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

Helmut Pein, Alexia Ville, Simona Pace, Veronika Temml, Ulrike Garscha, Martin Raasch, Khaled Alsabil, Guillaume Viault, Chau-Phi Dinh, David Guilet, Fabiana Troisi, Konstantin Neukirch, Stefanie König, Rosella Bilancia, Birgit Waltenberger, Hermann Stuppner, Maria Wallert, Stefan Lorkowski, Christina Weinigel, Silke Rummler, Marc Birringer, Fiorentina Roviezzo, Lidia Sautebin, Jean-Jacques Helesbeux, Denis Séraphin, Alexander S. Mosig, Daniela Schuster, Antonietta Rossi, Pascal Richomme, Oliver Werz () and Andreas Koeberle ()
Additional contact information
Helmut Pein: Friedrich-Schiller-University Jena
Alexia Ville: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
Simona Pace: Friedrich-Schiller-University Jena
Veronika Temml: University of Innsbruck
Ulrike Garscha: Friedrich-Schiller-University Jena
Martin Raasch: University Hospital Jena
Khaled Alsabil: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
Guillaume Viault: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
Chau-Phi Dinh: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
David Guilet: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
Fabiana Troisi: Friedrich-Schiller-University Jena
Konstantin Neukirch: Friedrich-Schiller-University Jena
Stefanie König: Friedrich-Schiller-University Jena
Rosella Bilancia: University of Naples Federico II
Birgit Waltenberger: University of Innsbruck
Hermann Stuppner: University of Innsbruck
Maria Wallert: Friedrich-Schiller-University Jena
Stefan Lorkowski: Friedrich-Schiller-University Jena
Christina Weinigel: University Hospital Jena
Silke Rummler: University Hospital Jena
Marc Birringer: Fulda University of Applied Sciences
Fiorentina Roviezzo: University of Naples Federico II
Lidia Sautebin: University of Naples Federico II
Jean-Jacques Helesbeux: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
Denis Séraphin: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
Alexander S. Mosig: University Hospital Jena
Daniela Schuster: University of Innsbruck
Antonietta Rossi: University of Naples Federico II
Pascal Richomme: Substances d’Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire
Oliver Werz: Friedrich-Schiller-University Jena
Andreas Koeberle: Friedrich-Schiller-University Jena

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06158-5

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