Omega-3 Discoveries: New Lipids, New Benefits

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Research on omega-3 polyunsaturated fatty acids (omega-3 LCPUFA) has grown tremendously over the past 10 years, and our knowledge about these LCPUFA-especially, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-has given way to new understandings of how they can benefit human health. 

In this article (the second in a two-part series), I will discuss how our understanding of omega-3 LCPUFA’s role in human health has evolved over time.

New Lipids Containing Omega-3s

Several new lipids containing omega-3 LCPUFA have received attention in the past decade.

Lysophospholipids containing DHA have taken a prominent place in our understanding of how DHA is transported between organs, ever since scientists discovered that the transporter Major Facilitator Superfamily Domain Containing 2A  (Mfsd2a) is a selective (sodium-dependent) transporter for DHA into the brain. This discovery was followed by the finding that Mfsd2a also transports DHA as lysophospholipid in the placenta and in the retina, suggesting that carrier-mediated uptake is an important component in the incorporation of DHA in some tissues with high demands for omega-3 LCPUFA. 

This discovery may have implications for the alleged higher efficacy for absorption and transport of omega-3 LCPUFA in the phospholipid form. (A number of studies so far have compared the bioavailability of different chemical forms of EPA and DHA upon oral intake, and if careful comparisons are made in the fed state over some reasonable period of time, little to no remarkable difference between digestion and absorption can be noted between triglycerides, ethyl esters, or phospholipids.)

Also, notable anti-inflammatory effects of EPA-monoglyceride and DHA-monoglyceride have been reported in the airways, colon, and joints.

Enzymatically Generated Oxygenated Derivatives

In addition to the growing appreciation for distinct biological activities and roles of various chemical forms of lipids containing omega-3, the last 10 years have seen more understanding about the enzymatically generated oxygenated derivatives of EPA and DHA, as well as docosapentaenoic acid (DPA). Many new studies have been published on the Specialized Proresolving Lipid Mediators (SPMs) that were uncovered from the beginning of the 2000s onwards. SPMs are endogenous derivatives of LCPUFA (lipid mediators) that activate a range of cellular changes that concertedly drive inflammatory responses towards their resolution. In other words, they are an important part of the body’s physiological mechanism to control the extent and magnitude of inflammation occurring in the body.

In the past decade, several SPMs that are made from omega-3 LCPUFA have been further characterized in terms of their chemical structure and biological activities, and new members, such as the DPA-derived 13S-series resolvins, and the DHA-derived protectin- and resolvin-sulfido conjugates, have been described. A newly uncovered DHA-derived metabolite, 19,20-epoxydocosapentaenoic acid, has potent activity in retinal and choroidal angiogenesis. Scientists have been busy elucidating the many biologically active derivatives of omega-3 fatty acids that regulate inflammation and tissue development in the body.

An increasing number of studies has addressed how dietary intake and supplementation with EPA/DHA-containing oils affects the formation and levels of these lipid mediators in the body. 

Also, the question of how specific nutrients affect the metabolism of EPA and DHA into these lipid mediators, and how omega-3 LCPUFA metabolism is dysregulated in diverse diseases, is gathering in force. For instance, obesity and aging are now recognized as exerting a negative influence on SPM-mediated healing responses after injury-for example, after myocardial infarction. Lipid mediators derived from omega-3 LCPUFA are now known not to be confined to the generation in local inflammatory reactions, but have been detected in saliva and in breast milk, suggesting important roles in protecting mucosal tissues and possibly in immunotolerance and gastrointestinal biotic health of infants. 

In a rabbit model of periodontitis, the local oral application of resolvin E1 was reported to have systemic anti-inflammatory effects. Further progress has been made in characterizing a more complete scope of immuno-resolvent actions that omega-3 LCPUFA-derived mediators exert in cells and tissues, in particular their endogenous antiseptic activity through the activation of phagocytosis of microbes. 

Omega-3s and Human Health

Ten years ago, it was quite clear that the role of omega-3 LCPUFA in the body is far more complex than simply influencing cell membrane properties. It was also known that omega-3 fatty acids played plausible roles in mediating tissue-protective and anti-inflammatory activities. Much more information is now available to support that omega-3 LCPUFA actually modulate disease risk. 

Ahead, we also look at what science has revealed about the implications of omega-3 LCPUFA intake on various aspects of human health.

Immune System

A shift in the way researchers think about the effects of omega-3 LCPUFA on the immune system has taken place in the last 10 years. Gradually, the poor classification that omega-3 PUFAs are immuno-suppressive is being replaced. 

Now, there is an understanding that omega-3 LCPUFA permit the execution of marked multi-cellular immuno-modulatory activities that can be interpreted as being immuno-stimulatory in nature-namely, specific parts of the immune system are triggered to become less active, and other immune cell types are activated to actively promote inflammation resolution.

Fatty Acid Distinction

Another notable change is a growing appreciation for the individual activities of distinct fatty acids in general. Even among omega-3 LCPUFA family members, there is recognition of distinct tissue distributions and, in some cases, notable differentiation in biological activities of EPA and DHA. 

Furthermore, omega-3s that are not EPA and DHA-for example DPA omega-3 and alpha-linolenic acid (ALA)-are increasingly being studied for their contributions to beneficial effects on health. 

With regard to ALA, although it is an essential fatty acid, no unique or distinct biological activity for this fatty acid itself has yet been identified; however, research nevertheless links the dietary intake of ALA to several benefits for health, in particular metabolic health, such as insulin sensitivity and body weight. 

Given the variable degrees of metabolic interconversion of the various omega-3 LCPUFA, their individual activities remain challenging to study and elucidate. 

Cardiovascular Disease

One area that has received much attention is cardiovascular disease, with EPA and DHA having been reported to exert a variety of beneficial effects. Clinically relevant effects have been concluded from both prospective cohort studies as well as randomized, controlled trials. The intake of EPA and DHA at several grams per day lowers blood pressure, a major risk factor for cardiovascular disease.

The omega-3 index is viewed as a marker for coronary heart disease, especially sudden cardiac death, and higher EPA/DHA issue levels may be causally involved in offering protection through their further metabolism into locally acting derivatives that delay the formation of atherosclerosis and stabilize advanced atherosclerotic plaques. The role of omega-3 LCPUFA in the prevention of specific cardiovascular disorders, such as peripheral artery disease, aortic calcification, and aneurysm development, has seen increased research attention.

Metabolic Syndrome

Ten years ago, the possibility that EPA and DHA intake was related to the amelioration of various aspects of metabolic syndrome was gaining increased attention. Metabolic syndrome principally encompasses overweight- and obesity-related disorders characterized by high blood pressure, alterations in blood lipids, elevated blood glucose, and a predisposition to a diverse array of disorders such as steatosis of the liver and pancreas, hypothalamic dysregulation, and type 2 diabetes. 

That interest has only expanded, and an enormous volume of clinical and preclinical information is now available on the relationship between omega-3 LCPUFA and metabolic inflammatory disorders associated with excessive net energy intake. Studies show a beneficial relationship between EPA/DHA intake and dyslipidemia, oxidation, inflammation, hypertension, glucose intolerance, overweight, and obesity.

Neurodegenerative & Cognitive

When it comes to neurodegenerative and cognitive disorders, our understanding of the relevance of omega-3 LCPUFA has improved significantly. Ten years ago, it was reported that a high omega-3 fatty acid intake is inversely proportionate to the prevalence of some affective disorders. Whereas at the time, insufficient clinical evidence was available to prove conclusively that treatment with omega-3 fatty acids has any beneficial effect on affective disorders, it is now becoming clear that stratification of patients by omega-3 index or by the level of oxidative stress can be useful, or is even necessary, to predict who may be responsive to increased omega-3 LCPUFA intake-for example in bipolar disorder, major depression, and cognitive decline preceding Alzheimer’s disease. 

In the case of major depression, our understanding that a high-dose intake of EPA, but not DHA, can be helpful in reducing symptoms has refined remarkably. Omega-3 LCPUFA are now considered to protect glutamatergic neurotransmission from damage induced by stress and glucocorticoids, particularly in the hippocampus, an activity which may counteract the development of stress-related disorders such as depression or anxiety. 

Significant progress in halting the progression of cognitive decline prior to Alzheimer’s disease has been demonstrated in elderly people with daily intake of EPA/DHA in combination with B-vitamins. Most likely this goes back to the restoration of a molecular defect in the liver, in which the hepatic biosynthesis of DHA-lysophosphatidylcholine, involved in the transport of DHA to the brain, is significantly reduced. High intake and blood levels of both B-vitamins and DHA are able to reduce cognitive decline >80% over a three-year controlled intervention period.

Cancer

Clinical evidence has now also started to appear supporting results from basic research indicating that the immune-modified state of certain cancers is amenable to interference by omega-3 LCPUFA, making cancer more susceptible to treatment. In the treatment of cancer, omega-3 LCPUFA have been found efficacious in sensitizing cancerous cells to anti-cancer agents, in triggering apoptosis selectively in cancerous cells, and decreasing their glycolytic metabolism. 

Both preventive as well as adjunct roles of omega-3s in cancer targeting are emerging-for example, in colorectal and breast cancer. Interesting applications have been developed, such as the capacity of DHA-loaded LDL nanoparticles to kill malignant hepatocytes.

Inflammation

Paradoxically, EPA and DHA appear to exert beneficial activity in low-grade inflammatory disorders in which significantly increased oxidative stress is a characteristic. Based on chemical reasons, one might expect that increased omega-3 LCPUFA tissue levels would aggravate such conditions through their facile participation in free radical propagating reactions leading to lipid peroxidation. Clearly, this does not seem to be the case in the intact biological setting, and the mechanisms involved seem to be the ability of omega-3 LCPUFA to activate cellular and tissue antioxidant defenses. 

Research during the last 10 years has provided many examples whereby EPA and DHA increase the levels of small molecule antioxidants and antioxidant enzymatic defense capacity, and decrease pro-oxidant generating activities. Increased turnover of DHA-containing phospholipids, activated through oxidative metabolism and increased neuroprotectin D1 formation, also constitutes a mechanism to maintain the functioning of DHA-rich membranes-for example, in the outer segments of retinal pigment epithelial cells needed for vision. 

Nevertheless, the potential for increased oxidation of endogenous membranes enriched with PUFA in the context of low antioxidant levels has also been reported, and understanding the mechanisms involved in the dynamic interplay between oxidation and compensatory protective reactions will remain an interesting field of research. Another interesting line of research addresses the newly gained understanding that omega-3 LCPUFA enhance the detoxification of some environmental contaminants, likely through the promotion of their elimination by the liver.

Oxidation

Ten years ago, we knew that polyunsaturated fatty acids were sensitive to oxidation by molecular oxygen. Marked appreciation has now evolved for the chemopreventive effects of omega-3 LCPUFA, which are likely mediated through reactive oxidation products activating antioxidant defenses. 

Cells can sense reactive products of EPA- and DHA-containing lipids through specific molecular sensor proteins, such as Keap1/Nrf2. The formation of non-enzymatic oxidation products from EPA and DHA, such as isoprostanes and neuroprostanes, can activate tissue-protective effects and mediate anti-arrhythmic and analgesic effects. Fascinatingly, these activities are not shared with those of the analogous autoxidation products from AA, suggesting that the body actively monitors non-enzymatic oxidation of omega-3 LCPUFA. 

I regret that it has been impossible to highlight a more complete spectrum of scientific discoveries and advancements of the past 10 years. References that support the mentioned scientific developments can be obtained from the author via e-mail at gerard@goedomega3.com. More information on the role of polyunsaturated fatty acids in health can be found at Fats of Life (www.fatsoflife.com).

Also read:

10 Years of Omega-3 Science: From Then to Now

2016 Omega-3 Market Update: Fish Oil, Krill Oil, Astaxanthin, and More