Identification of novel omega-3 fatty acid-derived bioactive metabolites based on a targeted lipidomics approach

Abstract

Omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid have beneficial effects in many inflammatory disorders. Although the mechanism of eicosapentaenoic acid and docosahexaenoic acid action is still not fully defined in molecular terms, recent studies have revealed that, during the course of acute inflammation, omega-3 polyunsaturated fatty acid-derived anti-inflammatory mediators including resolvins and protectins are produced. This review presents recent advances in understanding the formation and action of these mediators, especially focusing on the LC-MS/MS-based lipidomics approach and recently identified bioactive products with potent anti-inflammatory property.

Keywords: anti-inflammation; lipid mediator; metabolomics; omega-3 fatty acid.

Fig. 1

Possible mechanisms of omega-3 PUFAs’ anti-inflammatory actions. Omega-3 PUFAs are widely held to act via several possible mechanisms, such as preventing conversion of arachidonic acid (AA) into proinflammatory eicosanoids such as LTs and PGs via substrate competition, or serving as an alternative substrate to produce less potent products. In addition, EPA and DHA are converted to bioactive metabolites such as resolvins and protectins with anti-inflammatory and pro-resolving properties.

Fig. 2

Structures of omega-3 PUFA-derived mediators.

Fig. 3

LC-MS/MS-based lipidomics. (A) Flow chart depicting the system of LC-ESI-MS/MS-based lipidomics. After solid phase extraction, samples are separated by HPLC, and fatty acid metabolites are detected and quantified by MRM using triple quadrupole MS/MS. (B) Representative MRM chromatograms of fatty acid metabolites are depicted.

Fig. 4

Biosynthesis of E-series resolvins. EPA-derived 18-HEPE is converted via the sequential actions of LOX, which leads to formation of E-series Rvs. 5-LOX expressed in PMNs converts 18-HEPE into RvE1 and RvE2. 18-HEPE is also converted via the 12/15-LOX pathway into potent anti-inflammatory mediator RvE3 (17,18-diHEPE).

Fig. 5

EPA metabolome in the body. EPA is converted by COX or LOX, which leads to the formation of 3-series PGs or 5-series LTs. In addition, recent studies uncovered novel EPA metabolic pathway via omega-3 hydroxylation and epoxygenation, and found potent anti-inflammatory metabolites such as E-series Rvs and 12-OH-17,18-EpETE. These metabolic pathways may represent an endogenous mechanism acting as an anti-inflammatory cascade after dietary intake of EPA.