Fatty Acids and Associated Inflammatory Mediators

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(Last Updated On: April 23, 2017)
Fatty acid derived inflammatory mediators involving NFκB signalling pathway.

Fatty acid-derived inflammatory mediators involving NFκB signaling pathway.Credit: Calder, PC. 2011

Before describing how fatty acids are associated with inflammatory processes, I want to describe what the inflammation is and what the fatty acids are.

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What is an inflammation?

Inflammation is an initial defense system that protects the host organism from infection. It initiates different processes such as pathogen killing and tissue repair to restore the homeostasis at the infected site. Typical examples of inflammation are redness, swelling, pain, loss of function and heating. In response to the inflammation, different chemical mediators are released such as cytokines, eicosanoids, chemokines and reactive oxygen species.

Inflammatory responses are self-regulative in nature that involve in the activation of negative feedback mechanisms. These negative feedback mechanisms are; secretion of anti-inflammatory cytokines, inhibition of pro-inflammatory signaling cascades, activation of regulatory cells, and blocking the receptors for the inflammatory mediators.

Fatty acids

Fatty acids are the common dietary constituents that have some of the most important biological roles. They have metabolic, structural and functional roles in the body. Fatty acids are one of the important source of energy as well as the main components of the cell membrane. They are also the precursors of the signaling molecules.

Fatty acids can be saturated and unsaturated and length of the fatty acid can vary from 2-30 carbon or even more. Some of the important saturated fatty acids are octanoic acid (caprylic acid), decanoic acid (capric acid), dodecanoic acid (lauric acid), and hexacosanoic acid (palmitic acid) while some of the important unsaturated fatty acids are linoleic acid, α-linolenic acid, γ-linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA).

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Based on the distance of the first double bond from the methyl terminus, polyunsaturated fatty acids (PUFAs) are classified as omega-x (ω-x) where x determines the number of carbon atoms from the methyl terminus to the first double bond. There are two main classes of PUFAs; omega 3 or n-3 polyunsaturated fatty acids (such as α-linolenic) and omega 6 or n-6 polyunsaturated fatty acids (such as γ-linolenic acid).

Linoleic acid and α-linolenic acid are essential fatty acids because we can’t synthesize them in our body and must be taken through the diet. Though we can’t synthesize them but we can utilize them to synthesize other types of unsaturated fatty acids and inflammatory mediators. Metabolism of α-linolenic acid (ω-3 PUFA) will always give rise to other types of omega 3 fatty acids while metabolism of linoleic acid (ω-6 PUFA) will always give different types of omega 6 fatty acids.

PUFAs are important constituents of the membrane lipids such as phospholipids. However, the proportion of the omega 3 and omega 6 PUFAs may vary according to the dietary intake of the PUFAs. The α-linolenic acid can be obtained from green plant tissues while ω-6 PUFAs are abundant in vegetable oils. Other ω-3 PUFAs, such as EPA, DPA, and DHA are most abundant in fish.

Fatty acid-derived inflammatory mediators

Eicosanoids derived from arachidonic acid

Eicosanoids are the key metabolites that mediate and regulate the inflammatory processes. They are synthesized from arachidonic acid, a ω-6 polyunsaturated fatty acid (20C). There are different types of eicosanoids such as Prostaglandins (PGs), Leukotrienes (LTs), Thromboxanes and some other oxidized derivatives. Arachidonic acid is present in a higher concentration in the phospholipids of the inflammatory cell membranes where it constitutes the major precursor for the eicosanoid mediators.

It is now well established that animals fed with ω-6 arachidonic acid produce more prostaglandins while animals fed with omega 3 fatty acids such as eicosapentaenoic acid or docosahexaenoic acid produce lesser prostaglandins. However, eicosapentaenoic acid-derived eicosanoids have a different structure from the arachidonic acid-derived eicosanoids.

In addition to the differences in structure, eicosapentaenoic acid-derived eicosanoids are less biologically active than arachidonic acid-derived eicosanoids. However, in some case, they have the same potency. One of such example is the inhibition of the Tumor Necrosis Factor-α (TNF-α) production.

Eicosanoids derived from EPA and DHA

EPA and DHA-derived eicosanoids such as resolvins and protectins are some of the eicosanoids that have been shown to possess anti-inflammatory effects. For example, revolvin E1, D1, and protectin D1 have been found to inhibit transendothelial migration of the neutrophils thereby preventing the neutrophilic infiltration at the inflammatory site. In addition to these, revolving D1 has been shown to inhibit interleukin (IL)-1β production while protectin D1 inhibits the production of TNF-α and IL-1β.

Inflammatory gene expression follows NFκB pathway

Nuclear Factor κB (NF κB) is a potential transcription factor that is involved in the upregulation of the inflammatory mediators such as cytokines, adhesion molecules, and COX-2 genes. Signaling cascade begins when the extracellular inflammatory stimuli phosphorylate the inhibitory subunit of the NFκB. Phosphorylated inhibitory subunit of the NFκB dissociates allowing the translocation of its remaining part to the nucleus.

Bacterial endotoxin, lipopolysaccharide (LPS), induces the inflammation by activating NFκB. An in vitro study reveals that omega 3 fatty acids (EPA and DHA) can also inhibit the LPS-induced production of the inflammatory proteins such as COX-2, nitric oxide synthase and some inflammatory mediators such as TNF-α and interleukins in various inflammatory cells. It is found that omega 3 fatty acids decrease the phosphorylation of the inhibitory subunit of the NFκB by activating MAP kinases.

In contrast to this, saturated fatty acids such as lauric acid can also induce the phosphorylation of the inhibitory subunit of the NFκB thereby leads to the NFκB-based inflammatory processes in the macrophages and dendritic cells. In a study carried out by Lee et al. (2001), it has been reported that EPA and DHA along with other unsaturated fatty acids can prevent the induced inflammatory effect of the lauric acid in the macrophages.

Several more studies were carried out during which animal feeding assays were performed. In these studies, researchers found that activation of NFκB in LPS-activated murine spleen lymphocytes was lowered when animal fed with fish oil as compared to the one fed with corn oil. Fish oil feeding also lowered the production of interleukins and Tumor Necrosis Factor-α (TNF-α).

Inflammatory gene expression and fatty acid cell surface receptors

Peroxisome Proliferation Activator Receptor gamma (PPAR-γ) is a transcription factor that also acts as an anti-inflammatory molecule. It regulates expression of the inflammatory genes as well as it also interferes with the activation of NFκB thereby creating a link between these two transcription factors. And it is believed that PUFAs and their derivatives act as a ligand for the PPAR-γ.

In 2010, another study carried out revealing that DHA induces the production of PPAR-γ in dendritic cells thereby reducing the LPS-stimulated production of the TNF-α and IL-6. In the same year, another study about the G-protein-coupled cell surface receptors (GRPs) for the PUFAs involving the mediation of the inflammation.

During the study, researchers found that EPA and DHA but not arachidonic acid (saturated fatty acid) can inhibit the GRPs (GRP120) mediated expression of the inflammatory genes induced by LPS.

All these studies and observations reveal that omega 3 fatty acids are anti-inflammatory mediators that exert their effect by decreasing the production of inflammatory eicosanoids and cytokines and enhance the production of other anti-inflammatory mediators.

Conclusion

In conclusion, fatty acids can influence the inflammatory processes. For example, they act through the cell surface and intracellular receptors leading to the cascade of the inflammatory cell signaling and expression of the inflammatory genes.

Normally, cells involved in the inflammatory processes are rich in omega 6 fatty acids such as arachidonic acid. However, the contents of the arachidonic acid and other omega 3 fatty acids such as EPA and DHA can be altered through the dietary supplement of the omega 3 fatty acids.

Though omega 6 fatty acids and omega 3 fatty acids (such as EPA and DHA) produces their own types of eicosanoids but they are structurally and functionally distinct. Arachidonic acid-derived eicosanoids have inflammatory roles while EPA and DHA-derived eicosanoids have anti-inflammatory roles.

EPA and DHA-derived eicosanoids such as Resolvins and Protectins act as anti-inflammatory mediators and, therefore, n-3 PUFAs have therapeutic efficacies in inflammatory processes such as rheumatoid arthritis, atherosclerosis, and plaque rupture.

Reference: European Journal of Pharmacology

Article doi: 10.1016/j.ejphar.2011.05.085

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