Eicosapentaenoic acid

EPA is a polyunsaturated fatty acid (PUFA) that acts as a precursor for prostaglandin-3 (which inhibits platelet aggregation), thromboxane-3, and leukotriene-5 eicosanoids. EPA is both a precursor and the hydrolytic breakdown product of eicosapentaenoyl ethanolamide (EPEA: C₂₂H₃₅NO₂; 20:5,n−3). Although studies of fish oil supplements, which contain both docosahexaenoic acid (DHA) and EPA, have failed to support claims of preventing heart attacks or strokes, a recent multi-year study of Vascepa (ethyl eicosapentaenoate, the ethyl ester of the free fatty acid), a prescription drug containing only EPA, was shown to reduce heart attack, stroke, and cardiovascular death by 25% relative to a placebo in those with statin-resistant hypertriglyceridemia.

Forms

Commercially available dietary supplements are most often derived from fish oil and are typically delivered in the triglyceride (TG) form in supplements and the ethyl ester (EE) form in medications. There is debate among supplement manufacturers about the relative advantages and disadvantages of the different forms.

Fish oil is rich in the TG form. Algae is rich in the DGDG, MGDG, and PC forms while krill is rich in the PC and 2-LPC (both phospholipids) forms.

One form found naturally in algae, the polar lipid form (a mixture of various non-TG/EE forms, including PC, LPC, other PL, DGDG, and MGDG), 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 TG and phosphatidylcholines (PC) in a 2020 study.

Note:

PL includes LPC and PC.
LPC can be further broken down into sn-1 and sn-2 LPC depending on where the omega-3 fatty acid is located on the molecule (regiochemistry). Likewise, TG can be broken down into sn-1, 2, or 3 TG, with some claims of one being superior to others.

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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:

a desaturation at the sixth carbon of α-linolenic acid by a Δ6 desaturase to produce stearidonic acid (SDA, 18:4 ω−3),
elongation of the stearidonic acid by a Δ6 elongase to produce eicosatetraenoic acid (ETA, 20:4 ω−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 PKS pathway includes six enzymes namely, 3-ketoacyl synthase (KS), 2 ketoacyl-ACP-reductase (KR), dehydrase (DH), enoyl reductase (ER), dehydratase/2-trans-3-cis isomerase (DH/2,3I), dehydratase/2-trans, and 2-cis isomerase (DH/2,2I). The biosynthesis of EPA varies in marine species, but most of the marine species' ability to convert C18 PUFA to LC-PUFA is dependent on the fatty acyl desaturase and elongase enzymes. The molecule basis of the enzymes will dictate where the double bond is formed on the resulting molecule.

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.