Bioactive products formed in humans from fish oils

Abstract

The clinical cardiovascular utility of a diet rich in fi sh oils, particularly EPA and DHA, has been debated over the past 50 years ( 1-3 ). Large clinical outcome trials, such as the open-labeled GISSI-Prevenzione ( 4 ) or JELIS ( 5 ) studies, supported the notion that fi sh oil supplements confer therapeutic benefi t on patients with cardiovascular disease. However, an overview analysis of results of more than 50 randomized controlled trials and cohort studies addressing this question yielded equivocal results ( 6, 7 ). Consequently, the adoption of the dietary interventions with fi sh oil into clinical guidelines has been limited ( 8 ). Fish oil supplementation does infl uence a series of cardiovascular biomarkers: it decreases blood levels of triglycerides in patients with hypertriglyceridemia, an effect primarily driven by lowering the production of triglycerides from nonesterifi ed fatty acids ( 9 ); high doses reduce blood pressure in patients with essential hypertension ( 10, 11 ) and modestly inhibit indices of platelet activation ( 12 ). The mechanisms involved are unclear, but may involve a shift in formation of enzymatic and free radical-catalyzed prostanoids, refl ecting utilization of EPA and DHA rather than arachidonic acid (AA) as a substrate. It has been speculated also that cardiovascular benefi t might derive, in part, from anti-infl ammatory actions of fi sh oils: families of bioactive lipids which favor resolution of infl ammation have been suggested to be of particular importance ( 13 ). Synthetic versions of such specialized pro-resolving mediators (SPMs), products of transcellular metabolism of fi sh oils, exert anti-infl ammatory effects in vitro and when administered in vivo in several animal models ( 14-17 ). Quantities Abstract Resolvins, maresins, and protectins can be formed from fi sh oils. These specialized pro-resolving mediators (SPMs) have been implicated in the resolution of infl ammation. Synthetic versions of such SPMs exert anti-infl ammatory effects in vitro and when administered to animal models. However, their importance as endogenous products formed in suffi cient amounts to exert anti-infl ammatory actions in vivo remains speculative. We biased our ability to detect SPMs formed in healthy volunteers by supplementing fi sh oil in doses shown previously to infl uence blood pressure and platelet aggregation under placebo-controlled conditions. Additionally, we sought to determine the relative formation of SPMs during an acute infl ammatory response and its resolution, evoked in healthy volunteers by bacterial lipopolysaccharide (LPS). Bioactive lipids, enzymatic epoxyeicosatrienoic acids (EETs), and free radical-catalyzed prostanoids [isoprostanes (iPs)] formed from arachidonic acid and the fi sh oils, served as comparators. Despite the clear shift from -6 to -3 EETs and iPs, we failed to detect a consistent signal, in most cases, of SPM formation in urine or plasma in response to fi sh oil, and in all cases in response to LPS on a background of fi sh oil. Our results que...

A broad-spectrum lipidomics screen of antiinflammatory drug combinations in human blood

“…Despite the capacity-related feature of this assay, with provocation by inflammatory stimuli, only modest amounts of LXA 4 and RvE1 were evident, while most specialized proresolving mediators were not detected. We and others have also largely failed to detect endogenous production of these mediators in plasma or urine (37, 38) and failed to relate alterations in specialized proresolving mediator formation in vivo in response to the evocation of inflammation with LPS or its resolution or the dose-dependent provision of their theoretical substrate (38). …”

n-3 Fatty acid supplementation and proresolving mediators of inflammation

“…In the same report, SPMs were measured before and after an intravenous bolus of endotoxin that was administered to six volunteers who had taken 5 g/day n-3 fatty acids for 8 weeks. The authors reported that PD1 and PDX were present in plasma in low picograms quantities, but were unaffected by fish oil or endotoxin [26]. The study failed to detect any SPMs in urine after high-dose fish oil supplementation [26].…”

“…The authors reported that PD1 and PDX were present in plasma in low picograms quantities, but were unaffected by fish oil or endotoxin [26]. The study failed to detect any SPMs in urine after high-dose fish oil supplementation [26].…”

“…In a recent study examining bioactive products formed after fish oil supplementation, 12 volunteers were given a high dose of fish oil (17.6 g/day n-3 fatty acids as 9.7 g/day EPA and 7.9 g/day DHA) for an average of 24 days in an open trial [26]. Plasma RvE1, RvD1, PD1, PDX, and maresin were determined using a lipidomic approach before and after fish oil.…”

Short-term consumption of n-3 PUFAs increases murine IL-5 levels, but IL-5 is not the mechanistic link between n-3 fatty acids and changes in B-cell populations

“…One likely possibility is that dietary n-3 PUFAs, which serve as substrates for specific enzymes, are enhancing the production of pro-resolving lipid mediators [33]. Indeed, there is evidence in the literature to show that dietary n-3 PUFA supplementation can increase levels of pro-resolving lipid mediators, although there are some labs that question this possibility [34-36]. Furthermore, Phipps and co-workers have demonstrated that 17-HDHA, a hydroxylated DHA molecule, enhances the production of antibody secreting cells in vitro and in vivo [37, 38].…”