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5-lipoxygenase-dependent biosynthesis of novel 20:4 n-3 metabolites with anti-inflammatory activity

Gagnon KJ, Lefort N, Poirier SJ, Barnett DA, Surette ME (2018) PLEFA 2018 Oct; 138:  38-44 doi.org/10.1016/j.plefa.2018.10.005 

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Abstract:

Highlights

  • 5-lipoxygenase (5-LO) catalyzes the conversion of 20:4 n-3 into novel oxygenated metabolites.
  • Metabolites identified as Δ17-8‑hydroxy‑eicosatetraenoic acid (Δ17-8-HETE) and Δ17-8,15-dihydroxy-eicosatetraenoic acid (Δ17-8,15-diHETE).
  • Δ17-8,15-diHETE biosynthesis is inhibited by LTA4 hydrolase inhibitor SC 57461A.
  • Δ17-8,15-diHETE inhibits arachidonic acid-induced autocrine neutrophil stimulation and LTB4-induced neutrophil chemotaxis.

5-lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid (AA) into pro-inflammatory leukotrienes. N-3 PUFA like eicosapentaenoic acid are subject to a similar metabolism and are precursors of pro-resolving mediators. Stearidonic acid (18:4 n-3, SDA) is a plant source of n-3 PUFA that is elongated to 20:4 n-3, an analogue of AA. However, no 5-LO metabolites of 20:4 n-3 have been reported.

In this study, control and 5-LO-expressing HEK293 cells were stimulated in the presence of 20:4 n-3. Metabolites were characterized by LC-MS/MS and their anti-inflammatory properties assessed using AA-induced autocrine neutrophil stimulation and leukotriene B4-mediated chemotaxis. 8‑hydroxy‑9,11,14,17-eicosatetraenoic acid (Δ17-8-HETE) and 8,15-dihydroxy-9,11,13,17-eicosatetraenoic acid (Δ17-8,15-diHETE) were identified as novel metabolites. Δ17-8,15-diHETE production was inhibited by the leukotriene A4 hydrolase inhibitor SC 57461A. Autocrine neutrophil leukotriene stimulation and neutrophil chemotaxis, both BLT1-dependent processes, were inhibited by Δ17-8,15-diHETE at low nM concentrations.

These data support an anti-inflammatory role for Δ
17-8,15-diHETE, a novel 5-LO product.

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