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Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance

Abstract: Inflammation is a condition which contributes to a range of human diseases. It involves a multitude of cell types, chemical mediators, and interactions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte–endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of marine 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 peroxisome proliferator activated receptor γ and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked, although the full extent of this is not yet elucidated.

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Alex’s Notes: Inflammation is a critical part of our immune system; it works to create a deadly environment for pathogens and aid in the post-war clean-up and recovery response. And these effects are wonderful when inflammation is acute, which it should be. Normally inflammation resolves itself and goes away when the area of injury is healed, but a loss of its self-regulation process can lead to an excessive and chronic inflammatory response that ultimately causes more (sometimes irreparable) damage to body tissues.

This inappropriate inflammatory response is characteristic of many chronic diseases in modern society, and a seemingly relentless effort is being made to discover novel anti-inflammatories outside of easily obtained medications. One of these dietary and supplemental alternative medicines is omega-3 fatty acids. A great deal of attention has been given recently to the dietary ratio of n-3 fatty acids to omega-6 (n-6) fatty acids. Specifically, the focus is on the marine n-3 fatty acids found primarily in fish and other seafood: eicosapentaenoic acid (EPA; 20:5n-3), docosapentaenoic acid (DPA; 22:5n-3) and docosahexaenoic acid (DHA; 22:6n-3). Although bags of flax and chia seeds accurately promote the abundance of n-3 fatty acid they contain, this plant form is does not hold the same effects as marine n-3s and humans are not able to efficiently convert it into the latter.

Marine n-3 fatty acids and inflammation

The influence of fatty acids on inflammation lies primarily on their incorporation into cell membranes. A standard Western diet leads to cell membranes composed of about 15-20% the n-6 fatty acid arachidonic acid (ARA; 20:4n-6) and only 2.5-4% EPA & DHA. Numerous studies have demonstrated, however, that marine n-3 supplementation (usually fish oil) reduces the n-6 to n-3 ratio in cell membranes.

The primary inflammatory molecules within the body are eicosanoids, oxidized derivatives of polyunsaturated fatty acids (PUFAs) contained within cell membrane phospholipids. These molecules include prostaglandins (PGs), leukotrienes (LTs), thromboxanes (TXs), and lipoxins (LXs), but don’t get caught up in the names, as I only mention them for completeness. However, do appreciate that the initial substrate for their synthesis depends on the relative concentration of PUFAs within the cell membrane. Thus, because ARA is the most prevalent precursor PUFA in the standard Western diet, it is usually the substrate for eicosanoid creation.

The problem is that the precursor PUFA determines the eicosanoid type. ARA is acted upon by several enzymes to create 2-series PGs and TXs and 4-series LTs and LXs, which are some of the most well-known mediators and regulators of inflammation. One of the enzymes is COX-2, which is stimulated by bacterial endotoxins to create large amounts of PGs. To help illustrate the importance of this enzyme in the inflammatory response, appreciate that non-steroidal anti-inflammatory drug (NSAIDs) such as aspirin work through inhibition of COX-2. This is also where marine n-3s come into play. Not only will they reduce the creation of inflammatory molecules simply through competition as the initial substrate, but once chosen they result in the creation of 3-series PGs and TXs and 5-series LTs, which are far less biologically active than their ARA-derived counterparts. Additionally, EPA has been found to actually suppress the expression of COX-2 and thus inhibit ARA metabolism.

Other bioactive inflammatory mediators synthesized from cell membrane PUFAs are endocannabinoids, resolvins, and protectins. Endocannabinoids have demonstrated anti-inflammatory actions regardless of precursor, although those made from n-3s may be more potent. The real game-changers when it comes to inflammation are resolvins and protectins, which have shown to be anti-inflammatory and inflammation resolving. For instance, animal models have demonstrated resolvins to protect against inflammatory diseases such as arthritis, colitis, and asthma. Their importance is further demonstrated by the fact that human breast milk was recently shown to contain them.

Aside from affecting the inflammatory molecules directly, marine n-3s interact with molecules that are crucial for setting up inflammation to begin with. Cytokines are small protein molecules released by a broad range of inflammatory and immune cells as a form of communication. Well-known examples include TNF, various interleukins (ILs), interferons, and chemokines. In fact, elevated levels of TNF, IL-6, and IL-8 are a common feature of many inflammatory diseases. In rodent models, the feeding of fish oil has been shown to reduce the production of these cytokines in response to insult, as well as increase the production of more anti-inflammatory cytokines such as IL-10. In persons with rheumatoid arthritis, fish oil supplements have shown similar outcomes.

When cells receive the inflammation signal from cytokines, they start heading towards the site of injury in the body. Around this area, cytokines also lead to the expression of adhesion molecules on many cell types such as the endothelial cells of blood vessels and leukocytes (white blood cells). These molecules bind to one another to allow interaction between cell types. An example is the interaction between leukocytes in the bloodstream interact with the blood vessel wall and then leave the bloodstream to move to the site of injury. Their importance is emphasized in mice that do not produce them and become protected from atherosclerosis. Rats supplemented with fish oil show lower adhesion molecule expression, and supplementing the diet of healthy humans with fish oil providing about 1.5 g EPA + DHA per day showed similar effects.

Taken together, it appears as though fish oils exert their anti-inflammatory effects by modulating several important points on the inflammation spectrum. Fish oils interfere with the communication methods used by inflammatory cells and then further inhibit the ability for more inflammatory cells to arrive at the site of injury. They compete with ARA for incorporation into inflammatory eicosanoids, inhibit ARA-derived eicosanoid synthesis, and produce strong anti-inflammatory compounds.

Quite impressive, demanding the question, why?

Nuclear factor kappa B (NFĸB) is one of the main transcription factors involved in up-regulation of the genes encoding proteins involved in inflammation including many cytokines, adhesion molecules and COX-2.NFĸB is activated through a signaling cascade triggered by various extracellular inflammatory stimuli, including endotoxin binding to toll-like receptor (TLR) 4. Thus, NFĸB appears like a perfect target for marine n-3s. Indeed, fish oil does interact with it. Another way marine n-3s may interact with NFĸB is through PPAR-γ, which acts in an anti-inflammatory manner.One of the actions of PPAR-γ is to physically interfere with the translocation of NFĸB to the nucleus of the cells. As I’m sure you guessed, marine n-3s activate PPAR-γ.

So what can you do with this information? Not much, except perhaps to allow for a better understanding of the mechanisms behind fish oils. So the next time someone tells you fish oils are anti-inflammatory, now you can say, I know.

 

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