmalogen PC and PE containing DHA and ARA are reduced in maternal–fetal unit in pregnancies complicated by obesity and these differences are dependent on fetal sex.MethodsIn maternal, umbilical cord plasma and placentas from obese women (11 female/5 male infants) and normal weight women (9 female/7 male infants), all PC and PE species containing DHA and ARA were analyzed by LC–MS/MS. Placental protein expression of enzymes involved in phospholipid synthesis, were determined by immunoblotting. All variables were compared between control vs obese groups and separated by fetal sex, in each sample using the Benjamini–Hochberg false discovery rate adjustment to account for multiple testing.ResultsLevels of ester PC containing DHA and ARA were profoundly reduced by 60–92% in male placentas of obese mothers, while levels of ether and plasmalogen PE containing DHA and ARA were decreased by 51–84% in female placentas. PLA2G4C abundance was lower in male placentas and LPCAT4 abundance was lower solely in females in obesity. In umbilical cord, levels of ester, ether and plasmalogen PC and PE with DHA were reduced by 43–61% in male, but not female, fetuses of obese mothers.ConclusionsWe found a fetal sex effect in placental PE and PC ester, ether and plasmalogen PE and PC containing DHA in response to maternal obesity which appears to reflect an ability of female placentas to adapt to maintain optimal fetal DHA transfer in maternal obesity.

Metabolomic profiles of chronic distress are associated with cardiovascular disease risk and inflammation-related risk factors

BackgroundChronic psychological distress is associated with increased risk of cardiovascular disease (CVD) and investigators have posited inflammatory factors may be centrally involved in these relationships. However, mechanistic evidence and molecular underpinnings of these processes remain unclear, and data are particularly sparse among women. This study examined if a metabolite profile linked with distress was associated with increased CVD risk and inflammation-related risk factors. MethodsA plasma metabolite-based distress score (MDS) of twenty chronic psychological distress-related metabolites was developed in cross-sectional, 1:1 matched case-control data comprised of 558 women from the Nurses’ Health Study (NHS; 279 women with distress, 279 controls). This MDS was then evaluated in two other cohorts: the Women’s Health Initiative Observational Cohort (WHI-OS) and the Prevención con Dieta Mediterránea (PREDIMED) trial. We tested the MDS's association with risk of future CVD in each sample and with levels of C-reactive protein (CRP) in the WHI-OS. The WHI-OS subsample included 944 postmenopausal women (472 CHD cases; mean time to event = 5.8 years); the PREDIMED subsample included 980 men and women (224 CVD cases, mean time to event = 3.1 years). ResultsIn the WHI-OS, a 1-SD increase in the plasma MDS was associated with a 20% increased incident CHD risk (odds ratio [OR] = 1.20, 95% CI: 1.04 – 1.38), adjusting for known CVD risk factors excluding total and HDL cholesterol. This association was attenuated after including total and HDL cholesterol. CRP mediated an average 12.9% (95% CI: 4.9% – 28%, p < 10-15) of the total effect of MDS on CHD risk when adjusting for matching factors. This effect was attenuated after adjusting for known CVD risk factors. Of the metabolites in the MDS, tryptophan and threonine were inversely associated with incident CHD risk in univariate models. In PREDIMED, each one SD increase in the MDS was associated with an OR of 1.19 (95% CI: 1.00 – 1.41) for incident CVD risk, after adjusting all risk factors. Similar associations were observed in men and women. Four metabolites in the MDS were associated with incident CVD risk in PREDIMED in univariate models. Biliverdin and C36:5 phosphatidylcholine (PC) plasmalogen had inverse associations; C16:0 ceramide and C18:0 lysophosphatidylethanolamine(LPE) each had positive associations with CVD risk. ConclusionsOur study points to molecular alterations that may underlie the association between chronic distress and subsequent risk of cardiovascular disease in adults.

Association of healthy dietary patterns and cardiorespiratory fitness in the community.

To evaluate the associations of dietary indices and quantitative cardiorespiratory fitness (CRF) measures in a large, community-based sample harnessing metabolomic profiling to interrogate shared biology. Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise tests for CRF quantification (via peak VO2) and completed semi-quantitative food frequency questionnaires. Dietary quality was assessed by the Alternative Healthy Eating Index (AHEI) and Mediterranean-style Diet Score (MDS), and fasting blood concentrations of 201 metabolites were quantified. In 2380 FHS participants (54 ± 9 years, 54% female, body mass index 28 ± 5 kg/m2), 1 SD higher AHEI and MDS were associated with 5.2% (1.2 mL/kg/min, 95% CI 4.3-6.0%, P < 0.0001) and 4.5% (1.0 mL/kg/min, 95% CI 3.6-5.3%, P < 0.0001) greater peak VO2 in linear models adjusted for age, sex, total daily energy intake, cardiovascular risk factors, and physical activity. In participants with metabolite profiling (N = 1154), 24 metabolites were concordantly associated with both dietary indices and peak VO2 in multivariable-adjusted linear models (FDR < 5%). Metabolites that were associated with lower CRF and poorer dietary quality included C6 and C7 carnitines, C16:0 ceramide, and dimethylguanidino valeric acid, and metabolites that were positively associated with higher CRF and favourable dietary quality included C38:7 phosphatidylcholine plasmalogen and C38:7 and C40:7 phosphatidylethanolamine plasmalogens. Higher diet quality is associated with greater CRF cross-sectionally in a middle-aged community-dwelling sample, and metabolites highlight potential shared favourable effects on cardiometabolic health.

Gestational Diabetes Mellitus, Postpartum Lipidomic Signatures, and Subsequent Risk of Type 2 Diabetes: A Lipidome-Wide Association Study.

To identify a postpartum lipidomic signature associated with gestational diabetes mellitus (GDM) and investigate the role of the identified lipids in the progression to type 2 diabetes (T2D). This prospective cohort study enrolled 1,409 women at 24-72 h after delivery of a singleton baby and followed them prospectively at the Boston Medical Center. The lipidome was profiled by liquid chromatography-tandem mass spectrometry. Diagnoses of GDM and incident T2D were extracted from medical records and verified using plasma glucose levels. Mean (SD) age of study women at baseline was 28.5 (6.6) years. A total of 219 (16.4%) women developed incident diabetes over a median follow-up of 11.8 (interquartile range 8.2-14.8) years. We identified 33 postpartum lipid species associated with GDM, including 16 inverse associations (primarily cholesterol esters and phosphatidylcholine plasmalogens), and 17 positive associations (primarily diacyglycerols and triacyglycerols). Of these, four were associated with risk of incident T2D and mediated ∼12% of the progression from GDM to T2D. The identified lipid species modestly improved the predictive performance for incident T2D above classical risk factors when the entire follow-up period was considered. GDM was associated with a wide range of lipid metabolic alterations at early postpartum, among which some lipid species were also associated with incident T2D and mediated the progression from GDM to T2D. The improvements attained by including lipid species in the prediction of T2D provides new insights regarding the early detection and prevention of progression to T2D.

Association of Plasma Metabolomic Biomarkers With Persistent Tinnitus

Persistent tinnitus is common, disabling, and difficult to treat. To evaluate the association between circulating metabolites and persistent tinnitus. This was a population-based case-control study of 6477 women who were participants in the Nurses' Health Study (NHS) and NHS II with metabolomic profiles and tinnitus data. Information on tinnitus onset and frequency was collected on biennial questionnaires (2009-2017). For cases, metabolomic profiles were measured (2015-2021) in blood samples collected after the date of the participant's first report of persistent tinnitus (NHS, 1989-1999 and 2010-2012; NHS II, 1996-1999). Data analyses were performed from January 24, 2022, to January 14, 2023. In total, 466 plasma metabolites from 488 cases of persistent tinnitus and 5989 controls were profiled using 3 complementary liquid chromatography tandem mass spectrometry approaches. Logistic regression was used to estimate odds ratios (ORs) of persistent tinnitus (per 1 SD increase in metabolite values) and 95% CIs for each individual metabolite. Metabolite set enrichment analysis was used to identify metabolite classes enriched for associations with tinnitus. Of the 6477 study participants (mean [SD] age, 52 [9] years; 6477 [100%] female; 6121 [95%] White individuals) who were registered nurses, 488 reported experiencing daily persistent (≥5 minutes) tinnitus. Compared with participants with no tinnitus (5989 controls), those with persistent tinnitus were slightly older (53.0 vs 51.8 years) and more likely to be postmenopausal, using oral postmenopausal hormone therapy, and have type 2 diabetes, hypertension, and/or hearing loss at baseline. Compared with controls, homocitrulline (OR, 1.32; (95% CI, 1.16-1.50); C38:6 phosphatidylethanolamine (PE; OR, 1.24; 95% CIs, 1.12-1.38), C52:6 triglyceride (TAG; OR, 1.22; 95% CIs, 1.10-1.36), C36:4 PE (OR, 1.22; 95% CIs, 1.10-1.35), C40:6 PE (OR, 1.22; 95% CIs, 1.09-1.35), and C56:7 TAG (OR, 1.21; 95% CIs, 1.09-1.34) were positively associated, whereas α-keto-β-methylvalerate (OR, 0.68; 95% CIs, 0.56-0.82) and levulinate (OR, 0.60; 95% CIs, 0.46-0.79) were inversely associated with persistent tinnitus. Among metabolite classes, TAGs (normalized enrichment score [NES], 2.68), PEs (NES, 2.48), and diglycerides (NES, 1.65) were positively associated, whereas phosphatidylcholine plasmalogens (NES, -1.91), lysophosphatidylcholines (NES, -2.23), and cholesteryl esters (NES,-2.31) were inversely associated with persistent tinnitus. This population-based case-control study of metabolomic profiles and tinnitus identified novel plasma metabolites and metabolite classes that were significantly associated with persistent tinnitus, suggesting that metabolomic studies may help improve understanding of tinnitus pathophysiology and identify therapeutic targets for this challenging disorder.

Abstract P203: Healthy Lifestyle Plasma Metabolite Profile and Risk of Mortality in US Prospective Cohort Studies

Background: A healthy lifestyle is associated with a lower risk of premature death. Metabolic pathways of a healthy lifestyle and their association with mortality remain to be understood. This study aimed to identify the metabolomic profile of a healthy lifestyle score and examine its prospective association with all-cause and cause-specific mortality, including death from cardiovascular disease (CVD) and cancer. Methods: The population included 12,146 participants from the Nurses’ Health Study (NHS), NHS II and Health Professionals Follow-Up Study (HPFS)(83% women, 97% white, aged 55±9y). Plasma metabolites were profiled using high-throughput liquid chromatography mass-spectrometry at baseline (NHS:1989-1990; NHSII:1996-1999; HPFS:1993-1995). The healthy lifestyle score was computed by summing the total number of healthy lifestyle factors participants adhered to from validated questionnaires at baseline: healthy diet (Alternative Healthy Eating Index, upper 40%), moderate alcohol intake (women: 5-15 g/d; men: 5-30 g/d), moderate-to-vigorous physical activity (≥30min/d), never smoking and normal BMI (18.5-24.9kg/m 2 ). Deaths were ascertained with death certificates and medical records. The metabolite profile was identified using elastic net regressions with train test validation split (70-30%). Metabolic pathways were determined using Metabolite Set Enrichment Analysis (MSEA). Multivariable-adjusted Cox proportional hazards regressions were used to estimate hazard ratios and 95% confidence intervals (HR[CI]) per unit of score of the healthy lifestyle metabolite profile with mortality risk. Results: The identified profile included 88 metabolites and correlated with the healthy lifestyle score (Pearson r=0.43-0.44; p&lt;0.001). Triglyceride and diglyceride metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were directly associated (p&lt;0.001). Among individual lifestyle factors, the profile was most strongly correlated with normal BMI (r pb =0.43; p&lt;0.001). Over 32y of follow-up, there were 3,851 deaths, including 749 deaths from CVD and 994 from cancer. Participants with a higher healthy lifestyle metabolite profile score had lower risk of all-cause (HR=0.79[0.73, 0.85]) and CVD mortality (HR=0.77[0.58, 0.95]), but not cancer (HR=0.91[0.77, 1.05]). Significant associations persisted after further adjustment for the healthy lifestyle score. Conclusions: In US adults, we identified a metabolite profile related to a healthy lifestyle largely reflecting lipid metabolism pathways. A higher metabolite score was associated with lower subsequent all-cause mortality risk, specifically from CVD. Findings provide novel insights into potential metabolic pathways underlying the association between a healthy lifestyle and lower premature mortality.

Plasma Metabolomic Signature of Early Abuse in Middle-Aged Women.

Metabolomic profiling may provide insights into biological mechanisms underlying the strong epidemiologic links observed between early abuse and cardiometabolic disorders in later life. We examined the associations between early abuse and midlife plasma metabolites in two nonoverlapping subsamples from the Nurses' Health Study II, comprising 803 (mean age = 40 years) and 211 women (mean age = 61 years). Liquid chromatography-tandem mass spectrometry assays were used to measure metabolomic profiles, with 283 metabolites consistently measured in both subsamples. Physical and sexual abuse before age 18 years was retrospectively assessed by validated questions integrating type/frequency of abuse. Analyses were conducted in each sample and pooled using meta-analysis, with multiple testing adjustment using the q value approach for controlling the positive false discovery rate. After adjusting for age, race, menopausal status, body size at age 5 years, and childhood socioeconomic indicators, more severe early abuse was consistently associated with five metabolites at midlife (q value < 0.20 in both samples), including lower levels of serotonin and C38:3 phosphatidylethanolamine plasmalogen and higher levels of alanine, proline, and C40:6 phosphatidylethanolamine. Other metabolites potentially associated with early abuse (q value < 0.05 in the meta-analysis) included triglycerides, phosphatidylcholine plasmalogens, bile acids, tyrosine, glutamate, and cotinine. The association between early abuse and midlife metabolomic profiles was partly mediated by adulthood body mass index (32% mediated) and psychosocial distress (13%-26% mediated), but not by other life-style factors. Early abuse was associated with distinct metabolomic profiles of multiple amino acids and lipids in middle-aged women. Body mass index and psychosocial factors in adulthood may be important intermediates for the observed association.

Plasma metabolomic profiles for colorectal cancer precursors in women.

How metabolome changes influence the early process of colorectal cancer (CRC) development remains unknown. We conducted a 1:2 matched nested case-control study to examine the associations of pre-diagnostic plasma metabolome (profiled using LC-MS) with risk of CRC precursors, including conventional adenomas (n = 586 vs. 1141) and serrated polyps (n = 509 vs. 993), in the Nurses' Health Study (NHS) and NHSII. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). We used the permutation-based Westfall and Young approach to account for multiple testing. Subgroup analyses were performed for advanced conventional adenomas (defined as at least one adenoma of ≥ 10mm or with high-grade dysplasia, or tubulovillous or villous histology) and high-risk serrated polyps that were located in the proximal colon or with size of ≥ 10mm. After multiple testing correction, among 207 metabolites, higher levels of C36:3 phosphatidylcholine (PC) plasmalogen were associated with lower risk of conventional adenomas, with the OR (95% CI) comparing the 90th to the 10th percentile of 0.62 (0.48-0.81); C54:8 triglyceride (TAG) was associated with higher risk of serrated polyps (OR = 1.79, 95% CI: 1.31-2.43), and phenylacetylglutamine (PAG) was associated with lower risk (OR = 0.57, 95% CI:0.43-0.77). PAG was also inversely associated with advanced adenomas (OR = 0.57, 95% CI: 0.36-0.89) and high-risk serrated polyps (OR = 0.54, 95% CI: 0.32-0.89), although the multiple testing-corrected p value was > 0.05. Our findings suggest potential roles of lipid metabolism and phenylacetylglutamine, a microbial metabolite, in the early stage of colorectal carcinogenesis, particularly for the serrated pathway.

Effects of changing from a diet with saturated fat to a diet with n-6 polyunsaturated fat on the serum metabolome in relation to cardiovascular disease risk factors

PurposeReplacing saturated fatty acids (SFA) with polyunsaturated fatty acids (PUFA) is associated with a reduced risk of cardiovascular disease. Yet, the changes in the serum metabolome after this replacement is not well known. Therefore, the present study aims to identify the metabolites differentiating diets where six energy percentage SFA is replaced with PUFA and to elucidate the association of dietary metabolites with cardiometabolic risk markers.MethodsIn an 8-week, double-blind, randomized, controlled trial, 99 moderately hyper-cholesterolemic adults (25–70 years) were assigned to a control diet (C-diet) or an experimental diet (Ex-diet). Both groups received commercially available food items with different fatty acid compositions. In the Ex-diet group, products were given where SFA was replaced mostly with n-6 PUFA. Fasting serum samples were analysed by untargeted ultra-performance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS). Pre-processed data were analysed by double cross-validated Partial Least-Squares Discriminant Analysis (PLS-DA) to detect features differentiating the two diet groups.ResultsPLS-DA differentiated the metabolic profiles of the Ex-diet and the C-diet groups with an area under the curve of 0.83. The Ex-diet group showed higher levels of unsaturated phosphatidylcholine plasmalogens, an unsaturated acylcarnitine, and a secondary bile acid. The C-diet group was characterized by odd-numbered phospholipids and a saturated acylcarnitine. The Principal Component analysis scores of the serum metabolic profiles characterizing the diets were significantly associated with low-density lipoprotein cholesterol, total cholesterol, and triglyceride levels but not with glycaemia.ConclusionThe serum metabolic profiles confirmed the compliance of the participants based on their diet-specific metabolome after replacing SFA with mostly n-6 PUFA. The participants' metabolic profiles in response to the change in diet were associated with cardiovascular disease risk markers. This study was registered at clinicaltrials.gov as NCT 01679496 on September 6th 2012.

Changes in Plasma Phospholipid Metabolism Are Associated with Clinical Manifestations of Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and/or internal organs, causing a decrease in quality of life and survival. There is no causative therapy, and the pathophysiology of the SSc remains unclear. Studies showed that lipid metabolism was relevant for autoimmune diseases, but little is known about the role of lipids in SSc. In the present study, we sought to explore the phospholipid profile of SSc by using the lipidomics approach. We also aimed to analyze lipidomics results for different clinical manifestations of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry for the lipidomic profiling of plasma samples from patients with SSc. Our study showed, for the first time, significant changes in the level of phospholipids such as plasmalogens and sphingomyelins from the plasma of SSc patients as compared to controls. Phosphatidylcholine plasmalogens species and sphingomyelins were significantly increased in SSc patients as compared to controls. Our results also demonstrated a significant association of changes in the metabolism of phospholipids (phosphatidylcholine and phosphatidylethanolamine plasmalogens species and sphingomyelins) with different clinical manifestations of SSc. Further lipidomic studies might lead to the detection of lipids as new biomarkers or therapeutic targets of SSc.

Plasma Lipidomic Profiles and Risk of Diabetes: 2 Prospective Cohorts of HIV-Infected and HIV-Uninfected Individuals.

Antiretroviral therapy (ART) use is associated with disrupted lipid and glucose metabolism in people with HIV infection. We aimed to identify plasma lipid species associated with risk of diabetes in the context of HIV infection. We profiled 211 plasma lipid species in 491 HIV-infected and 203 HIV-uninfected participants aged 35 to 55 years from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. Cox proportional hazards model was used to examine associations between baseline lipid species and incident diabetes (166 diabetes cases were identified during a median follow-up of 12.6 years). We identified 11 lipid species, representing independent signals for 8 lipid classes/subclasses, associated with risk of diabetes (P < 0.05 after FDR correction). After adjustment for multiple covariates, cholesteryl ester (CE) (22:4), lysophosphatidylcholine (LPC) (18:2), phosphatidylcholine (PC) (36:4), phosphatidylcholine plasmalogen (34:3), and phosphatidylethanolamine (PE) (38:2) were associated with decreased risk of diabetes (HRs = 0.70 to 0.82 per SD increment), while diacylglycerol (32:0), LPC (14:0), PC (38:3), PE (36:1), and triacylglycerol (50:1) were associated with increased risk of diabetes (HRs = 1.26 to 1.56 per SD increment). HIV serostatus did not modify any lipid-diabetes associations; however, most of these lipid species were positively associated with HIV and/or ART use, including 3 diabetes-decreased ( CE [22:4], LPC [18:2], PE [38:2]) and all 5 diabetes-increased lipid species. This study identified multiple plasma lipid species associated with incident diabetes. Regardless of the directions of their associations with diabetes, most diabetes-associated lipid species were elevated in ART-treated people with HIV infection. This suggests a complex role of lipids in the link between ART and diabetes in HIV infection.

Lipidomic Signatures of Post-Hepatectomy Liver Failure Using Porcine Hepatectomy Models

Introduction: Clinical diagnosis of post-hepatectomy liver failure (PHLF) can only be made on or after 5th postoperative day. Biomarker for early diagnosis is considered as a critical unmet need. Method: Pigs underwent sham operation (n=6), 70% (n=7) and 90% (n=7) partial hepatectomy (PH). A comprehensive lipidomic analysis was conducted using sera collected at pre-operation (PO), 14 h, 30 h, and 48 h after PH using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Results: Of the 184 quantified lipids, 14 lipids showed significant differences between the two resection groups starting at 30 h after surgery. Four phosphatidylcholine (PC) plasmalogen species (p-16:0/16:0, p-18:0/18:2, p-18:0/20:4, and p-18:0/22:6) and PC 32:2 significantly increased in the 90% PH group while these returned to PO level after 30 h in the 70% PH group, presumably implying the failure markers. However, eight triacylglycerol (TG) species (40:0, 42:1, 42:0, 44:1, 44:2, 46:1, 46:2, and 48:3) and sphingomyelin d18:1/20:0 showed an opposite trend, wherein they significantly decreased in the 90% PH group while these in the 70% PH group were abruptly increased until 30 h but returned to near PO levels at 48 h , implying the recovery markers. Same trends were also observed in PC plasmalogen and TG classes in addition to selected individual lipid species. Conclusions: Characteristic lipidomic signatures of PHLF could be identified using large animal models. These candidates have potentials to serve as a tool for early diagnosis and may open new path to the study to overcome PHLF.

Lipidomic signatures of post-hepatectomy liver failure using porcine hepatectomy models.

BackgroundClinical diagnosis of post-hepatectomy liver failure (PHLF) can only be made on or after the 5th postoperative day. Biomarker for early diagnosis is considered as a critical unmet need.MethodsTwenty domestic female crossbreed (Yorkshire-landrace and duroc) pigs underwent sham operation (n=6), 70% (n=7) and 90% (n=7) partial hepatectomy (PH). A comprehensive lipidomic analysis was conducted using sera collected at pre-operation (PO), 14, 30, and 48 h after PH using nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry.ResultsOf the 184 quantified lipids, 14 lipids showed significant differences between the two resection groups starting at 30 h after surgery. Four phosphatidylcholine (PC) plasmalogen species (P-16:0/16:0, P-18:0/18:2, P-18:0/20:4, and P-18:0/22:6) and PC 32:2 significantly increased in the 90% PH group while these returned to PO level after 30 h in the 70% PH group, presumably implying the failure markers. In contrast, eight triacylglycerol (TG) species (40:0, 42:1, 42:0, 44:1, 44:2, 46:1, 46:2, and 48:3) and sphingomyelin d18:1/20:0 showed an opposite trend, wherein they significantly decreased in the 90% PH group while these in the 70% PH group were abruptly increased until 30 h but returned to near PO levels at 48 h, implying the recovery markers. Same trends could also be observed in the level of whole lipid classes of PC plasmalogens and TGs, in addition to selected individual lipid species.ConclusionsCharacteristic lipidomic signatures of PHLF could be identified using large animal models. These candidates have a potential to serve as a tool for early diagnosis and may open new paths to the study to overcome PHLF.

Cannabidiol-Mediated Changes to the Phospholipid Profile of UVB-Irradiated Keratinocytes from Psoriatic Patients

UVB phototherapy is treatment for psoriasis, which increases phospholipid oxidative modifications in the cell membrane of the skin. Therefore, we carried out lipidomic analysis on the keratinocytes of healthy individuals and patients with psoriasis irradiated with UVB and treated with cannabidiol (CBD), phytocannabinoid with antioxidant and anti-inflammatory properties. Our results showed that, in psoriatic keratinocytes phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylserine (PS), and ether-linked phosphoethanolamine (PEo), were downregulated, while SM (d41:2) was upregulated. These changes were accompanied by an increase in negative zeta potential, which indicates translocation of PS to the outer layer of the membrane. CBD treatment of psoriatic keratinocytes led to downregulation of PC, PS, and upregulation of certain PEo and an SM species, SM (d42:2), and the zeta potential. However, UVB irradiation of psoriatic keratinocytes resulted in upregulation of PC, PC plasmalogens (PCp), PEo, and a decrease in the negative zeta potential. The exposure of UVB-irradiated cells to CBD led to a decrease in the level of SM (d42:2). Our results suggest that CBD induces pro-apoptotic mechanisms in psoriatic keratinocytes while simultaneously improving the antioxidant properties and preventing the loss of transepidermal water of keratinocytes of patients irradiated with UVB. Thus, CBD has potential therapeutic value in the treatment of psoriasis.

Quantitative and comparative study of plasmalogen molecular species in six edible shellfishes by hydrophilic interaction chromatography mass spectrometry

Shellfishes contain plasmalogens correlating to the functions of brain, heart, etc. Herein, a mild acid hydrolysis and hydrophilic interaction chromatography (HILIC) tandem mass spectrometry method was developed for analyzing plasmalogens in six shellfish species. A total of 19 plasmalogen molecular species were successfully identified, including nine phosphatidylcholine plasmalogen (plasPC), seven phosphatidylethanolamine plasmalogen (plasPE), and three phosphatidylserine plasmalogen (plasPS). The quantitative results indicated that mussel (32 μg·mg−1) possessed the highest content of plasmalogens, followed by oyster (21 μg·mg−1) and razor clam (15 μg·mg−1). The statistic models showed that the plasPE P-18:0/20:5 (m/z 748), plasPE P-16:0/22:2 & P-18:0/20:2 (m/z 754) and plasPS were the most contributing difference between shellfishes. The results indicated that this method was sensitive and precise to determine plasmalogens in shellfish, and mussel was demonstrated to be a good choice for the large-scale preparation of plasmalogens.