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

Nat Commun. 2018 Sep 20;9(1):3834. doi: 10.1038/s41467-018-06158-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Arachidonate 5-Lipoxygenase / chemistry
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Bronchial Hyperreactivity / pathology
  • Cell Survival / drug effects
  • Cell-Free System
  • Humans
  • Inflammation / pathology*
  • Inhibitory Concentration 50
  • Leukocytes / metabolism
  • Lipoxygenase Inhibitors / pharmacology
  • Liver / drug effects
  • Liver / metabolism
  • Metabolome
  • Mice
  • Middle Aged
  • Peritonitis / pathology
  • Recombinant Proteins / metabolism
  • Vitamin E / chemistry
  • Vitamin E / metabolism*
  • Young Adult

Substances

  • Lipoxygenase Inhibitors
  • Recombinant Proteins
  • Vitamin E
  • Arachidonate 5-Lipoxygenase