The role of n-3 PUFA-derived fatty acid derivatives and their oxygenated metabolites in the modulation of inflammation

Abstract

Notwithstanding the ongoing debate on their full potential in health and disease, there is general consensus that n-3 PUFAs play important physiological roles. Increasing dietary n-3 PUFA intake results in increased DHA and EPA content in cell membranes as well as an increase in n-3 derived oxylipin and-endocannabinoid concentrations, like fatty acid amides and glycerol-esters. These shifts are believed to (partly) explain the pharmacological and anti-inflammatory effects of n-3 PUFAs. Recent studies discovered that n-3 PUFA-derived endocannabinoids can be further metabolized by the oxidative enzymes CYP-450, LOX and COX, similar to the n-6 derived endocannabinoids. Interestingly, these oxidized n-3 PUFA derived endocannabinoids of eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) have higher anti-inflammatory and anti-proliferative potential than their precursors. In this review, an overview of recently discovered n-3 PUFA derived endocannabinoids and their metabolites is provided. In addition, the use of chemical probes will be presented as a promising technique to study the n-3 PUFA and n-3 PUFA metabolism within the field of lipid biochemistry. Highlights  Fatty acid conjugation with amines results in the formation of signalling molecules  Several of these have immune-modulating, anti-inflammatory properties  n-3 PUFA intake changes circulating PUFA, oxylipin and endocannabinoid profiles  Oxidized metabolites of DHEA and EPEA are also potentially anti-inflammatory  Chemical probes can be used to study n-3 PUFA metabolism within lipid biochemistry

N‐docosahexaenoyl ethanolamine (synaptamide) has antinociceptive effects in male mice

“…However, the levels of free DHA released are likely to be physiologically irrelevant. Furthermore, DHEA could be metabolized by either cytochrome P450 (CYP450) or 15-lipooxygenase (15-LOX) into hydroxylated or epoxidized metabolites, with some of these compounds showing biological activity in vitro (de Bus, Witkamp, Zuilhof, Albada, & Balvers, 2019;McDougle et al, 2017;Rouzer & Marnett, 2011;Yang et al, 2011).…”

Biological Role of Unsaturated Fatty Acid Desaturases in Health and Disease

“…ARA is a precursor of pro-inflammatory eicosanoids, whereas EPA and DGLA are substrates for the synthesis of anti-inflammatory eicosanoids. DHA is also a precursor of anti-inflammatory and immunomodulatory docosanoids, such as resolvins and protectins [7,8]. Considering their biological functions mentioned above, both omega-3 and omega-6 FAs are considered key factors in the prevention of some undesirable bodily reactions, such as autoimmune response.…”

n–3 Polyunsaturated Fatty Acid Amides: New Avenues in the Prevention and Treatment of Breast Cancer

“…Specifically, three enzyme families are mainly responsible for the oxygenation of n−3 PUFAs, namely, cyclooxygenases (COX), lipoxygenases, and cytochromes P450 [46][47][48]. Studies have extensively investigated the generation of oxidized metabolites that have been produced through these enzymes [49,50]. Endogenous generation of electrophilic oxo-derivatives of n−3 PUFAs has been observed in in vitro and ex vivo human models and dietary supplementation of n−3 PUFAs has been also reported to increase their formation [50].…”

“…Studies have extensively investigated the generation of oxidized metabolites that have been produced through these enzymes [49,50]. Endogenous generation of electrophilic oxo-derivatives of n−3 PUFAs has been observed in in vitro and ex vivo human models and dietary supplementation of n−3 PUFAs has been also reported to increase their formation [50]. Interestingly, such n−3 PUFA derivatives act as mediators of the beneficial actions observed upon dietary administration of n−3 PUFAs and, therefore, there has been a growing interest also in characterizing their formation and signaling actions in health and diseases.…”