Understanding the difference between ethyl esters, triglycerides and polar forms of omega-3 essential fatty acids.
The Issue
We all know that omega-6 and omega-3 fatty acids are essential for human life, which means we must consume them in our diets or as a supplement because our bodies do not make them. We are likely aware of the many benefits they offer when we achieve an ideal ratio of omega-6 to omega-3 lipids in our diets. What is that ideal ratio, and what is the best source of omega-3 lipids? This depends upon individual health status, diet, lifestyle and even genetics. For this reason, we as practitioners must stay up to date on the latest developments in lipid research.
Both omega-3 and omega-6 fats are considered polyunsaturated fatty acids (PUFAs). While land-growing plants, such as flax, chia, perilla and hemp can provide a shorter chain omega-3 precursor called alpha-linolenic acid (ALA), and conversion to the biologically essential longer chain eicosapentanoic Acid (EPA) is theoretically possible, this conversion uses an enzyme pathway that is shared by omega-6. Most people on the standard American diet (SAD) do not convert enough ALA to EPA, leading them to be even more deficient downstream in the conversion of EPA to DPA and DHA. This leads many of our patients down a pathway of inflammation dysregulation,1 now known to manifest in multiple health conditions recognized today, such as metabolic syndrome with type 2 diabetes and cardiovascular disease, Alzheimer’s and other dementias, Parkinson’s, depression and anxiety, gastrointestinal disorders, as well as many types of cancers. For this reason, this exploration will focus on very long chain omega-3 PUFAs directly sourced from fish, roe, krill and microalgae.
Aquatic Sources of Omega-3 Fatty Acids: In Order of the Food Chain
Fish
The biggest global sources of omega-3s are smaller oily fish like herring, mackerel, anchovy, sardine and menhaden. Additionally, some dietary supplement brands source omega-3s from pollock, cod and salmon. Other compelling products even originate from the heads, tails, or fatty trim of large tuna. Whichever the source, lipids derived from fish bodies, heads or livers is a triacylglycerol form, commonly termed triglyceride (TG). These lipids contain a variety of fatty acids, including fully formed EPA, DPA and DHA as the predominant omega-3s. Fish yield on average 30 percent omega-3s, but ratios of EPA to DHA vary widely, and subsequent processing is necessary to create a consistent profile.
Manufacturers typically process the smaller fish whole, separating oils from protein and bone. The rest of the fish meal goes into other products, including human and animal protein sources and agricultural fertilizers. Where whole fish are processed, there are often heavy metals and other man-made contaminants like PCBs and POCs to eliminate, because these accumulate more in the muscle, bone and viscera of the fish. Tuna heads and fatty trim are naturally lower in mercury metals. No matter the fish of origin, the crude oil which is still in its natural triglyceride (TG) form, is typically dismantled through trans-esterification, and the desired individual EPA, DPA and DHA fatty acids are then concentrated upwards. Whether this processing occurs by the classic molecular distillation, or by MSET, TMET, CO2 extraction, and whether human grade solvents are used, the goal is to create specified concentrations of omega-3 EPA, DPA and DHA fatty acids, and to eliminate most of the omega-6 and saturated fats in the crude oil. This leaves the omega-3s in what is called an ethyl ester (EE) fatty acid form, with each fatty acid bound to the alcohol component, ethanol. This form has been used in many clinical studies, and is the form offered in pharmaceutical products like Lovaza. It is not, however, the form we consume in our diets. Unless consumed with a high fat meal, EE fatty acids are less bioavailable than triglycerides. Other pharmaceuticals such as EpaNova contain an omega-3 carboxylic acid, to improve bioavailability. In the natural products industry most manufacturers convert the EE form into a reverse triglyceride form (rTG) using various methods to join only the desired omega-3 fatty acids back to a glycerol backbone.
In essence, to get concentrated EPA, DPA or DHA, the natural triacylglycerols are dismantled, and targeted free fatty acids are concentrated. Often the desired fatty acids are reassembled into an rTG to be more like the naturally occurring lipids. The higher the heat and the more processing needed to clean up or isolate certain desired components, the more delicate but important naturally-occurring compounds are lost. These may include vitamins, minerals, phospholipids, pro-resolving mediators (PRMs), and specialized pro-resolving mediators (SPMs). However, this method is still the best way to isolate and concentrate EPA and DHA, so that they can be therapeutically administered to rebalance the omega-6:3 ratio in our daily diets. Most integrative practitioners seek to approximate the level consumed by people in areas with the longest lifespans and health spans (living without major preventable health concerns), typically 4:1 or 3:1. More gentle processing methods are being developed by manufacturers seeking to optimize the retention of PRMs and SPMs, and additionally vitamins A and D as are naturally occurring in cod liver.
Roe
Highly prized in many traditional diets still tied into ancestral practices, fish eggs deliver excellent nutrition in a small package. Unfertilized herring caviar typically contain more than 30 percent of their lipids as fully formed long chain omega-3s, with the ratio in being much higher in DHA, typically 3:1 or 4:1 DHA:EPA, which is also the ratio is human breast milk. Seventy percent of these lipids are in a polar form.2 Phospholipids (PL) are what make an omega-3 polar, and polar means the fats can navigate and mix in a watery environment, enabling them to be digested more thoroughly, be evenly dispersed in the watery medium of the blood stream, and to pass through cell membranes easily for functional uses. Lyso-phosphatidylcholine also acts as an escort for transporting DHA to the retina and across the blood-brain barrier.3 DHA comprises up to 50 percent of the lipids in the retina, and 25 percent of all the lipids in the brain.
Krill
Krill are small crustaceans which feed on phytoplankton and some zooplankton and are an important part of the food chain for small and large fish, sea mammals and sea birds. Krill yields about 15 percent omega-3 fatty acids and provides a highly bioavailable polar form of EPA and DHA, typically in a 2:1 ratio of EPA:DHA. Yielding omega-3 lipids is more expensive in krill than in fish, and most supplements contain much smaller potencies of EPA and DHA than typical fish-derived products.
Microalgae: The Original EPA and DHA Factories
Omega-3 fatty acids are essential for many creatures on this planet, and microalgae are the unicellular factories producing these important nutrients, among many other products. Like humans, fish do not make EPA, DPA and DHA. Larger fish eat smaller fish, smaller fish eat copepods, krill, zooplankton and microalgae. Even copepods, krill and zooplankton obtain their omega-3s from microalgae.
Enter Nannochloropsis sp., a self-reliant little alga that thrives in little more than seawater, sunlight and CO2, releasing oxygen. It produces both phospholipids and glycolipids. The benefit of these polar lipids is realized in their unparalleled bioavailability. EPA from Nannochloropsis sp. appears in the blood plasma twice as fast as EPA from krill oil, seemingly due to the additional presence of the glycolipids.4 Although Nannochloropsis sp. algal oil offers no significant DHA, DHA levels in the brain rise.5 In the case of EPA in polar forms, it may be that DHA need not be provided at all. This could make algal EPA very useful now that more recent studies on rTG and EE omega-3 fatty acids for improving cardiovascular markers have demonstrated that EPA-only formulations are more effective than those including high doses of DHA.6 However, metanalysis are showing that high dose EPA as used in EE pharmaceuticals may cause more adverse events or side effects, including arrhythmias.7 Ongoing studies on algal EPA in polar lipid form are showing that it can be as effective in improving certain cardiovascular health metrics as prescription EE EPA, but in less than ¼ of the dose.8 Like all commercial algae, these species are grown in conditions where light intensity and duration, temperature, salinity and contaminants are tightly controlled. They are not subject to the variability of an ocean environment.
Schizochytrium sp. has been a common algal source of DHA for decades. With one proprietary exception, these species produce only DHA in significant amounts, some DPA and little to no EPA. This type of DHA has been used in infant formulas for quite some time now. Commercially, Schizochytrium sp. are cultured in fermentation tanks and require carbohydrates as their source of both energy and carbon. DHA from these species is a part of a lipid complex and comes only in a neutral, triglyceride-bound form, like we find it in fish. However, some of the best suppliers offer either emulsified forms for higher bioavailability, or are partnering with algal polar EPA suppliers.
What Does This Mean for Us as Practitioners?
While research shows that health benefits are delivered using lesser amounts of polar omega-3s than of neutral rTG or EE forms, we still have not settled on an exact number. This is where testing to determine plasma levels of circulating PUFAs or to closely monitor related blood markers can be very crucial for our patients’ progress. Current research shows the benefit of combining more expensive PL-rich omega-3s with less expensive neutral rTGs, yielding products that are a bit higher in EPA or DHA, but have been lent the bioavailability provided by naturally occurring phospholipids.9 Based on the most current evidence, and ongoing research showing immense promise, it is worth considering some changes to our protocols as we recommend omega-3 supplements for our patients and clients who do not regularly consume oily fish.
For those who have cardiovascular health concerns with poor markers of triglycerides, lipid profiles and clotting factors, an EPA-only product may be more effective. However, high doses of EPA, especially as required for the EE form to be effective, may also have their side effects. Some of these side effects or adverse events may be more damaging in patients with multiple co-morbidities. A more targeted choice may be lower dose (below 2 g) rTG fish EPA with inflammation resolving PRMs and SPMs or a polar EPA from Nannochloropsis sp.10 This does not mean we should avoid DHA altogether in patients who might need it for cognitive support or blood sugar balance, for instance. Studies seem to show both that rTg DHA supplemented separately from and in lesser amounts than EPA may not interfere with the therapeutic benefits of EPA, and that polar DHA is less likely to interfere because is taken up quickly by tissues that need it, such as the brain.
Algal polar EPA may also be a better choice for mental health, based both on the older studies showing the benefits of EPA only, and more recent studies showing the ability of polar EPA to cross the blood brain barrier and elevate DHA as needed.5
In prenatal health for fetal development and perinatal health while breastfeeding or in formulas, DHA is still highly prized. For those wanting a vegan or “plant-based” source, Schizochytrium sp. DHA has been a dependable option for a few decades. However, the herring caviar/roe oil providing the same ratio of DHA to EPA as in human breastmilk (3:1) looks like an ideal choice for those mothers with no preference. It may also be the best choice for mothers who have long been on the SAD and have poor reserves of omega-3s in their own bodies.
For immune support, which is centered around attaining immune balance and resilience, it is prudent to recommend an omega-3 which retains naturally occurring PRMs and SPMs—not those isolated and added, as there is not yet sufficient research to support this approach. High quality cod liver fills this requirement, as do some rTG omega-3 products from salmon and tuna, however only high-quality cod liver oil may also contain naturally occurring forms of vitamins A and D. It is very important to choose products with clear labeling indicating the quantifiable levels of these nutrients, not those alluding vaguely to their possible presence. Herring caviar oil contains some vitamin D, PRMs and SPMs, and the phospholipids. If only one product had it all! However, we can combine products or rotate our patients through different options based upon co-morbidities and secondary health concerns.
For brain health and cognitive functioning, and for eye health, the lyso-phosphatidylcholine in the herring caviar oil is highly compelling, carrying the DHA into the brain and retina.3 For patients determined to have a vegan or “plant-based” source, a combination of Nannochloropsis sp. EPA and Scizochytrium sp. DHA may offer similar benefits.
For overall health and longevity, prevention of disease, and maintenance of metabolic resilience, we should always recommend supplementing like we eat, or at least like we used to eat. In this case high-quality cod liver oil and herring caviar oil are stellar options. For those attempting to detoxify from, or offset the effects of, a SAD high in unhealthy sources of omega-6 fats, higher doses of EPA and DHA may be advisable. This can be accomplished by adding higher potency rTG fish oils, separately or in the same product when available. And for those seeking vegan and “plant-based” options for daily health, the Nannochloropsis sp. EPA and Scizochytrium sp. DHA combinations are dependable for most people in the face of the stressors of today’s modern living and diets.
References:
1 https://doi.org/10.1016/j.plefa.2018.03.004. Omega-6 fatty acids and inflammation – Prostaglandins, Leukotrienes and Essential Fatty Acids (plefa.com).
2 Marine Omega-3 Phospholipids: Metabolism and Biological Activities – PMC (nih.gov). www.ncbi.nlm.nih.gov/pmc/articles/PMC3509649/.
3 Fish roe phospholipids and health: composition, extraction, storage and brain health application – ScienceDirect. www.sciencedirect.com/science/article/abs/pii/B9780128198933000059.
4 Kagan ML, West AL, Zante C, & Calder PC (2013) Acute appearance of fatty acids in human plasma–a comparative study between polar-lipid rich oil from the microalgae Nannochloropsis oculata and krill oil in healthy young males. Lipids in Health and Disease 12:102. www.lipidworld.com/content/12/1/102.
5 Dietary lysophosphatidylcholine-EPA enriches both EPA and DHA in the brain: potential treatment for depression Crossref DOI link: https://doi.org/10.1194/jlr.m090464.
6 Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events, Front Cardiovasc Med. 2023; 10: 1229130. Published online 2023 Aug 23. doi: 10.3389/fcvm.2023.1229130.
7 Safety of Supplementation of Omega-3 Polyunsaturated Fatty Acids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials, Advances in Nutrition, Volume 14, Issue 6, November 2023, Pages 1326-1336 www.sciencedirect.com/science/article/pii/S2161831323013534?via%3Dihub.
8 Rao, Amanda, Briskey, David, Nalley, Jakob O., and Ganuza, Eneko (2020). Omega-3 eicosapentaenoic acid (Epa) rich extract from the microalga nannochloropsis decreases cholesterol in healthy individuals: A double-blind, randomized, placebo-controlled, three-month supplementation study. Nutrients 12 (6) 1869 1-14. https://doi.org/10.3390/nu12061869.
9 Comparison of the effects of a phospholipid-enhanced fish oil versus krill oil product on plasma levels of eicosapentaenoic and docosahexaenoic acids after acute administration: A randomized, double-blind, crossover study – ScienceDirect. www.sciencedirect.com/science/article/pii/S0899900723001193.
10 Lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS) isolated from Nannochloropsis microalgae improves high-density lipoprotein (HDL) functions https://doi.org/10.1002/biof.1580.
Amber Lynn Vitale is Board Certified in Holistic Nutrition®, a Certified Dietary Supplement Professional™ and an Ayurvedic Clinical Consultant. Since 2008 she has been producing written and video educational content for many publications, an educational YouTube channel, and Instagram and Facebook pages. Vitale is passionate about raw materials sourcing, labeling transparency, legitimate certifications and education. Recently she founded Trifecta For Health, LLC using her years of experience to develop synergistic health protocols tailored to individual needs, and provide brand support for quality materials in the Natural Products Industry.
