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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 ?-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 (?-T-13'-COOH) can be synthesized from ?-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. ?-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 ?-tocopherol depend on its endogenous metabolite ?-T-13'-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.

SUBMITTER: Pein H

PROVIDER: S-EPMC6148290 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Pein Helmut H Ville Alexia A Pace Simona S Temml Veronika V Garscha Ulrike U Raasch Martin M Alsabil Khaled K Viault Guillaume G Dinh Chau-Phi CP Guilet David D Troisi Fabiana F Neukirch Konstantin K König Stefanie S Bilancia Rosella R Waltenberger Birgit B Stuppner Hermann H Wallert Maria M Lorkowski Stefan S Weinigel Christina C Rummler Silke S Birringer Marc M Roviezzo Fiorentina F Sautebin Lidia L Helesbeux Jean-Jacques JJ Séraphin Denis D Mosig Alexander S AS Schuster Daniela D Rossi Antonietta A Richomme Pascal P Werz Oliver O Koeberle Andreas A

Nature communications 20180920 1

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 hu ...[more]

PMID: 30237488

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

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

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