Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?

Abstract

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n-3 fatty acids found in oily fish and fish oil supplements. These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving resolvins and protectins. Mechanisms underlying the anti-inflammatory actions of n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor NR1C3 (i.e. peroxisome proliferator activated receptor γ) and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked. In adult humans, an EPA plus DHA intake greater than 2 g day⁻¹ seems to be required to elicit anti-inflammatory actions, but few dose finding studies have been performed. Animal models demonstrate benefit from n-3 fatty acids in rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta-analyses of the data. Clinical trails of fish oil in patients with IBD and asthma are inconsistent with no overall clear evidence of efficacy.

Figure 1

The conversion of plant essential n‐6 and n‐3 polyunsaturated fatty acids to their longer chain, more unsaturated derivatives. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid

Figure 2

The pathways of eicosanoid synthesis from arachidonic acid. AEA, arachidonoyl ethanolamine (anandamide); 2‐AG, 2‐arachidonoyl glycerol; ARA, arachidonic acid; COX, cyclo‐oxygenase; CYT p450, cytochrome P450 enzymes; DAG, diacylglycerol; DHET, dihydroxyeicosatrienoic acid; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid; LOX, lipoxygenase; LT, leukotriene; PE, phosphatidyl ethanolamine; PG, prostaglandin; TX, thromboxane. Note that not all enzymes are named and that not all metabolites are shown

Figure 3

Overview of the pathways of lipid mediator synthesis from eicosapentaenoic and docosahexaenoic acids. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HEPE, hydroxyeicosapentaenoic acid; HPEPE, hydroperoxyeicosapentaenoic acid; LT, leukotriene; PG, prostaglandin. Note that the enzymes involved are not named and that not all metabolites are shown

Figure 4

Summary of the anti‐inflammatory actions of marine n‐3 polyunsaturated fatty acids. ARA, arachidonic acid; COX, cyclo‐oxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GPR, G‐protein coupled receptor; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa B, PPAR, peroxisome proliferator activated receptor. Dotted lines indicate inhibition