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Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Lipid Metabolism".

Deadline for manuscript submissions: closed (15 August 2022) | Viewed by 17317

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Special Issue Editors

Dr. Cécile Gladine

E-Mail Website
Guest Editor

Université Clermont Auvergne, INRAE, UNH, Clermont-Ferrand, France
Interests: cardiometabolic diseases; aging; inflammation; inter-individual variability; oxylipins; nutrition; omega-3 fatty acids; biomarker

Dr. John William Newman

E-Mail Website1 Website2
Co-Guest Editor

1. Obesity and Metabolism Research Unit, USDA-ARS-WHNRC, Davis, CA 95616, USA
2. Department of Nutrition, University of California, Davis, CA 95616, USA
Interests: targeted and untargeted metabolomics; lipoprotein; energy metabolism; diet

Prof. Dr. Harold M. Aukema

E-Mail Website
Co-Guest Editor

Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
Interests: oxylipins; dietary fatty acids; human nutrition

Special Issue Information

Dear Colleagues,

Background. The term “oxylipins” refers to a superfamily of signaling lipids generated from the oxygenation of polyunsaturated fatty acids (PUFAs). Similar to cytokines, oxylipins are major mediators of the innate immune response that are involved in infection and inflammation, as well as in the resolution of inflammation. Advances in analytical methods now allow the quantitative profiling of dozens of oxylipins providing a comprehensive systems biology approach for understanding and treating diseases implicating oxylipin signaling. MS-based lipidomic profiling can be used to determine global changes in oxylipin levels in various physiopathological situations and to provide scientists with a mechanistic understanding of the disease and potential new therapeutic targets.

Aims. This Special Issue of Metabolites on “Lipidomic Profiling of Oxylipins to Characterize Inflammatory-Related Diseases” will discuss the potential of lipidomic profiling of oxylipins to provide a mechanistic understanding of inflammatory-related diseases. Studies on changes in oxylipin profiles in patients with inflammatory-related diseases (e.g., cardiometabolic diseases, CVD, immune diseases, cancer, infectious diseases or inflammaging) as well on the modulation of the oxylipin production by anti-inflammatory or pro-resolving therapeutic or dietary approaches are welcome. Clinical or population studies as well as reviews in this topic area will be considered for peer review.

Dr. Cécile Gladine
Dr. John William Newman
Prof. Dr. Harold M. Aukema
Guest Editors

Manuscript Submission Information

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Keywords

oxylipins
MS-based lipidomics
inflammation
immune response
anti-inflammatory treatment
specialized pro-resolving mediators

Published Papers (9 papers)

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Research

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15 pages, 297 KiB

Open AccessEditor’s ChoiceArticle

Associations between Plasma Lipid Mediators and Chronic Daily Headache Outcomes in Patients Randomized to a Low Linoleic Acid Diet with or without Added Omega-3 Fatty Acids

by Qing Shen, Jun Yang, Daisy Zamora, Mark Horowitz, Keturah R. Faurot, Beth A. MacIntosh, J. Douglas Mann, Bruce D. Hammock, Christopher E. Ramsden and Ameer Y. Taha

Metabolites 2023, 13(6), 690; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo13060690 - 25 May 2023

Viewed by 1280

Abstract

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA reduction alone (L6 diet). The trial also showed that targeted dietary manipulation alters PUFA-derived lipid mediators and endocannabinoids. However, several additional classes of lipid mediators associated with pain in preclinical models were not measured. The current secondary analysis investigated whether the clinical benefits of the H3-L6 diet were related to changes in plasma unesterified PUFA-derived lipid mediators known to be involved in nociception, including prostanoids. Lipid mediators were measured by ultra-high-pressure liquid chromatography coupled with tandem mass-spectrometry. Compared to baseline, dietary LA lowering with or without added omega-3 fatty acids did not alter unesterified n-6 PUFA-derived lipid mediators, although several species derived from LA, di-homo-gamma-linolenic acid, and arachidonic acid were positively associated with headache frequency and intensity, as well as mental health burden. Alpha-linolenic acid (ALA)-derived metabolites were also associated with increased headache frequency and intensity, although they did not change from the baseline in either dietary group. Compared to baseline, docosahexaenoic acid (DHA)-derived epoxides were more elevated in the H3-L6 group compared to the L6 group. Diet-induced elevations in plasma DHA-epoxides were associated with reduced headache frequency, better physical and mental health, and improved quality of life (p < 0.05). Prostanoids were not detected, except for PGF2-alpha, which was not associated with any outcomes. This study demonstrates that diet-induced changes in DHA-epoxides were associated with pain reduction in patients with chronic headaches, whereas n-6 PUFA and ALA metabolites were associated with nociception. Lipid mediator associations with mental health and quality of life paralleled pain management outcomes in this population. The findings point to a network of multiple diet-modifiable lipid mediator targets for pain management in individuals with CDHs. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

16 pages, 1475 KiB

Open AccessArticle

Determination of Lipoxygenase, CYP450, and Non-Enzymatic Metabolites of Arachidonic Acid in Essential Hypertension and Type 2 Diabetes

by Guillaume Feugray, Tony Pereira, Michèle Iacob, Lucile Moreau-Grangé, Gaëtan Prévost, Valéry Brunel, Robinson Joannidès, Jérémy Bellien and Thomas Duflot

Metabolites 2022, 12(9), 859; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12090859 - 13 Sep 2022

Cited by 4 | Viewed by 1932

Abstract

Type 2 diabetes (T2D) and hypertension (HTN) are common risk factors of cardiovascular diseases (CVD) characterized by chronic low-grade systemic inflammation and impaired endothelial function. This study aimed to assess whether levels of non-enzymatic, lipoxygenase (LOX)- and cytochrome P450 (CYP)-derived arachidonic acid (ARA) metabolites, which are known regulators of vascular homeostasis, are affected by HTN and T2D. For this objective, 17 plasma level derivatives of ARA were quantitated by chromatography coupled with mass spectrometry in 44 patients (12 healthy, 8 HTN, 7 T2D, and 17 HTN + T2D). Effects of hyperglycemic and hyperinsulinemic clamps on ARA metabolite levels were assessed in seven healthy subjects. No significant differences in the plasma levels of ARA metabolites were observed for T2D patients compared with healthy volunteers. HTN was associated with an alteration of ARA metabolite correlation patterns with increased 20-, 19-, 15-, and 8-hydroxyeicosatrienoic acid (HETE). A decrease of 20-HETE was also observed during both hyperglycemic and hyperinsulinemic clamps. Additional experiments are needed to assess whether the modulation of HETE metabolites in HTN may be of interest. Furthermore, although not affected by T2D, it remains to investigate whether the decrease of 20-HETE observed during clamps may be related to the regulation of glucose tolerance and insulin signaling. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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14 pages, 1434 KiB

Open AccessArticle

Potential Cardioprotective Effects and Lipid Mediator Differences in Long-Chain Omega-3 Polyunsaturated Fatty Acid Supplemented Mice Given Chemotherapy

by Austin Angelotti, Deena B. Snoke, Kate Ormiston, Rachel M. Cole, Kamil Borkowski, John W. Newman, Tonya S. Orchard and Martha A. Belury

Metabolites 2022, 12(9), 782; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12090782 - 24 Aug 2022

Cited by 1 | Viewed by 1696

Abstract

Many commonly used chemotherapies induce mitochondrial dysfunction in cardiac muscle, which leads to cardiotoxicity and heart failure later in life. Dietary long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have demonstrated cardioprotective function in non-chemotherapy models of heart failure, potentially through the formation of LC n-3 PUFA-derived bioactive lipid metabolites. However, it is unknown whether dietary supplementation with LC n-3 PUFA can protect against chemotherapy-induced cardiotoxicity. To test this, 36 female ovariectomized C57BL/6J mice were randomized in a two-by-two factorial design to either a low (0 g/kg EPA + DHA) or high (12.2 g/kg EPA + DHA) LC n-3 PUFA diet, and received either two vehicle or two chemotherapy (9 mg/kg anthracycline + 90 mg/kg cyclophosphamide) tail vein injections separated by two weeks. Body weight and food intake were measured as well as heart gene expression and fatty acid composition. Heart mitochondria were isolated using differential centrifugation. Mitochondrial isolate oxylipin and N-acylethanolamide levels were measured by mass spectrometry after alkaline hydrolysis. LC n-3 PUFA supplementation attenuated some chemotherapy-induced differences (Myh7, Col3a1) in heart gene expression, and significantly altered various lipid species in cardiac mitochondrial preparations including several epoxy fatty acids [17(18)-EpETE] and N-acylethanolamines (arachidonoylethanolamine, AEA), suggesting a possible functional link between heart lipids and cardiotoxicity. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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16 pages, 2915 KiB

Open AccessArticle

Linoleate-Rich Safflower Oil Diet Increases Linoleate-Derived Bioactive Lipid Mediators in Plasma, and Brown and White Adipose Depots of Healthy Mice

by Deena B. Snoke, Austin Angelotti, Kamil Borkowski, Rachel M. Cole, John W. Newman and Martha A. Belury

Metabolites 2022, 12(8), 743; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12080743 - 12 Aug 2022

Cited by 7 | Viewed by 1922

Abstract

Polyunsaturated fats are energy substrates and precursors to the biosynthesis of lipid mediators of cellular processes. Adipose tissue not only provides energy storage, but influences whole-body energy metabolism through endocrine functions. How diet influences adipose–lipid mediator balance may have broad impacts on energy metabolism. To determine how dietary lipid sources modulate brown and white adipose tissue and plasma lipid mediators, mice were fed low-fat (15% kcal fat) isocaloric diets, containing either palm oil (POLF) or linoleate-rich safflower oil (SOLF). Baseline and post body weight, adiposity, and 2-week and post fasting blood glucose were measured and lipid mediators were profiled in plasma, and inguinal white and interscapular brown adipose tissues. We identified over 30 species of altered lipid mediators between diets and found that these changes were unique to each tissue. We identified changes to lipid mediators with known functional roles in the regulation of adipose tissue expansion and function, and found that there was a relationship between the average fold difference in lipid mediators between brown adipose tissue and plasma in mice consuming the SOLF diet. Our findings emphasize that even with a low-fat diet, dietary fat quality has a profound effect on lipid mediator profiles in adipose tissues and plasma. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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12 pages, 1524 KiB

Open AccessArticle

The Plasma Oxylipidome Links Smoking Status to Peripheral Artery Disease

by Stephanie P. B. Caligiuri, Grant N. Pierce, Amir Ravandi and Harold M. Aukema

Metabolites 2022, 12(7), 627; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12070627 - 07 Jul 2022

Cited by 3 | Viewed by 1591

Abstract

Peripheral artery disease (PAD) is prevalent among individuals with a history of tobacco smoking. Although oxidation of lipids may contribute to atherogenesis in vascular disease, enzymatically and nonenzymatically produced oxidized lipids can have varying and contrasting physiological effects. The underlying mechanisms of atherogenic vulnerability can be better elucidated with the recent advances in oxylipidome quantification using HPLC-MS/MS technology. In a randomized, controlled clinical trial, the plasma oxylipidome was analyzed in participants living with PAD by smoking status (n = 98) and in nonsmoking comparators without chronic disease (n = 20). Individuals with PAD had approximately a four-fold higher level of total plasma oxylipins versus the comparator. Cessation of smoking in individuals with PAD was associated with significantly lower levels of linoleic acid-derived TriHOMEs, greater levels of omega-3 fatty acid-derived oxylipins, and greater levels of nonfragmented oxidized phosphatidylcholines (OxPCs). Individuals living with PAD but without a history of smoking, exhibited higher levels of the putative atherogenic fragmented OxPCs versus individuals who currently or previously smoked. These data implicate the plasma oxylipidome in PAD and that smoking cessation is associated with a less inflammatory profile. Furthermore, fragmented OxPCs may play a more significant role in the pathophysiology of PAD in individuals without a history of smoking. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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15 pages, 3592 KiB

Open AccessArticle

Serum Oxylipin Profiles Identify Potential Biomarkers in Patients with Acute Aortic Dissection

by Yi Jiang, Xinlong Tang, Yali Wang, Wei Chen, Yunxing Xue, Hailong Cao, Bomin Zhang, Jun Pan, Qing Zhou, Dongjin Wang and Fudong Fan

Metabolites 2022, 12(7), 587; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12070587 - 23 Jun 2022

Cited by 2 | Viewed by 1744

Abstract

Aortic dissection (AD) is a life-threatening cardiovascular disease with a dismal prognosis. Inflammation plays an important role in AD. Oxylipins are bioactive lipids involved in the modulation of inflammation and may be involved in the pathogenesis and progression of AD. This study aims to identify possible metabolites related to AD. A total of 10 type A Aortic dissection (TAAD) patients, 10 type B Aortic dissection (TBAD) patients and 10 healthy controls were included in this study. Over 100 oxylipin species were identified and quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis. Our investigation demonstrated substantial alterations in 91 oxylipins between AD and healthy individuals. Patients with TAAD had 89 entries accessible compared to healthy controls. According to orthogonal partial least squares discriminant analysis (OPLS-DA), fitness (R²X = 0.362 and R²Y = 0.807, p = 0.03) and predictability (Q² = 0.517, p = 0.005) are the validation parameters between the two groups. Using multivariate logistic regression, 13-HOTrE and 16(17)-EpDPE were the risk factors in the aortic patients group compared to healthy people (OR = 2.467, 95%CI:1.256–7.245, p = 0.035; OR = 0.015, 95%CI:0.0002–0.3240, p = 0.016, respectively). In KEGG enrichment of differential metabolites, the arachidonic acid metabolism pathway has the most metabolites involved. We established a diagnostic model in distinguishing between AD and healthy people. The AUC was 0.905. Oxylipins were significantly altered in AD patients, suggesting oxylipin profile is expected to exploit a novel, non-invasive, objective diagnosis for AD. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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17 pages, 2009 KiB

Open AccessArticle

Plasma Oxylipin Profile Discriminates Ethnicities in Subjects with Non-Alcoholic Steatohepatitis: An Exploratory Analysis

by Tagreed A. Mazi, Kamil Borkowski, Oliver Fiehn, Christopher L. Bowlus, Souvik Sarkar, Karen Matsukuma, Mohamed R. Ali, Dorothy A. Kieffer, Yu-Jui Y. Wan, Kimber L. Stanhope, Peter J. Havel, John W. Newman and Valentina Medici

Metabolites 2022, 12(2), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12020192 - 19 Feb 2022

Cited by 4 | Viewed by 2707

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common liver pathology that includes steatosis, or non-alcoholic fatty liver (NAFL), and non-alcoholic steatohepatitis (NASH). Without a clear pathophysiological mechanism, it affects Hispanics disproportionately compared to other ethnicities. Polyunsaturated fatty acids (PUFAs) and inflammatory lipid mediators including oxylipin (OXL) and endocannabinoid (eCB) are altered in NAFLD and thought to contribute to its pathogenesis. However, the existence of ethnicity-related differences is not clear. We employed targeted lipidomic profiling for plasma PUFAs, non-esterified OXLs and eCBs in White Hispanics (HIS, n = 10) and Caucasians (CAU, n = 8) with biopsy-confirmed NAFL, compared with healthy control subjects (HC; n = 14 HIS; n = 8 CAU). NAFLD was associated with diminished long chain PUFA in HIS, independent of histological severity. Differences in plasma OXLs and eCBs characterized ethnicities in NASH, with lower arachidonic acid derived OXLs observed in HIS. The secondary analysis comparing ethnicities within NASH (n = 12 HIS; n = 17 CAU), confirms these ethnicity-related differences and suggests lower lipoxygenase(s) and higher soluble epoxide hydrolase(s) activities in HIS compared to CAU. While causes are not clear, these lipidomic differences might be with implications for NAFLD severity and are worth further investigation. We provide preliminary data indicating ethnicity-specific lipidomic signature characterizes NASH which requires further validation. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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Review

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14 pages, 1365 KiB

Open AccessReview

Esterified Oxylipins: Do They Matter?

by Carmen E. Annevelink, Rachel E. Walker and Gregory C. Shearer

Metabolites 2022, 12(11), 1007; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12111007 - 22 Oct 2022

Cited by 4 | Viewed by 1425

Abstract

Oxylipins are oxygenated metabolites of fatty acids that share several similar biochemical characteristics and functions to fatty acids including transport and trafficking. Oxylipins are most commonly measured in the non-esterified form which can be found in plasma, free or bound to albumin. The non-esterified form, however, reflects only one of the possible pools of oxylipins and is by far the least abundant circulating form of oxylipins. Further, this fraction cannot reliably be extrapolated to the other, more abundant, esterified pool. In cells too, esterified oxylipins are the most abundant form, but are seldom measured and their potential roles in signaling are not well established. In this review, we examine the current literature on experimental oxylipin measurements to describe the lack in reporting the esterified oxylipin pool. We outline the metabolic and experimental importance of esterified oxylipins using well established roles of fatty acid trafficking in non-esterified fatty acids and in esterified form as components of circulating lipoproteins. Finally, we use mathematical modeling to simulate how exchange between cellular esterified and unesterified pools would affect intracellular signaling.. The explicit inclusion of esterified oxylipins along with the non-esterified pool has the potential to convey a more complete assessment of the metabolic consequences of oxylipin trafficking. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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23 pages, 1086 KiB

Open AccessReview

Oxylipins as Potential Regulators of Inflammatory Conditions of Human Lactation

by Rachel E. Walker

Metabolites 2022, 12(10), 994; https://0-doi-org.brum.beds.ac.uk/10.3390/metabo12100994 - 20 Oct 2022

Cited by 2 | Viewed by 1504

Abstract

Chronic low-grade inflammation can be associated with obesity or subclinical mastitis (SCM), which is associated with poor infant growth in low- to middle-income country settings. It is unknown what physiological mechanisms are involved in low milk supply, but our research group has shown that mothers with low milk supply have higher inflammatory markers. Studies investigating oxylipin signaling have the potential to help explain mechanisms that mediate the impacts of inflammation on milk production. Animal studies have reported various elevated oxylipins during postpartum inflammation, mastitis, and mammary involution in ruminant models. Several investigations have quantified oxylipins in human milk, but very few studies have reported circulating oxylipin concentrations during lactation. In addition, there are technical considerations that must be addressed when reporting oxylipin concentrations in human milk. First, the majority of milk oxylipins are esterified in the triglyceride pool, which is not routinely measured. Second, total milk fat should be considered as a covariate when using milk oxylipins to predict outcomes. Finally, storage and handling conditions of milk samples must be carefully controlled to ensure accurate milk oxylipin quantitation, which may be affected by highly active lipases in human milk. Full article

(This article belongs to the Special Issue Lipidomic Profiling of Oxylipins for a Mechanistic Understanding of Inflammatory-Related Diseases)

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