What Are the Real Differences Between EPA and DHA?

Where do you want your EPA and DHA to go? Know the signs.

When you read anything about fish oil, the acronyms EPA and DHA always go together. But what do they really mean, and what’s the difference between them? The reality is that the two key omega-3 fatty acids (EPA and DHA found in fish oil) do a lot of different things, and as a result the benefits of EPA and DHA are often very different. That’s why you need them both. But as to why, let me go into more detail.

Benefits of EPA

The ultimate goal of using omega-3 fatty acids is the reduction of cellular inflammation. Since eicosanoids derived from arachidonic acid (AA), an omega-6 fatty acid, are the primary mediators of cellular inflammation, EPA is the most important of the omega-3 fatty acids to reduce cellular inflammation for a number of reasons.

  • EPA is an inhibitor of the enzyme delta-5-desaturase (D5D) that produces AA.
  • The more EPA you have in the diet, the less AA you produce.

This essentially chokes off the supply of AA necessary for the production of pro-inflammatory eicosanoids (prostaglandins, thromboxanes, leukotrienes, etc.)

DHA is not an inhibitor of this enzyme because it can’t fit into the active catalytic site of the enzyme due to its larger spatial size. As an additional insurance policy, EPA also competes with AA for the enzyme phospholipase A2 necessary to release AA from the membrane phospholipids (where it is stored). Inhibition of this enzyme is the mechanism of action used by corticosteroids. If you have adequate levels of EPA to compete with AA (i.e. a low AA/EPA ratio), you can realize many of the benefits of corticosteroids but without their side effects. That’s because if you don’t release AA from the cell membrane, you can’t make inflammatory eicosanoids.

Because of its increased spatial dimensions, DHA is not a good competitor of phospholipase A2 relative to EPA. On the other hand, EPA and AA are very similar spatially so they are in constant competition for the phospholipase A2 enzyme, just as both fatty acids are in constant competition for the delta-5 desaturase enzyme. This is why measuring the AA/EPA ratio is such a powerful predictor of the state of cellular inflammation in your body.

The various enzymes (COX and LOX) that make inflammatory eicosanoids able to accommodate both AA and EPA, but again due to the greater spatial size of DHA, these enzymes will have difficulty-converting DHA into eicosanoids. This makes DHA a poor substrate for these key inflammatory enzymes. Thus DHA again has little effect on cellular inflammation, whereas EPA can have a powerful impact.

Finally, it is often assumed since there are not high levels of EPA in the brain, that it is not important for neurological function. Actually, it is key for reducing neuro-inflammation by competing against AA for access to the same enzymes needed to produce inflammatory eicosanoids. However, once EPA enters into the brain, it is rapidly oxidized.This is not the case with DHA.

The only way to control cellular inflammation in the brain is to maintain high levels of EPA in the blood. This is why all the work on depression, ADHD, brain trauma, etc., has demonstrated that EPA is superior to DHA.

Benefits of DHA

At this point, you might think that DHA is useless. Just the opposite, because DHA can do a lot of different things than EPA and some of them are even better.

First is in the area of omega-6 fatty acid metabolism. Whereas EPA is the inhibitor of the enzyme (D5D) that directly produces AA, DHA is an inhibitor of another key enzyme, delta-6-desaturase (D6D), that produces the first metabolite from linoleic acid known as gamma linolenic acid or GLA.

However, this is not exactly an advantage. Even though reduction of GLA will eventually decrease AA production, it also has the more immediate effect of reducing the production of the next metabolite known as dihomo gamma linolenic acid or DGLA. This can be a disaster as a great number of powerful anti-inflammatory eicosanoids are derived from DGLA. This is why if you use high-dose DHA, it is essential to add back trace amounts of GLA to maintain sufficient levels of DGLA to continue to make anti-inflammatory eicosanoids.

In my opinion, the key benefit of DHA lies in its unique spatial characteristics. As mentioned earlier, the extra double bonds and length of DHA compared to EPA means it takes up a lot more space in the membrane. Although this increase in spatial volume makes DHA a poor substrate for phospholipase A2 as well as the COX and LOX enzymes, it does a great job of making membranes (especially those in the brain) a lot more fluid as the DHA sweeps out a much greater volume in the membrane than EPA.

This increase in membrane fluidity is critical for synaptic vesicles and the retina of the eye because it allows receptors to rotate more effectively, thus increasing the transmission of signals from the surface of the membrane to the interior of the nerve cells. This is why DHA is a critical component of these parts of the nerves. On the other hand, the myelin membrane is essentially an insulator so that relatively little DHA is found in that part of the membrane.

This constant sweeping motion of DHA also causes the breakup of lipid rafts in membranes. Disruption of these islands of relatively solid lipids makes it more difficult for cancer cells to continue to survive and more difficult for inflammatory cytokines to initiate the signaling responses to turn on inflammatory genes. In addition, these greater spatial characteristics of DHA increase the size of LDL particles to a greater extent compared to EPA.

As a result DHA helps reduce the entry of these enlarged LDL particles into the muscle cells that line the artery, thus reducing the likelihood of developing atherosclerotic lesions. Thus the increased spatial territory swept out by DHA is good news for making certain areas of membranes more fluid or lipoprotein particles larger, even though it reduces the benefits of DHA in competing with AA for key enzymes important in the development of cellular inflammation.

Common Effects for Both EPA and DHA

Not surprisingly, there are some areas in which both EPA and DHA appear to be equally beneficial. For example, both are equally effective in reducing triglyceride levels. This is probably due to the relatively equivalent activation of the gene transcription factor (PPAR alpha) that causes the enhanced synthesis of the enzymes that oxidize fats in lipoprotein particles.

There is also apparently equal activation of the anti-inflammatory gene transcription factor PPAR-gamma. Both seem to be equally effective in making powerful anti-inflammatory eicosanoids known as resolvins. Finally, although both have no effect on total cholesterol levels, DHA can increase the size of LDL particle to a greater extent than EPA can.

So Now What?

EPA and DHA do different things, so you need them both.

If your goal is reducing cellular inflammation, then you probably need more EPA than DHA. How much more? The most effective way to find out how much fish oil you need is to test your blood. Our Cellular Inflammation Test Kit allows you to test your personal levels at home. You will receive a detailed report with your AA and EPA levels, as well as your Cellular Inflammation Score, and personalized wellness recommendations. Then, you will never need to guess how much fish oil you should take.

Already know how much fish oil to take? Dr. Sears’ OmegaRx Fish Oil is the best way to get high levels of both EPA and DHA.

Find out your Cellular Inflammation Score
Take the easy finger-stick Cellular Inflammation Test today.

Zone Labs AA/EPA Ratio Blood Test KitEverything inside the Zone Cellular Inflammation Test Kit.

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About Dr. Barry Sears

Dr. Barry Sears is a leading authority on the impact of the diet on hormonal response, genetic expression, and inflammation. A former research scientist at the Boston University School of Medicine and the Massachusetts Institute of Technology, Dr. Sears has dedicated his research efforts over the past 45 years to the study of lipids. He has published 40 scientific articles and holds 14 U.S. patents in the areas of intravenous drug delivery systems and hormonal regulation for the treatment of cardiovascular disease. He has also written 14 books, including the New York Times #1 best-seller "The Zone". His books have sold more than 6 million copies in the U.S. and have been translated into 22 different languages.

Comments

  1. debbie

    Hi how does algae compare to fish oil in bioavailability of EPA and DHA, and also as it is lower in the food chain, would it be safe to assume there would be less mercury toxicity ?

    Reply
  2. Rob A

    Some doctors prescribe Vascepa to patients with high triglycerides. It is claimed that DHA can cause additional rise in Triglycerides. All of the Omega3 supplements seem to have DHA. Is there such a thing as a supplement without it or at lower doses? I’m struggling to find something as Vascepa is very expensive. Thanks for any guidance.

    Reply
    • Barry Sears

      I believe you are discussing the potential rise in LDL cholesterol levels, not TG levels. That assumption comes from very old data submitted in 1990s for Lovaza, and is continually used by Vascepa to promote their product (unsuccessfully). The clinical data over the past decade has demonstrated a consistent lowering of TG with combination products of EPA and DHA. As far as LDL cholesterol levels, neither EPA or DHA will have a great effect other than making the LDL particles larger and thus less atherogenic. As will discuss in my next blog, OmegaRx 2 has higher purity standards with regards to PCBs and rancidity than generic prescription omega-3 products, but at a much lower cost.

      Reply
  3. Sam

    In what proportions would you recommend patients take EPA and DHA, please, Doctor Sears.

    Reply
    • Barry Sears

      It’s not the proportions as much as the absolute amounts. I like to have a 2:1 ratio of EPA to DHA since both fatty acids different functions, but the most important criteria is consuming at least 1.6 grams of EPA per day and at least 0.6 of DHA per day.

      Reply
  4. Maurice

    Dr. Sears.
    Found you via Mark Hyman, and am now an avid reader.
    Thanks for making the effort to publish your research.

    Reply
  5. Andy

    Hi Dr Sears,

    Thank you for your response. I understand what you are saying, what I was really looking for were citations of studies that back that up.

    Regards,
    Andy

    Reply
    • Barry Sears

      DHA needs to use the enzyme delta-6-desaturase in two separate steps to be formed. The first is the convert 18:3n-3 into 18:4n-3. The second time is when it makes 24:5 n-3 that is then oxidized back to DHA. The structural similarity of DHA to 24:5 n-3 makes it a better inhibitor of delta-6-desaturase than EPA.

      Portolesi R, Powell BC, Gibson RA. Competition between 24:5n-3 and ALA for Delta 6 desaturase may limit the accumulation of DHA in HepG2 cell membranes. J Lipid Res (United States), Jul 2007, 48(7) p1592-8

      On the other hand, EPA is very similar in 3-D structure to AA. This is why EPA is better inhibitor of delta-5 desaturase than is DHA.

      Barham JB, Edens MB, Fonteh AN, et al. Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans. J Nutr (United States), Aug 2000, 130(8) p1925-31

      Reply
  6. Andy

    Dr Sears,

    You state in your article that DHA is an inhibitor of another key enzyme, delta-6-desaturase (D6D), that produces the first metabolite from linoleic acid known as gamma linolenic acid or GLA.

    However, from my research it seems both DHA and EPA can inhibit delta-6-desaturase.

    http://www.ncbi.nlm.nih.gov/pubmed/7840871

    Can you please direct me to research that shows the DHA and not EPA inhibits delta-6-desaturase please.

    Thanks!

    Reply
    • Dr. Sears

      A feedback inhibitor is a metabolite that formed using an enzyme from a starting material. As the levels of the end product of the enzymatic reaction builds up, the metabolite or end product inhibits the enzyme that was making it in the first place. EPA is immediate feedback inhibitor of delta-5-desaturase, whereas DHA is the feedback inhibitor of delta-6-desaturase as that enzyme is used in the last steps of making DHA. Although there is some cross-reactivity between EPA and DHA, the 3-dimensional structures of the two molecules are quite different meaning their relative inhibiting power is for a particular desaturase enzyme is also different.

      Reply
  7. Lyn

    Hi,
    I heard that Omega 3 fish oil is highly contaminated with pollutants, such as, mercury and PCB. Therefore, it does more harm to the body than good.

    Reply
    • Dr. Sears

      Most of the mercury is associated with the protein protein and relatively minor refining removes it from most fish oils. PCBs are another problem. They can only be removed with extensive refining. All fish oils contain some PCBs. This is why our minimum standards for PCB levels are 18 times lower than for the industry. This is also why Zone Labs is the only company that posts the actual levels of PCBs in every lot of omega-3 fatty acid product we sell on our website.

      Reply
  8. Robert

    BUT YOU STILL HAVE NOT EXPLAINED IN THIS PIECE WHERE EPA OR DHA HELPS THE CARDIOVASCULAR SYSTEM AS WE ARE ALWAYS TOLD IT DOES. SO WHICH IS IT? WHICH ONE HELPS THE CARDIO SYSTEM? DHA OR EPS? NOT A HARD QUESTION, DOCS….. AYYYY….

    Reply
  9. Almokashfi

    Hi
    It’s very informative and fruitfully text.
    I am a pharmacist from Sudan. We are interesting in Omega 3 marketing and distribution.
    I would like to know more about these molecules uses and benefits in rheumatoid arthritis, Diabetes, Cardiac insufficiency, Depression, Psychosis and other mental and physical troubles.

    Regards
    Almokashfi Mohamed
    00249 122138137

    Reply
    • Pham le Dung

      Dear Sir,
      I am a Vietnamese. I would like knowing the difference between NATTOPES and EPA DHA ( produced by Japan from soya bean fermentated ) and EPA DHA from fish oil ( omega3, 6)

      Reply
      • Dr. Sears

        Fermented soy beans contain no EPA or DHA. Only fish and algae sources contain EPA and DHA. The soybean contains short chain omega-3 fatty acids alpha linolenic acid.

        Reply

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