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.

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence

“…These metabolites are excreted in urine and faeces [22]. Recent literature suggested the health benefits of vitamin E depend on its endogenous long chain metabolites [28]. The apparent elimination half-life of αT3, γT3, and δT3 was found to be short, approximately 4.4, 4.3, and 2.3 h respectively.…”

Vitamin E: Regulatory role in the cardiovascular system

“…In addition to the regulation of oxLDL uptake and lipotoxicity, alpha long‐chain metabolites may be involved in modulating the inflammatory response via reducing LPS‐mediated secretion of pro‐inflammatory cytokines and nitric oxide production . The emerging function of alpha long‐chain metabolites, especially α‐13′‐carboxychromanol, was also observed in the suppression of acute inflammation as well as bronchial hyper‐reactivity via accumulating at the sites of inflammation followed by the inhibition of 5‐lipoxygenase and the production of 5‐lipoxygenase‐derived lipid mediators .…”

“…In addition to the regulation of oxLDL uptake and lipotoxicity, alpha long-chain metabolites may be involved in modulating the inflammatory response via reducing LPSmediated secretion of pro-inflammatory cytokines and nitric oxide production (97,98). The emerging function of alpha longchain metabolites, especially α-13 0 -carboxychromanol, was also observed in the suppression of acute inflammation as well as bronchial hyper-reactivity via accumulating at the sites of inflammation followed by the inhibition of 5-lipoxygenase and the production of 5-lipoxygenase-derived lipid mediators (99). Beside side chain oxidation, the phosphorylated form of α-tocopherol, known as α-TP, might be more active and unique than α-tocopherol in regulating cellular events, including proliferation, survival/apoptosis, enzyme translocation, and lipid transport, due to its similarity to phosphorylated messenger lipids and ability to modulate protein-membrane interactions (100,101).…”

Vitamin E – The Next 100 Years

“…Vitamin E catabolism produces a short‐chain metabolite 2,5,7,8‐tetramethyl‐2(2α‐carboxyethyl)‐6‐hydroxychroman (α‐CEHC) and long‐chain metabolites with regulatory functions on cellular lipids as cyclooxygenase inhibitors or 5‐lipoxygenase inhibitors . Analysis protocols have been developed to measure vitamin E metabolites that have been utilized in the study of vitamin E metabolism in healthy subjects and in pathologic conditions .…”