Quantitative profiling of oxylipins through comprehensive LC-MS/MS analysis: application in cardiac surgery

Strassburg, Katrin; Huijbrechts, Annemarie M. L.; Kortekaas, Kim E.; Lindeman, J.; Pedersen, Theresa L.; Dane, Adrie; Berger, Ruud; Brenkman, Arjan B.; Hankemeier, Thomas; Duynhoven, John van; Kalkhoven, Eric; Newman, John W.; Vreeken, Rob J.

doi:10.1007/s00216-012-6226-x

Cited by 218 publications

(194 citation statements)

References 61 publications

(65 reference statements)

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“…It was not clear which of these are oxidized during ferroptosis, and whether each lipid species has any functional role in the lethal phenotype of ferroptosis. Delineation of lipid oxidation events in the context of ferroptosis may provide insights into the mechanism of GPX4 regulation, as well as the execution mechanism for ferroptosis; many oxidized lipids (oxylipins) act as signaling molecules (22).…”

Section: Resultsmentioning

confidence: 99%

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

Yang

Kim

Gaschler

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

1,551

1,345

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Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown. We report here the mechanism of lipid peroxidation during ferroptosis, which involves phosphorylase kinase G2 (PHKG2) regulation of iron availability to lipoxygenase enzymes, which in turn drive ferroptosis through peroxidation of polyunsaturated fatty acids (PUFAs) at the bis-allylic position; indeed, pretreating cells with PUFAs containing the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) prevented PUFA oxidation and blocked ferroptosis. We further found that ferroptosis inducers inhibit GPX4 by covalently targeting the active site selenocysteine, leading to accumulation of PUFA hydroperoxides. In summary, we found that PUFA oxidation by lipoxygenases via a PHKG2-dependent iron pool is necessary for ferroptosis and that the covalent inhibition of the catalytic selenocysteine in Gpx4 prevents elimination of PUFA hydroperoxides; these findings suggest new strategies for controlling ferroptosis in diverse contexts.

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Section: Resultsmentioning

confidence: 99%

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

Yang

Kim

Gaschler

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

1,551

1,345

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“…Additionally, we used a novel quantitative mass spectrometry lipidomics approach (22) to profile 120 inflammatory eicosanoids (17)(18)(19)26). iDCs stimulated with IgG-opsonized E. coli demonstrated clear synergistic differences in the secretion of cyclooxygenase (COX)-dependent and lipoxygenase (LOX)-dependent metabolites compared with iDCs stimulated with E. coli (Table I).…”

Section: Resultsmentioning

confidence: 99%

Antibody-Opsonized Bacteria Evoke an Inflammatory Dendritic Cell Phenotype and Polyfunctional Th Cells by Cross-Talk between TLRs and FcRs

Bakema

Tuk

Vliet

et al. 2015

The Journal of Immunology

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During secondary immune responses, Ab-opsonized bacteria are efficiently taken up via FcRs by dendritic cells. We now demonstrate that this process induces cross-talk between FcRs and TLRs, which results in synergistic release of several inflammatory cytokines, as well as altered lipid metabolite profiles. This altered inflammatory profile redirects Th1 polarization toward Th17 cell responses. Interestingly, GM-CSF–producing Th cells were synergistically evoked as well, which suggests the onset of polyfunctional Th17 cells. Synergistic cytokine release was dependent on activation via MyD88 and ITAM signaling pathways through TLRs and FcRs, respectively. Cytokine regulation occurred via transcription-dependent mechanisms for TNF-α and IL-23 and posttranscriptional mechanisms for caspase-1–dependent release of IL-1β. Furthermore, cross-talk between TLRs and FcRs was not restricted to dendritic cells. In conclusion, our results support that bacteria alone initiate fundamentally different immune responses compared with Ab-opsonized bacteria through the combined action of two classes of receptors and, ultimately, may refine new therapies for inflammatory diseases.

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“…A decrease in serum fatty acid levels has been reported following salicylate administration in rats20, 21, 43 and in healthy and diabetic humans 22, 44, 45, 46, 47. There is evidence that salicylates inhibit lipolysis and enhance fatty acid re‐esterification in animal adipose tissue ex‐vivo23, 48 and downregulate the expression and activity of adipose 11β‐hydroxysteroid dehydrogenase type 1, a lipolytic enzyme 24, 49. However, all previous studies have used high dose of salicylates (minimum 1 g per day for 4 days25, 44).…”

Section: Discussionmentioning

confidence: 99%

Oxylipid Profile of Low‐Dose Aspirin Exposure: A Pharmacometabolomics Study

Ellero‐Simatos¹,

Beitelshees

Lewis

et al. 2015

JAHA

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BackgroundWhile aspirin is a well‐established and generally effective anti‐platelet agent, considerable inter‐individual variation in drug response exists, for which mechanisms are not completely understood. Metabolomics allows for extensive measurement of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response.Methods and ResultsWe used a mass‐spectrometry‐based metabolomics platform to investigate the changes in the serum oxylipid metabolome induced by an aspirin intervention (14 days, 81 mg/day) in healthy subjects (n=156). We observed a global decrease in serum oxylipids in response to aspirin (25 metabolites decreased out of 30 measured) regardless of sex. This decrease was concomitant with a significant decrease in serum linoleic acid levels (−19%, P=1.3×10−5), one of the main precursors for oxylipid synthesis. Interestingly, several linoleic acid‐derived oxylipids were not significantly associated with arachidonic‐induced ex vivo platelet aggregation, a widely accepted marker of aspirin response, but were significantly correlated with platelet reactivity in response to collagen.ConclusionsTogether, these results suggest that linoleic acid‐derived oxylipids may contribute to the non‐COX1 mediated variability in response to aspirin. Pharmacometabolomics allowed for more comprehensive interrogation of mechanisms of action of low dose aspirin and of variation in aspirin response.

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Quantitative profiling of oxylipins through comprehensive LC-MS/MS analysis: application in cardiac surgery

Cited by 218 publications

References 61 publications

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis

Antibody-Opsonized Bacteria Evoke an Inflammatory Dendritic Cell Phenotype and Polyfunctional Th Cells by Cross-Talk between TLRs and FcRs

Oxylipid Profile of Low‐Dose Aspirin Exposure: A Pharmacometabolomics Study

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