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Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

Abstract : Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.
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Soumis le : vendredi 27 mars 2020 - 12:21:08
Dernière modification le : mercredi 3 novembre 2021 - 06:06:29

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Helmut Pein, Alexia Ville, Simona Pace, Veronika Temml, Ulrike Garscha, et al.. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.3834. ⟨10.1038/s41467-018-06158-5⟩. ⟨hal-02521285⟩



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