Changes In Lipidome Research Articles

A set of gene knockouts as a resource for global lipidomic changes

Enzyme specificity in lipid metabolic pathways often remains unresolved at the lipid species level, which is needed to link lipidomic molecular phenotypes with their protein counterparts to construct functional pathway maps. We created lipidomic profiles of 23 gene knockouts in a proof-of-concept study based on a CRISPR/Cas9 knockout screen in mammalian cells. This results in a lipidomic resource across 24 lipid classes. We highlight lipid species phenotypes of multiple knockout cell lines compared to a control, created by targeting the human safe-harbor locus AAVS1 using up to 1228 lipid species and subspecies, charting lipid metabolism at the molecular level. Lipid species changes are found in all knockout cell lines, however, some are most apparent on the lipid class level (e.g., SGMS1 and CEPT1), while others are most apparent on the fatty acid level (e.g., DECR2 and ACOT7). We find lipidomic phenotypes to be reproducible across different clones of the same knockout and we observed similar phenotypes when two enzymes that catalyze subsequent steps of the long-chain fatty acid elongation cycle were targeted.

Effect of Drought Stress on Degradation and Remodeling of Membrane Lipids in Nostoc flagelliforme.

Nostoc flagelliforme is a kind of terrestrial edible cyanobacteria with important ecological and economic value which has developed special mechanisms to adapt to drought conditions. However, the specific mechanism of lipidome changes in drought tolerance of N. flagelliforme has not been well understood. In this study, the ultra-high-performance liquid chromatography and mass spectrometry were employed to analyze the lipidome changes of N. flagelliforme under dehydration. A total of 853 lipid molecules were identified, of which 171 were significantly different from that of the control group. The digalactosyldiacylglycerol/monogalactosyldiacylglycerol (DGDG/MGDG) ratio was increased. The amount of wax ester (WE) was sharply decreased during drought stress, while Co (Q10) was accumulated. The levels of odd chain fatty acids (OCFAs) were increased under dehydration, positively responding to drought stress according to the energy metabolism state. In conclusion, the lipidomic data corroborated that oxidation, degradation, and biosynthesis of membrane lipids took place during lipid metabolism, which can respond to drought stress through the transformation of energy and substances. Besides, we constructed a lipid metabolic model demonstrating the regulatory mechanism of drought stress in N. flagelliforme. The present study provides insight into the defense strategies of cyanobacteria in lipid metabolic pathways.

Changes in the lipidome of water buffalo milk during intramammary infection by non-aureus Staphylococci

This study aimed to determine the lipidome of water buffalo milk with intramammary infection (IMI) by non-aureus staphylococci (NAS), also defined as coagulase-negative staphylococci, using an untargeted lipidomic approach. Non-aureus Staphylococci are the most frequently isolated pathogens from dairy water buffalo milk during mastitis. A total of 17 milk samples from quarters affected by NAS-IMI were collected, and the lipidome was determined by liquid chromatography-quadrupole time-of-flight mass spectrometry. The results were compared with the lipidome determined on samples collected from 16 healthy quarters. The study identified 1934 different lipids, which were classified into 15 classes. The abundance of 72 lipids changed in NAS-IMI milk compared to healthy quarters. Significant changes occurred primarily in the class of free fatty acids. The results of this study provided first-time insight into the lipidome of dairy water buffalo milk. Moreover, the present findings provide evidence that NAS-IMI induces changes in water buffalo milk's lipidome.

MEDB-03. Medulloblastoma cerebrospinal fluid reveals hypoxic indicators (metabolites and lipids) and cancer-specific RNAs

Medulloblastoma (MB) is the most common malignant brain tumor in children. There remains an unmet need for diagnostics to sensitively detect the disease, particularly recurrences. Cerebrospinal fluid (CSF) provides a window into the central nervous system, and liquid biopsy of CSF could provide a relatively non-invasive means for disease diagnosis. There has yet to be an integrated analysis of the transcriptomic, metabolomic, and lipidomic changes occurring in the CSF of children with MB. CSF samples from patients with (n=40) or without (n=11; no cancer) MB were subjected to RNA-sequencing and high-resolution mass spectrometry to identify RNA, metabolite, and lipid profiles. Differentially expressed transcripts, metabolites, and lipids were identified and their biological significance assessed by pathway analysis. Multivariate analysis method DIABLO (R package mixOmics) was used to integrate the molecular changes characterizing the CSF of MB patients. Differentially expressed transcripts, metabolites, and lipids in CSF were discriminatory for the presence of MB but not the exact molecular subtype. One hundred ten genes and ten circular RNAs were differentially expressed in MB CSF compared to normal representing TGF-β signaling, TNF-a signaling via NF-kB, and adipogenesis pathways. Tricarboxylic acid cycle and other metabolites (malate, fumarate, succinate, α-ketoglutarate, hydroxypyruvate, N-acetyl-aspartate) and total triacylglycerols were significantly upregulated in MB CSF compared to normal CSF. Although the transcriptomic, metabolomic, and lipid signatures in CSF to differentiate MB subgroup separation was challenging, we were able to identify a group of omics signatures that could separate cancer from normal CSF. Metabolic and lipidomic profiles both contained indicators of tumor hypoxia. Our approach provides several candidate signatures that deserve further validation, including the novel circular RNA circ_463, and insights into the impact of MB on the CSF microenvironment.

1349-P: Bariatric Surgery Causes an Early Improvement in the Lipidomic Profile and a Decrease in Plasma Ceramides and Diacylglycerols in Patients with Type 2 Diabetes and NAFLD

Bariatric surgery (BarS) is known to improve insulin resistance (IR) , atherogenic dyslipidemia and steatohepatitis in patients (pts) with type 2 diabetes (T2D) . Total ceramides (Cer) and diacylglycerols (DAGs) have been implicated in the development of IR and nonalcoholic fatty liver disease (NAFLD) , but the impact of BarS on their plasma concentration remains unclear. The aim of this study was to assess early changes in the plasma lipidome, before and 3-6 months post BarS. To this end, we recruited 17 pts with NAFLD who underwent BarS (age 47±3, BMI 46±2 kg/m2, 76% with T2D) , and 6 controls without T2D (baseline data only, age 47±6, BMI 31.2±2.1 kg/m2) . Global lipidomic profiling was performed on orbitrap mass spectrometer with UHPLC. Data was analysed using LipidMatch software. Plasma levels of total lipids (TL) (34%; p=0.01) , Cer (20%; p=0.31) , DAGs (50%; p=0.03) and total triglycerides (TG) (79%; p=0.01) were higher in pts with NAFLD compared to controls. Bariatric surgery reduced plasma TL (-26%) , Cer (-31%) , DAGs (-34%) and TG (-43%) levels (all p<0.01) . In pts with vs. without T2D, plasma TL were higher (28%; p=0.01) . There was a reduction in TL (-29%; p<0.01) , Cer (-22%; 0.27) , DAGs (-41%; p=0.02) and TG (-52%; p<0.01) post BarS and a similar pattern was observed across the lipidomic profile (cholesterol esters, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol) . Reduction in weight after BarS correlated with lower DAGs (r=0.81; p=0.03) and TG (r=0.66; p=0.07) . Reduction in Cer correlated with improved HOMA-IR (r= 0.71; p=0.04) and Adipo-IR (r= 0.63; p=0.09) . In conclusion, pts with NAFLD and T2D have a significantly worse lipidomic profile compared to pts without T2D. The unfavorable lipidomic profile was normalized after BarS, in particular Cer and DAG levels, known to be linked to IR. Assessment of the lipidomic profile may provide further insights into insulin sensitivity changes after BarS. Disclosure S.Kalavalapalli: None. A.Zarrinpar: None. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk. D.Barb: None. R.E.Dillard: None. E.Godinez: None. J.Friedman: n/a. N.Fanous: None. C.O.Warren: None. F.Bril: None. R.Lomonaco: None.

Thermal plasticity of coral reef symbionts is linked to major alterations in their lipidome composition

AbstractCoral bleaching caused by ocean warming is leading to worldwide coral decline. The physiological processes underlying this ecological event are still incompletely understood, although previous research has suggested oxidative stress as major player in the impairment of symbiont thylakoid membranes and in symbiosis breakdown. Lipids are interesting targets of investigation, given their susceptibility to thermal and oxidative stresses. Here, an untargeted lipidomic approach was employed to examine changes in lipidome and pigments of three coral reef symbionts (Symbiodiniaceae) after a heat shock in in vitro experiments. The acute thermal stress induced species‐specific changes in lipidome and pigments compositions of both heat sensitive and tolerant symbionts. Heat sensitivity was characterized by a steep and steady decline in cell densities over time (4 and 240 h after heat shock). At the membrane level, heat sensitive symbiont displayed a quantitative decrease in glycolipids linked to polyunsaturated fatty acids, followed by enrichment in oxidized lipids and sphingolipids. Despite showing distinct adaptations, the two heat tolerant symbionts were characterized by the preservation of membrane lipids after heat shock, particularly glycolipids. This finding suggests the action of powerful antioxidant systems, preventing the escalation of oxidized lipids concentration in thylakoid membranes under thermal stress. Although limited by the examination of free‐living symbionts, our study provides a solid baseline for the investigation of lipidome and pigments alterations of Symbiodiniaceae in response to heat stress. Novel potential lipid biomarkers linked to thermal stress are suggested. In particular, oxidized lipids—which are implicated in coral symbiosis establishment and breakdown—appear as attractive targets for further research.

Adaptations of the 3T3-L1 adipocyte lipidome to defective ether lipid catabolism upon Agmo knockdown

Little is known about the physiological role of alkylglycerol monooxygenase (AGMO), the only enzyme capable of cleaving the 1-O-alkyl ether bond of ether lipids. Expression and enzymatic activity of this enzyme can be detected in a variety of tissues including adipose tissue. This labile lipolytic membrane-bound protein uses tetrahydrobiopterin as a cofactor, and mice with reduced tetrahydrobiopterin levels have alterations in body fat distribution and blood lipid concentrations. In addition, manipulation of AGMO in macrophages led to significant changes in the cellular lipidome, and alkylglycerolipids, the preferred substrates of AGMO, were shown to accumulate in mature adipocytes. Here, we investigated the roles of AGMO in lipid metabolism by studying 3T3-L1 adipogenesis. AGMO activity was induced over 11 days using an adipocyte differentiation protocol. We show that RNA interference-mediated knockdown of AGMO did not interfere with adipocyte differentiation or affect lipid droplet formation. Furthermore, lipidomics revealed that plasmalogen phospholipids were preferentially accumulated upon Agmo knockdown, and a significant shift toward longer and more polyunsaturated acyl side chains of diacylglycerols and triacylglycerols could be detected by mass spectrometry. Our results indicate that alkylglycerol catabolism has an influence not only on ether-linked species but also on the degree of unsaturation in the massive amounts of triacylglycerols formed during in vitro 3T3-L1 adipocyte differentiation.

Rodents on a high-fat diet born to mothers with gestational diabetes exhibit sex-specific lipidomic changes in reproductive organs.

Maternal gestatonal diabetes mellitus (GDM) and offspring high-fat diet (HFD) have been shown to have sex-specific detrimental effects on the health of the offspring. Maternal GDM combined with an offspring HFD alters the lipidomic profiles of offspring reproductive organs with sex hormones and increases insulin signaling, resulting in offspring obesity and diabetes. The pre-pregnancy maternal GDM mice model is established by feeding maternal C57BL/6 mice and their offspring are fed with either a HFD or a low-fat diet (LFD). Testis, ovary and liver are collected from offspring at 20 weeks of age. The lipidomic profiles of the testis and ovary are characterized using gas chromatography-mass spectrometry. Male offspring following a HFD have elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers have decreased testes weights and testosterone levels, while female offspring from GDM mothers show increased ovary weights and estrogen levels. Maternal GDM aggravates the effects of an offspring HFD in male offspring on the AKT pathway, while increasing the risk of developing inflammation when expose to a HFD in female offspring liver. Testes are prone to the effect of maternal GDM, whereas ovarian metabolite profiles are upregulated in maternal GDM and downregulated in offspring following an HFD. Maternal GDM and an offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in the offspring, such as obesity and diabetes.

Space- and Time-Resolved Metabolomics of a High-Grade Serous Ovarian Cancer Mouse Model.

Simple SummaryThe underlying mechanisms associated with ovarian cancer progression remain largely unknown, making it one of the most lethal cancers. To understand the disease pathogenesis, our study involved longitudinal serum metabolomics profiling of a triple-mutant mouse model of ovarian cancer that captured the dynamic metabolic response from disease onset until mouse death. These experiments were complemented with spatial lipidomic profiling of the entire reproductive system of the triple-mutant mice, enabling us to visualize the tissue heterogeneity and lipid alterations within tumors. A combined longitudinal and spatial map of metabolomic alterations associated with ovarian cancer progression is presented, serving as a comprehensive guide towards understanding the disease origin and progression.The dismally low survival rate of ovarian cancer patients diagnosed with high-grade serous carcinoma (HGSC) emphasizes the lack of effective screening strategies. One major obstacle is the limited knowledge of the underlying mechanisms of HGSC pathogenesis at very early stages. Here, we present the first 10-month time-resolved serum metabolic profile of a triple mutant (TKO) HGSC mouse model, along with the spatial lipidome profile of its entire reproductive system. A high-coverage liquid chromatography mass spectrometry-based metabolomics approach was applied to longitudinally collected serum samples from both TKO (n = 15) and TKO control mice (n = 15), tracking metabolome and lipidome changes from premalignant stages to tumor initiation, early stages, and advanced stages until mouse death. Time-resolved analysis showed specific temporal trends for 17 lipid classes, amino acids, and TCA cycle metabolites, associated with HGSC progression. Spatial lipid distributions within the reproductive system were also mapped via ultrahigh-resolution matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and compared with serum lipid profiles for various lipid classes. Altogether, our results show that the remodeling of lipid and fatty acid metabolism, amino acid biosynthesis, TCA cycle and ovarian steroidogenesis are critical components of HGSC onset and development. These metabolic alterations are accompanied by changes in energy metabolism, mitochondrial and peroxisomal function, redox homeostasis, and inflammatory response, collectively supporting tumorigenesis.

Lipidome Alterations with Exercise Among People With and Without HIV: An Exploratory Study.

Age-related comorbidities and physical function impairments in aging people with HIV (PWH) can be improved through exercise interventions. The mechanisms underlying these improvements, including lipidomic changes, are unknown. Sedentary adults (50-75 years old) with or without HIV participated in supervised endurance/resistance exercise for 24 weeks. Plasma lipid concentrations (∼1,200 lipid species from 13 lipid classes) at baseline and week 24 were measured by mass spectrometry. Given multiple comparisons, unadjusted and Benjamini-Hochberg corrected p values are reported. Analyses are considered exploratory. Twenty-five PWH and 24 controls had paired samples at baseline and week 24. The change in total triacylglycerol (TAG) concentrations after exercise intervention differed between groups (unadj-p = 0.006, adj-p = 0.078) with concentrations increasing among controls, but not among PWH. Changes in concentrations of TAG species composed of long-chain fatty acids differed between groups (unadj-p < 0.04) with increases among controls, but not among PWH. Changes in total diacylglycerol (DAG) concentration from baseline to week 24 differed between groups (unadj-p = 0.03, adj-p = 0.2) with an increase in PWH and a nonsignificant decrease in controls. Baseline to week 24 changes in DAGs composed of palmitic acid (16:0), palmitoleic acid (16:1), and stearic acid (18:0) differed by serostatus (unadj-p = 0.009-0.03; adj-p 0.10-0.12), with nonsignificant increases and decreases in concentrations in PWH and controls, respectively. Concentrations of individual lysophosphatidylcholine (LPC) and ceramide (CER) species also differed by HIV serostatus (unadj-p < = 0.05). Although exploratory, the effects of exercise on the lipidome may differ among people with and without HIV, potentially due to underlying alterations in lipid processing and fatty acid oxidation in PWH. Clinical Trials NCT02404792.

Endo- and Exometabolome Crosstalk in Mesenchymal Stem Cells Undergoing Osteogenic Differentiation.

This paper describes, for the first time to our knowledge, a lipidome and exometabolome characterization of osteogenic differentiation for human adipose tissue stem cells (hAMSCs) using nuclear magnetic resonance (NMR) spectroscopy. The holistic nature of NMR enabled the time-course evolution of cholesterol, mono- and polyunsaturated fatty acids (including ω-6 and ω-3 fatty acids), several phospholipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelins, and plasmalogens), and mono- and triglycerides to be followed. Lipid changes occurred almost exclusively between days 1 and 7, followed by a tendency for lipidome stabilization after day 7. On average, phospholipids and longer and more unsaturated fatty acids increased up to day 7, probably related to plasma membrane fluidity. Articulation of lipidome changes with previously reported polar endometabolome profiling and with exometabolome changes reported here in the same cells, enabled important correlations to be established during hAMSC osteogenic differentiation. Our results supported hypotheses related to the dynamics of membrane remodelling, anti-oxidative mechanisms, protein synthesis, and energy metabolism. Importantly, the observation of specific up-taken or excreted metabolites paves the way for the identification of potential osteoinductive metabolites useful for optimized osteogenic protocols.

Large Airway Bronchial Wash Lipidomics as Novel Biomarkers for Chronic Lung Allograft Dysfunction

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is the primary cause of long-term mortality after lung transplantation. Aspiration of bile acids has been associated with CLAD and lipidomic dysregulation. This study evaluates the role of large airway bronchial wash (LABW) lipidomics and diagnosis of CLAD. <h3>Methods</h3> LABW (n=611) samples were obtained from 305 lung transplant recipients at different timepoints. Concentrations of 26 specific lipid subfamilies were obtained using liquid chromatography mass spectrometry. Lipid percentages where stratified by highest tertiles. The primary outcome of interest was development of CLAD from sampling time. Time-to-event analysis was done using Kaplan-Meier functions and a multivariable Cox proportional hazards model adjusting for baseline comorbidities. <h3>Results</h3> Samples with CLAD at the time of collection showed higher percentages of hexosylceramides (HEXCER), CE, sphingomyelin (SM) and lactosylceramide (LACCER). A high percentage of bismethyl-phosphatidic acid (BMP), CE, phosphatidylethanolamine (PEP), dehydrosphingosine (DHSM), lysophosphatidylethanolamine (LPE), ganglioside (GM3), phosphatidyl-serine (PS) were associated with an increased hazards of CLAD by univariable analysis. A high percentage of CE (HR: 1.48, 95% CI: 1.09-2.03, <i>P</i>=0.013) were independent predictors of CLAD by multivariable analysis. High percentages of CER (HR: 0.49, 95% CI: 0.36-0.66, <i>P</i><0.001) and a high LACCER:CER ratio (HR: 0.45, 95% CI: 0.34-0.62, <i>P</i><0.001) were independently associated with decreased hazards of CLAD. <h3>Conclusion</h3> Airway lipidomic qualititative changes show a distinct phenotype that associate with the presence and risk of development of CLAD. Percentages of CE, CER and LACCER:CER ratios correlate independently with increased risk of development of CLAD. Changes in LABW lipids may serve as biomarkers for CLAD and elucidate pathophysiologic changes after transplant.

Lipid Homeostasis and Its Links With Protein Misfolding Diseases.

The maintenance of lipid homeostasis is essential for the normal functioning of living organisms. Alterations of the lipid homeostasis system remodel the composition of the lipidome, potentially leading to the formation of toxic lipid species. In turn, lipidome changes can affect the protein homeostasis system by causing perturbations that elicit protein condensation phenomena such as protein liquid-liquid phase separation and protein aggregation. Lipids can also be more directly involved the formation of aberrant condensed states of proteins by facilitating the early events that initiate these processes and by stabilizing the condensed states themselves. These observations suggest that lipid-induced toxicity can contribute to protein misfolding diseases, including Alzheimer’s and Parkinson’s diseases. According to this view, an impairment of the lipid homeostasis system generates toxic states of lipids that disturb the protein homeostasis system and promote the formation of toxic states of proteins.

Abstract EP35: Longitudinal Lipidomic Profiling Of Left Ventricular Mass In American Indians: The Strong Heart Study

Background: Dyslipidemia is a major risk factor for CVD. Left ventricular mass (LVM) is an independent predictor of heart failure and other cardiovascular events. It is unclear whether and how altered plasma lipidome (all lipids in a plasma sample) affects LVM. The relationship between longitudinal change in plasma lipidome and change in LVM is also unstudied in any racial/ethnic group. Objective: To identify molecular lipid species associated with LVM, independent of traditional risk factors. Methods: Using an untargeted LC-MS, we repeatedly measured 1,542 lipids in 3,162 fasting plasma samples collected at two time points (2001-2003, 2006-2009, mean 5.5 years apart) from 1,581 American Indians in the Strong Heart Family Study. All participants were free of overt CVD at both time points. LVM was measured by M-mode echocardiography and LVM index (LVMI) was calculated as LVM/height 2.7 . Lipids associated with LVMI were identified by generalized estimating equation (GEE) models, adjusting for age, sex, center, BMI, smoking, blood pressure, renal function, LDL-c, and diabetes. We first conducted the analysis at each time point, separately, and then combined the results by meta-analysis. The longitudinal association between change in lipids and change in LVMI was examined by GEE, adjusting for the same covariates plus baseline lipids and LVMI. Multiple testing was controlled by false discovery rate at 0.05. Results: The mean age of participants was 39.8 years (62.5% women) at baseline and 45.1 years at follow-up. We identified 325 lipids (125 known), largely fatty acyls, sterol lipids, sphingolipids, glycerolipids, and glycerophospholipids, significantly associated with LVMI at both time points. Longitudinal changes in 17 lipids, including glycerolipids, glycerophospholipids, and sphingolipids, were either positively (ORs: 1.09 -1.95) or negatively (ORs: 0.50 - 0.69) associated with change in LVMI over 5 years of follow-up. Changes in lipids explain up to 1.58% of the variability in the change of LVMI during follow-up. Additional adjustments for use of anti-hypertensive and lipid-lowering drugs did not change the results. Conclusion: Altered fasting plasma lipidome and its longitudinal change over time were significantly associated with LVMI beyond clinical factors and baseline lipids. Our results shed light on the mechanisms through which dyslipidemia may affect LV remodeling, thereby contributing to heart failure or other cardiovascular events.

Abstract EP07: A Longitudinal Lipidomics Profiling For Risk Of Chronic Kidney Disease In American Indians: The Strong Heart Family Study

Background: Dyslipidemia is associated with and often precedes the onset of chronic kidney disease (CKD). However, standard lipid panels fail to describe the full spectrum of blood lipidome. A longitudinal profiling of the full spectrum of blood lipidome associated with the risk of CKD is still lacking in any racial/ethnic group, including American Indians, a population that suffered a disproportionately high burden of CKD. Objective: To identify novel lipids and lipidomic signatures associated with risk of CKD in American Indians, independent of traditional risk factors. Methods: We included 1,910 American Indians who attended two examinations (~5.5 years apart) and were free of CKD and cardiovascular disease (CVD) at baseline. CKD was defined based on the estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI formula. Fasting plasma levels of 1,542 lipids in 3,916 samples at two-time points were repeatedly measured by untargeted LC-MS. Machine learning (elastic net) was used to identify lipidomic predictors of CKD beyond traditional risk factors (age, sex, center, BMI, hypertension, diabetes, urinary albumin/creatinine ratio, HDL, triglyceride, and use of lipid-lowering medications). Mixed-effect linear models were used to examine the relationship between changes (baseline to 5-year follow-up) in lipidome and change in kidney function (eGFR), adjusting for traditional risk factors mentioned above, baseline lipid, and baseline eGFR. Multivariate analysis was conducted to identify discriminatory lipidomic signatures that can differentiate between high- and low-risk individuals. Results: Of 1,910 participants free of CKD and CVD (17.8% diabetic) at baseline, 55 (2.9%) developed incident CKD by the end of a 5-year follow-up. Elastic net identified 106 (24 known) lipids, largely glycerophospholipids (GPs), sphingomyelins (SMs), triacylglycerols (TAGs), fatty acids (FAs), and acylcarnitines (ACs), whose altered baseline levels were associated with the risk of CKD, independent of traditional risk factors. A composite lipid score composed of the 24 known lipids improved CKD risk prediction beyond traditional risk factors (AUROC improved from 0.944 to 0.963, P = 0.006). Longitudinal changes in 182 lipids (75 known) lipids, largely GPs, FAs, SMs, TAGs, ACs, and diacylglycerols (DAGs), explained up to 4.8% of the variation of the eGFR change. Multivariate analysis identified distinct lipidomic signatures that separated high- from low-risk participants. Conclusion: We identified novel molecular lipids that significantly predict CKD onset and progression among American Indians beyond traditional risk factors. Our findings shed light on the mechanisms by which dyslipidemia affects CKD and provide instrumental data for biomarker identification, risk prediction and stratification, prognosis, and potential therapeutics.

Medulloblastoma cerebrospinal fluid reveals metabolites and lipids indicative of hypoxia and cancer-specific RNAs

Medulloblastoma (MB) is the most common malignant brain tumor in children. There remains an unmet need for diagnostics to sensitively detect the disease, particularly recurrences. Cerebrospinal fluid (CSF) provides a window into the central nervous system, and liquid biopsy of CSF could provide a relatively non-invasive means for disease diagnosis. There has yet to be an integrated analysis of the transcriptomic, metabolomic, and lipidomic changes occurring in the CSF of children with MB. CSF samples from patients with (n = 40) or without (n = 11; no cancer) MB were subjected to RNA-sequencing and high-resolution mass spectrometry to identify RNA, metabolite, and lipid profiles. Differentially expressed transcripts, metabolites, and lipids were identified and their biological significance assessed by pathway analysis. The DIABLO multivariate analysis package (R package mixOmics) was used to integrate the molecular changes characterizing the CSF of MB patients. Differentially expressed transcripts, metabolites, and lipids in CSF were discriminatory for the presence of MB but not the exact molecular subtype. One hundred and ten genes and ten circular RNAs were differentially expressed in MB CSF compared with normal, representing TGF-β signaling, TNF-α signaling via NF-kB, and adipogenesis pathways. Tricarboxylic acid cycle and other metabolites (malate, fumarate, succinate, α-ketoglutarate, hydroxypyruvate, N-acetyl-aspartate) and total triacylglycerols were significantly upregulated in MB CSF compared with normal CSF. Although separating MBs into subgroups using transcriptomic, metabolomic, and lipid signatures in CSF was challenging, we were able to identify a group of omics signatures that could separate cancer from normal CSF. Metabolic and lipidomic profiles both contained indicators of tumor hypoxia. Our approach provides several candidate signatures that deserve further validation, including the novel circular RNA circ_463, and insights into the impact of MB on the CSF microenvironment.

Effect of Omega-3 Polyunsaturated Fatty Acids on Lipid Metabolism in Patients With Metabolic Syndrome and NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. n‐3 polyunsaturated fatty acids (n‐3‐PUFAs) have been reported to ameliorate the progression of NAFLD in experimental studies; however, clinical trials have yielded contradictory results. The aim of our study was to assess the effects of n‐3‐PUFA administration on lipid metabolism and the progression of NAFLD in patients with metabolic syndrome. Sixty patients with metabolic syndrome and NAFLD were randomized in a double‐blind placebo‐controlled trial (3.6 g/day n‐3‐PUFA vs. placebo). During the 1‐year follow‐up, the patients underwent periodic clinical and laboratory examinations, liver stiffness measurements, magnetic resonance spectroscopy of the liver, and plasma lipidomic analyses. After 12 months of n‐3‐PUFA administration, a significant decrease in serum GGT activity was recorded compared with the placebo group (2.03 ± 2.8 vs. 1.43 ± 1.6; P < 0.05). Although no significant changes in anthropometric parameters were recorded, a significant correlation between the reduction of liver fat after 12 months of treatment—and weight reduction—was observed; furthermore, this effect was clearly potentiated by n‐3‐PUFA treatment (P < 0.005). In addition, n‐3‐PUFA treatment resulted in substantial changes in the plasma lipidome, with n‐3‐PUFA‐enriched triacylglycerols and phospholipids being the most expressed lipid signatures. Conclusion: Twelve months of n‐3‐PUFA treatment of patients with NAFLD patients was associated with a significant decrease in GGT activity, the liver fat reduction in those who reduced their weight, and beneficial changes in the plasma lipid profile.

The lipid transporter Mfsd2a maintains pulmonary surfactant homeostasis

Pulmonary surfactant is a lipoprotein complex essential for lung function, and insufficiency or altered surfactant composition is associated with major lung diseases, such as acute respiratory distress syndromes, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Pulmonary surfactant is primarily composed of phosphatidylcholine (PC) in complex with specialized surfactant proteins and secreted by alveolar type 2 (AT2) cells. Surfactant homeostasis on the alveolar surface is balanced by the rates of synthesis and secretion with reuptake and recycling by AT2 cells, with some degradation by pulmonary macrophages and loss up the bronchial tree. However, whether phospholipid (PL) transporters exist in AT2 cells to mediate reuptake of surfactant PL remains to be identified. Here, we demonstrate that major facilitator superfamily domain containing 2a (Mfsd2a), a sodium-dependent lysophosphatidylcholine (LPC) transporter, is expressed at the apical surface of AT2 cells. A mouse model with inducible AT2 cell–specific deficiency of Mfsd2a exhibited AT2 cell hypertrophy with reduced total surfactant PL levels because of reductions in the most abundant surfactants, PC containing dipalmitic acid, and PC species containing the omega-3 fatty acid docosahexaenoic acid. These changes in surfactant levels and composition were mirrored by similar changes in the AT2 cell lipidome. Mechanistically, direct tracheal instillation of fluorescent LPC and PC probes indicated that Mfsd2a mediates the uptake of LPC generated by pulmonary phospholipase activity in the alveolar space. These studies reveal that Mfsd2a-mediated LPC uptake is quantitatively important in maintaining surfactant homeostasis and identify this lipid transporter as a physiological component of surfactant recycling.

Impact of myocardial reperfusion on human plasma lipidome

SummaryThe primary aim of the study is to investigate the temporal changes in plasma lipidome before and after reperfusion in patients with ST-segment elevation myocardial infarction (STEMI) and their association with myocardial injury. We found that 56% of the identified lipid species were significantly altered (corrected p< 0.05) in the first 24 h following reperfusion in patients with STEMI. Three lipid species, namely, acylcarnitine 18:2, TG 51:0, and LPC 17:1 were associated with a change in troponin concentration (delta troponin) and in-hospital cardiovascular events. Of these, acylcarnitine 18:2, and LPC 17:1 and their respective whole class levels, were significantly higher (p < 0.05) in the STEMI population than the age/sex-matched control subjects. Overall, our analyses showed a large shift in plasma lipidome in patients that undergo myocardial reperfusion. The differences found for acylcarnitines and LPC species and their association with both cardiac markers and cardiac outcomes need further validation.

Long-Term Effects on the Lipidome of Acute Coronary Syndrome Patients.

Lipids modified by oxidative stress are key players in atherosclerosis progression. Superimposed thrombosis with subsequent closure of the coronary artery leads to the clinical manifestation of acute coronary syndrome (ACS). While several studies focusing on alterations in lipid metabolism in the acute phase have been conducted, no information is available on patients’ lipidome alterations over longer time periods. In the current follow-up study, we analyzed plasma samples obtained from 17 patients three years after their ACS event (group AC). Originally, these patients were sampled 3–5 days after an index event (group B). Lipidome stability over time was studied by untargeted lipidomics using high performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC–HRMS). Multi-dimensional statistics used for data processing indicated that plasmalogen lipids were the most prominent lipids separating the above patient groups and that they increased in the follow-up AC group. A similar trend was observed for lysophosphatidylethanolamine (LPE) and phosphatidylethanolamine (PE). The opposite trend was observed for two fatty acyls of hydroxy fatty acid (FAHFAs) lipids and free stearic acid. In addition, a decrease in the “classic” oxitadive stress marker, malondialdehyde (MDA), occurred during the follow-up period. Our findings present unique information about long-term lipidome changes in patients after ACS.