Eicosapentaenoic acid

Sources

EPA is obtained in the human diet by eating oily fish, e.g., cod liver, herring, mackerel, salmon, menhaden and sardine, various types of edible algae, or by taking supplemental forms of fish oil or algae oil. It is also found in human breast milk.

Fish, like most vertebrates, can synthesize very little EPA from dietary alpha-linolenic acid (ALA). Because of this extremely low conversion rate, fish primarily obtain it from the algae they consume. It is available to humans from some non-animal sources (e.g., commercially, from Yarrowia lipolytica, and from microalgae such as Nannochloropsis oculata, Monodus subterraneus, Chlorella minutissima and Phaeodactylum tricornutum, which are being developed as a commercial source). EPA is not usually found in higher plants, but it has been reported in trace amounts in purslane. In 2013, it was reported that a genetically modified form of the plant camelina produced significant amounts of EPA.

The human body converts a portion of absorbed alpha-linolenic acid (ALA) to EPA. ALA is itself an essential fatty acid, and humans need an appropriate supply of it. The efficiency of the conversion of ALA to EPA, however, is much lower than the absorption of EPA from food containing it. Because EPA is also a precursor to docosahexaenoic acid (DHA), ensuring a sufficient level of EPA on a diet containing neither EPA nor DHA is harder both because of the extra metabolic work required to synthesize EPA and because of the use of EPA to metabolize into DHA. Medical conditions like diabetes or certain allergies may significantly limit the human body's capacity for metabolization of EPA from ALA.

Forms

Commercially available dietary supplements are most often derived from fish oil and are typically delivered in the triglyceride, ethyl ester, or phospholipid form of EPA. There is debate among supplement manufacturers about the relative advantages and disadvantages of the different forms. One form found naturally in algae, the polar lipid form, has been shown to have improved bioavailability over the ethyl ester or triglyceride form. Similarly, DHA or EPA in the lysophosphatidylcholine (LPC) form was found to be more efficient than triglyceride and phosphatidylcholines (PC) in a 2020 study.

Biosynthesis

Aerobic eukaryote pathway

Aerobic eukaryotes, specifically microalgae, mosses, fungi, and most animals (including humans), perform biosynthesis of EPA usually as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes. This pathway, originally identified in Thraustochytrium, applies to these groups:

1. a desaturation at the sixth carbon of alpha-linolenic acid by a Δ6 desaturase to produce stearidonic acid (SDA, 18:4 ω-3),
2. elongation of the stearidonic acid by a Δ6 elongase to produce eicosatetraenoic acid (ETA, 20:4 ω-3),
3. desaturation at the fifth carbon of eicosatetraenoic acid by a Δ5 desaturase to produce eicosapentaenoic acid (EPA, 20:5 ω-3),

Polyketide synthase pathway

Marine bacteria and the microalgae Schizochytrium use an anerobic polyketide synthase (PKS) pathway to synthesize DHA.

The proposed polyketide synthesis pathway of EPA in Shewanella (a marine bacterium) is a repetitive reaction of reduction, dehydration, and condensation that uses acetyl-CoA and malonyl-CoA as building blocks. The mechanism of α-linolenic acid to EPA involves the condensation of malonyl-CoA to the pre-existing α-linolenic acid by KS. The resulting structure is converted by NADPH dependent reductase, KR, to form an intermediate that is dehydrated by the DH enzyme. The final step is the NADPH-dependent reduction of a double bond in trans-2-enoyl-ACP via ER enzyme activity. The process is repeated to form EPA.

Clinical significance

The US National Institute of Health's MedlinePlus lists medical conditions for which EPA (alone or in concert with other ω-3 sources) is known or thought to be an effective treatment. Most of these involve its ability to lower inflammation.

Intake of large doses (2.0 to 4.0 g/day) of long-chain omega−3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant ( 15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater than 500 mg/dL).

Dietary supplements containing EPA and DHA lower triglycerides in a dose dependent manner; however, DHA appears to raise low-density lipoprotein (the variant which drives atherosclerosis, sometimes inaccurately called "bad cholesterol") and LDL-C values (a measurement/estimate of the cholesterol mass within LDL-particles), while EPA does not. This effect has been seen in several meta-analyses that combined hundreds of individual clinical trials in which both EPA and DHA were part of a high dose omega−3 supplement, but it is when EPA and DHA are given separately that the difference can be seen clearly.

Ordinary consumers commonly obtain EPA and DHA from foods such as fatty fish, fish oil dietary supplements, and less commonly from algae oil supplements in which the omega−3 doses are lower than those in clinical experiments.

Omega−3 fatty acids, particularly EPA, have been studied for their effect on autistic spectrum disorder (ASD). Some have theorized that, since omega−3 fatty acid levels may be low in children with autism, supplementation might lead to an improvement in symptoms. Well-controlled studies have shown no statistically significant improvement in symptoms as a result of high-dose omega−3 supplementation.

In addition, studies have shown that omega−3 fatty acids may be useful for treating depression.

EPA and DHA ethyl esters (all forms) may be absorbed less well, thus work less well, when taken on an empty stomach or with a low-fat meal.

Notes

References

References

1. (May 2011). "N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans". Nature.
2. Zimmer, Carl. (September 17, 2015). "Inuit Study Adds Twist to Omega-3 Fatty Acids' Health Story". [[The New York Times]].
3. O'Connor, Anahad. (March 30, 2015). "Fish Oil Claims Not Supported by Research". The New York Times.
4. (March 2014). "Clinical trial evidence and use of fish oil supplements". JAMA Internal Medicine.
5. (January 3, 2019). "Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia". New England Journal of Medicine.
6. (November 10, 2018). "Vascepa® (icosapent ethyl) 26% Reduction in Key Secondary Composite Endpoint of Cardiovascular Death, Heart Attacks and Stroke Demonstrated in REDUCE-IT™".
7. (2011). "Nutrient requirements of fish and shrimp". The National Academies Press.
8. Bishop-Weston, Yvonne. "Plant based sources of vegan & vegetarian Docosahexaenoic acid – DHA and Eicosapentaenoic acid EPA & Essential Fats".
9. (February 2015). "Sustainable source of omega-3 eicosapentaenoic acid from metabolically engineered Yarrowia lipolytica: from fundamental research to commercial production". Applied Microbiology and Biotechnology.
10. (1998). "Eicosapentaenoic acid and docosahexaenoic acid production potential of microalgae and their heterotrophic growth". Journal of the American Oil Chemists' Society.
11. (February 2012). "Bioprospecting microalgae as potential sources of "Green Energy"—challenges and perspectives". Applied Biochemistry and Microbiology.
12. Halliday, Jess. (12 January 2007). "Water 4 to introduce algae DHA/EPA as food ingredient".
13. Simopoulos, Artemis P. (2002). "Omega-3 fatty acids in wild plants, nuts and seeds". Asia Pacific Journal of Clinical Nutrition.
14. (January 2014). "Successful high-level accumulation of fish oil omega-3 long-chain polyunsaturated fatty acids in a transgenic oilseed crop". The Plant Journal.
15. Coghlan, Andy. (4 January 2014). "Designed plant oozes vital fish oils". New Scientist.
16. (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.
17. (December 2019). "Enrichment of brain docosahexaenoic acid (DHA) is highly dependent upon the molecular carrier of dietary DHA: lysophosphatidylcholine is more efficient than either phosphatidylcholine or triacylglycerol.". The Journal of Nutritional Biochemistry.
18. Qiu, Xiao. (2003-02-01). "Biosynthesis of docosahexaenoic acid (DHA, 22:6-4, 7,10,13,16,19): two distinct pathways". Prostaglandins, Leukotrienes and Essential Fatty Acids.
19. (2013-10-21). "Biosynthesis of Polyunsaturated Fatty Acids in Marine Invertebrates: Recent Advances in Molecular Mechanisms". Marine Drugs.
20. (July 2018). "Polyunsaturated fatty acids in marine bacteria and strategies to enhance their production". Applied Microbiology and Biotechnology.
21. NIH Medline Plus. "MedlinePlus Herbs and Supplements: Omega-3 fatty acids, fish oil, alpha-linolenic acid".
22. (February 2018). "Eicosapentaenoic acid and docosahexaenoic acid containing supplements modulate risk factors for cardiovascular disease: a meta-analysis of randomised placebo-control human clinical trials.". Journal of Human Nutrition and Dietetics.
23. (26 March 2020). "Effects of eicosapentaenoic acid and docosahexaenoic acid versus α-linolenic acid supplementation on cardiometabolic risk factors: a meta-analysis of randomized controlled trials.". Food & Function.
24. (August 2009). "Omega-3 fatty acids for autistic spectrum disorder: a systematic review". Journal of Autism and Developmental Disorders.
25. (2015-03-21). "A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism". Molecular Autism.
26. (December 2006). "Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry". The Journal of Clinical Psychiatry.
27. (28 April 2015). "Therapeutic Lifestyle Change. A new treatment for depression".
28. (2015). "National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2". Journal of Clinical Lipidology.