n-3 Fatty acids, inflammation and immunity: new mechanisms to explain old actions
01 Aug 2013-Vol. 72, Iss: 3, pp 326-336
TL;DR: A number of new mechanisms of action are identified that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity.
Abstract: Numerous effects of n-3 fatty acids EPA and DHA on functional responses of cells involved in inflammation and immunity have been described. Fatty acid-induced modifications in membrane order and in the availability of substrates for eicosanoid synthesis are long-standing mechanisms that are considered important in explaining the effects observed. More recently, effects on signal transduction pathways and on gene expression profiles have been identified. Over the last 10 years or so, significant advances in understanding the mechanisms of action of n-3 fatty acids have been made. These include the identification of new actions of lipid mediators that were already described and of novel interactions among those mediators and the description of an entirely new family of lipid mediators, resolvins and protectins that have anti-inflammatory actions and are critical to the resolution of inflammation. It is also recognised that EPA and DHA can inhibit activation of the prototypical inflammatory transcription factor NF-κB. Recent studies suggest three alternative mechanisms by which n-3 fatty acids might have this effect. Within T-cells, as well as other cells of relevance to immune and inflammatory responses, EPA and DHA act to disrupt very early events involving formation of the structures termed lipid rafts which bring together various proteins to form an effective signalling platform. In summary, recent research has identified a number of new mechanisms of action that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity.
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TL;DR: Mechanisms underlying the anti-inflammatory actions of marine n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, and inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes.
1,173 citations
TL;DR: Current knowledge of how macronutrient metabolism by the gut microbiome influences human health is summarized and knowledge gaps that could contribute to the understanding of overall human wellness will be identified.
Abstract: The human gut microbiome is a critical component of digestion, breaking down complex carbohydrates, proteins, and to a lesser extent fats that reach the lower gastrointestinal tract. This process results in a multitude of microbial metabolites that can act both locally and systemically (after being absorbed into the bloodstream). The impact of these biochemicals on human health is complex, as both potentially beneficial and potentially toxic metabolites can be yielded from such microbial pathways, and in some cases, these effects are dependent upon the metabolite concentration or organ locality. The aim of this review is to summarize our current knowledge of how macronutrient metabolism by the gut microbiome influences human health. Metabolites to be discussed include short-chain fatty acids and alcohols (mainly yielded from monosaccharides); ammonia, branched-chain fatty acids, amines, sulfur compounds, phenols, and indoles (derived from amino acids); glycerol and choline derivatives (obtained from the breakdown of lipids); and tertiary cycling of carbon dioxide and hydrogen. Key microbial taxa and related disease states will be referred to in each case, and knowledge gaps that could contribute to our understanding of overall human wellness will be identified.
594 citations
TL;DR: D dietary n − 3 in fish feeds can be defined by three levels; the minimum level required to satisfy EFA requirements and thus prevent nutritional pathologies, that required to sustain maximum growth and optimum health in fish being fed modern high-energy diets, and the balance between different PUFA and LC-PUFA, which far exceeds the biological requirements of the fish itself.
524 citations
Cites background from "n-3 Fatty acids, inflammation and i..."
...Therefore, n-3 LC-PUFA have a combination of effects acting to reduce the respiratory burst and increase resolution (Calder, 2013)....
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...…acids (Tur et al., 2012), that have well-known and generally accepted beneficial effects in a range of human pathologies including cardiovascular and inflammatory diseases, and an important role in neural development (Gil et al., 2012; Delgado-Lista et al, 2012; Campoy et al., 2012; Calder, 2013)....
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...However, there is considerable research showing a wide range of mechanisms potentially underpinning the effects of n-3 LC-PUFA on inflammatory responses and immune pathways (Chapkin et al., 2009; Calder, 2013)....
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TL;DR: If conversion of ALA to EPA and DHA is limited, then ALA may have a smaller health benefit than EPA andDHA, and SDA appears to offer better potential for health improvement than ALA.
278 citations
17 Oct 2017
TL;DR: Roles for n-3 docosapentaenoic acid and DHA are now also emerging, and these roles are linked to certain health or clinical benefits, particularly related to CVD, cancer, inflammation and neurocognitive function.
Abstract: EPA and DHA appear to be the most important n-3 fatty acids, but roles for n-3 docosapentaenoic acid are now also emerging. Intakes of EPA and DHA are usually low, typically below those recommended. Increased intakes result in higher concentrations of EPA and DHA in blood lipids, cells and tissues. Increased content of EPA and DHA modifies the structure of cell membranes and the function of membrane proteins. EPA and DHA modulate the production of lipid mediators and through effects on cell signalling can alter the patterns of gene expression. Through these mechanisms, EPA and DHA alter cell and tissue responsiveness in a way that often results in more optimal conditions for growth, development and maintenance of health. DHA has vital roles in brain and eye development and function. EPA and DHA have a wide range of physiological roles, which are linked to certain health or clinical benefits, particularly related to CVD, cancer, inflammation and neurocognitive function. The benefits of EPA and DHA are evident throughout the life course. Future research will include better identification of the determinants of variation of responses to increased intake of EPA and DHA; more in-depth dose-response studies of the effects of EPA and DHA; clearer identification of the specific roles of EPA, docosapentaenoic acid and DHA; testing strategies to enhance delivery of n-3 fatty acids to the bloodstream; and exploration of sustainable alternatives to fish-derived very long-chain n-3 fatty acids.
242 citations
Cites background from "n-3 Fatty acids, inflammation and i..."
...It seems likely that many of the anti-inflammatory and immune modulating actions of EPA and DHA that are described in the literature((52,53,72,81)) are mediated through resolvins, protectins and maresins....
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...In addition to their effects on lipid mediators (prostaglandins, leukotrienes, resolvins, protectins, maresins), EPA and DHA modulate many other aspects of inflammatory processes including leucocyte migration and production of inflammatory cytokines((52,53,72,81))....
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References
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TL;DR: It is now becoming clear that lipid micro-environments on the cell surface — known as lipid rafts — also take part in this process of signalling transduction, where protein–protein interactions result in the activation of signalling cascades.
Abstract: Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.
6,080 citations
"n-3 Fatty acids, inflammation and i..." refers background in this paper
...Lipid rafts are regions of membranes with a distinct, characteristic structural composition((116,117))....
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TL;DR: New cellular and molecular mechanisms for the resolution of inflammation are presented, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins, which have anti-inflammatory and pro-resolution properties.
Abstract: Active resolution of acute inflammation is a previously unrecognized interface between innate and adaptive immunity. Once thought to be a passive process, the resolution of inflammation is now shown to involve active biochemical programmes that enable inflamed tissues to return to homeostasis. This Review presents new cellular and molecular mechanisms for the resolution of inflammation, revealing key roles for eicosanoids, such as lipoxins, and recently discovered families of endogenous chemical mediators, termed resolvins and protectins. These mediators have anti-inflammatory and pro-resolution properties, thereby protecting organs from collateral damage, stimulating the clearance of inflammatory debris and promoting mucosal antimicrobial defence.
2,619 citations
TL;DR: At sufficiently high intakes, long-chain n-3 polyunsaturated fatty acids (PUFAs), as found in oily fish and fish oils, decrease the production of inflammatory eicosanoids, cytokines, and reactive oxygen species and the expression of adhesion molecules, and are potentially potent antiinflammatory agents.
2,293 citations
"n-3 Fatty acids, inflammation and i..." refers background in this paper
...These effects have been interpreted in the context of reducing inflammation that would lead to benefit in inflammatory conditions, as discussed elsewhere((46))....
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TL;DR: This work has shown that crosstalk constitutes a decision-making process that determines the consequences of NF-κB and IKK activation and, ultimately, cell fate.
Abstract: Nuclear factor (NF)-kappaB and inhibitor of NF-kappaB kinase (IKK) proteins regulate many physiological processes, including the innate- and adaptive-immune responses, cell death and inflammation. Disruption of NF-kappaB or IKK function contributes to many human diseases, including cancer. However, the NF-kappaB and IKK pathways do not exist in isolation and there are many mechanisms that integrate their activity with other cell-signalling networks. This crosstalk constitutes a decision-making process that determines the consequences of NF-kappaB and IKK activation and, ultimately, cell fate.
2,169 citations
TL;DR: GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
1,989 citations