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LimeMap: a comprehensive map of lipid mediator metabolic pathways.

ABSTRACT: Lipid mediators are major factors in multiple biological functions and are strongly associated with disease. Recent lipidomics approaches have made it possible to analyze multiple metabolites and the associations of individual lipid mediators. Such systematic approaches have enabled us to identify key changes of biological relevance. Against this background, a knowledge-based pathway map of lipid mediators would be useful to visualize and understand the overall interactions of these factors. Here, we have built a precise map of lipid mediator metabolic pathways (LimeMap) to visualize the comprehensive profiles of lipid mediators that change dynamically in various disorders. We constructed the map by focusing on ω-3 and ω-6 fatty acid metabolites and their respective metabolic pathways, with manual curation of referenced information from public databases and relevant studies. Ultimately, LimeMap comprises 282 factors (222 mediators, and 60 enzymes, receptors, and ion channels) and 279 reactions derived from 102 related studies. Users will be able to modify the map and visualize measured data specific to their purposes using CellDesigner and VANTED software. We expect that LimeMap will contribute to elucidating the comprehensive functional relationships and pathways of lipid mediators.

SUBMITTER: Nishi A

PROVIDER: S-EPMC7840682 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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LimeMap: a comprehensive map of lipid mediator metabolic pathways.

Nishi Akinori A Ohbuchi Katsuya K Kaifuchi Noriko N Shimobori Chika C Kushida Hirotaka H Yamamoto Masahiro M Kita Yoshihiro Y Tokuoka Suzumi M SM Yachie Ayako A Matsuoka Yukiko Y Kitano Hiroaki H

NPJ systems biology and applications 20210127 1

Lipid mediators are major factors in multiple biological functions and are strongly associated with disease. Recent lipidomics approaches have made it possible to analyze multiple metabolites and the associations of individual lipid mediators. Such systematic approaches have enabled us to identify key changes of biological relevance. Against this background, a knowledge-based pathway map of lipid mediators would be useful to visualize and understand the overall interactions of these factors. Her ...[more]

PMID: 33504811

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Project description:BackgroundAs cows transition from pregnancy to lactation, free fatty acids (FFA) are mobilized from adipose tissues (AT) through lipolysis to counter energy deficits. In clinically healthy cows, lipolysis intensity is reduced throughout lactation; however, if FFA release exceeds tissue demands or the liver's metabolic capacity, lipid byproducts accumulate, increasing cows' risk of metabolic and infectious disease. Endocannabinoids (eCBs) and their congeners, N-acylethanolamines (NAEs), are lipid-based compounds that modulate metabolism and inflammation. Their synthesis and release depend upon the availability of FFA precursors and the abundance of synthesizing and degrading enzymes and transporters. Therefore, we hypothesized that eCB production and transcription of endocannabinoid system components are modulated by lipolysis pathways in adipocytes. To test this hypothesis, we stimulated canonical (isoproterenol, 1 µmol/L; ISO) and inflammatory (lipopolysaccharide, 1 µg/mL; LPS) lipolysis pathways in adipocytes isolated from the AT of 5 Holstein dairy cows. Following, we assessed lipolysis intensity, adipocytes' release of eCBs, and transcription of endocannabinoid system components.ResultsWe found that ISO and LPS stimulated lipolysis at comparable intensities. Exposure to either treatment tended to elevate the release of eCBs and NAEs by cultured adipocytes; however, specific eCBs and NAEs and the transcriptional profiles differed by treatment. On one hand, ISO enhanced adipocytes' release of 2-arachidonoylglycerol (2-AG) but reduced NAE production. Notably, ISO enhanced the cells' expression of enzymes associated with 2-AG biosynthesis (INPP5F, GDPD5, GPAT4), transport (CD36), and adipogenesis (PPARG). Conversely, LPS enhanced adipocytes' synthesis and release of N-arachidonoylethanolamide (AEA). This change coincided with enhanced transcription of the NAE-biosynthesizing enzyme, PTPN22, and adipocytes' transcription of genes related to eCB degradation (PTGS2, MGLL, CYP27B1). Furthermore, LPS enhanced adipocytes' transcription of eCB and NAE transporters (HSPA1A, SCP2) and the expression of the anti-adipogenic ion channel, TRPV3.ConclusionsOur data provide evidence for distinct modulatory roles of canonical and inflammatory lipolysis pathways over eCB release and transcriptional regulation of biosynthesis, degradation, transport, and ECS signaling in cows' adipocytes. Based on our findings, we conclude that, within adipocytes, eCB production and ECS component expression are, at least in part, mediated by lipolysis in a pathway-dependent manner. These findings contribute to a deeper understanding of the molecular mechanisms underlying metabolic regulation in dairy cows' AT, with potential implications for prevention and treatment of inflammatory and metabolic disorders.

Project description:ObjectivesSpecialized proresolving lipid mediators have emerged as powerful modulators of inflammation and activators of resolution. Animal models show significant benefits of specialized proresolving lipid mediators on survival and wound healing after major burn trauma. To date, no studies have investigated specialized proresolving lipid mediators and their relation to other lipid mediator pathways in humans after trauma. Here we determine if patients with poor outcomes after trauma have dysregulated lipid mediator pathways.DesignWe studied blood leukocyte expression of 18 genes critical to the synthesis, signaling, and metabolism of specialized proresolving lipid mediators and proinflammatory lipid mediators, and we correlated these expression patterns with clinical outcomes in trauma patients from the Inflammation and the Host Response to Injury study.SettingSeven U.S. medical trauma centers.SubjectsNinety-six patients enrolled in the Inflammation and Host Response to Injury study, after blunt trauma and unambiguously classified as having uncomplicated or complicated recoveries. Twenty-eight healthy volunteers were enrolled as controls.InterventionsNone.Measurements and main resultsWithin each patient, the 18 genes of interest were used to calculate scores for distinct families of lipid mediators, including resolvins, lipoxins, prostaglandins, and leukotrienes, as well as leukotriene to resolvin score ratios. Scores were built using a simple weighting scheme, taking into consideration both dependent and independent activities of enzymes and receptors responsible for lipid mediator biosynthesis and function. Individually, ALOX12, PTGS2, PTGES, PTGDS, ALOX5AP, LTA4H, FPR2, PTGER2, LTB4R, HPGD, PTGR1, and CYP4F3 were expressed differentially over 28 days posttrauma between patients with uncomplicated and complicated recoveries (p < 0.05). When all genes were combined into scores, patients with uncomplicated recoveries had differential and higher resolvin scores (p < 0.001) and lower leukotriene scores (p < 0.001). A final combined ratio was calculated for each patient, and posttrauma leukotriene score to resolvin score ratios were significantly lower in patients with uncomplicated clinical courses (p < 0.001).Conclusionsproresolving lipid mediator lipidomics and/or protein expression, and identifying associated therapeutic targets, may influence the clinical management of trauma patients.

Project description:BackgroundCommon metabolic diseases, including type 2 diabetes, coronary artery disease, and hypertension, arise from disruptions of the body's metabolic homeostasis, with relatively strong contributions from genetic risk factors and substantial comorbidity with obesity. Although genome-wide association studies have revealed many genomic loci robustly associated with these diseases, biological interpretation of such association is challenging because of the difficulty in mapping single-nucleotide polymorphisms (SNPs) onto the underlying causal genes and pathways. Furthermore, common diseases are typically highly polygenic, and conventional single variant-based association testing does not adequately capture potentially important large-scale interaction effects between multiple genetic factors.MethodsWe analyzed moderately sized case-control data sets for type 2 diabetes, coronary artery disease, and hypertension to characterize the genetic risk factors arising from non-additive, collective interaction effects, using a recently developed algorithm (discrete discriminant analysis). We tested associations of genes and pathways with the disease status while including the cumulative sum of interaction effects between all variants contained in each group.ResultsIn contrast to non-interacting SNP mapping, which produced few genome-wide significant loci, our analysis revealed extensive arrays of pathways, many of which are involved in the pathogenesis of these metabolic diseases but have not been directly identified in genetic association studies. They comprised cell stress and apoptotic pathways for insulin-producing β-cells in type 2 diabetes, processes covering different atherosclerotic stages in coronary artery disease, and elements of both type 2 diabetes and coronary artery disease risk factors (cell cycle, apoptosis, and hemostasis) associated with hypertension.ConclusionsOur results support the view that non-additive interaction effects significantly enhance the level of common metabolic disease associations and modify their genetic architectures and that many of the expected genetic factors behind metabolic disease risks reside in smaller genotyping samples in the form of interacting groups of SNPs.

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LimeMap: a comprehensive map of lipid mediator metabolic pathways.

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LimeMap: a comprehensive map of lipid mediator metabolic pathways.

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