More Evidence that Too Much Fish Oil (5g+ of EPA + DHA) Increases Inflammation + May Promote NAFLD | Confirmed: Bioavailability of Krill Oil > Fish Oil - Implications?

There's something fishy about high dose fish oil supplementation. Increased inflammation and beginning fatty liver disease clearly indicate that the dose-response curve for EPA + DHEA is U-shaped. Meaning: More doesn't help more!

Don't worry! I am not going to tell you that you have to drop your beloved fish oil supplements altogether. Next to making sure that they are not filled with unwanted Persistent Organic Pollutants (POPs | learn more in a recent SV article), though, the results of a recent stuy by researchers from the University of São Paulo, the University of Southampton and the Campus Universitário in Londrina should remind you that "more does not always help more".

Against that background, I am not sure how relevant the increased bioavailability of krill vs. fish oil actually is in terms of the desired beneficial effects your supplements are supposed to have on your health. In spite of that, I would like you to know that European researchers have recently confirmed what previous rodent experiments did already suggest: Compared to the triglyceride-bound DHA and EPA from fish oil supplements, the phospholipid-bound DHA and EPA from krill oil supplements have a significantly higher bioavailability.

You can learn more about omega-3 & co at the SuppVersity

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• Dietary Docosahexaenoic Acid and Eicosapentaenoic Acid Influence Liver Triacylglycerol and Insulin Resistance in Rats Fed a High-Fructose Diet
  
  In their latest study, researchers from the University of Sao Paulo examined the benefits of different amounts of omega-3 (n-3) polyunsaturated fatty acids from fish oil (FO) on lipid metabolism, insulin resistance and gene expression in rats fed a high-fructose diet.
  Male Wistar rats were separated into two groups: Control (C, n = 6) and Fructose (Fr, n = 32), the latter receiving a diet containing 63% by weight fructose for 60 days. After this period, 24 animals from Fr group were allocated to three groups: FrFO2 (n = 8) receiving 63% fructose and 2% FO plus 5% soybean oil; FrFO5 (n = 8) receiving 63% fructose and 5% FO plus 2% soybean oil; and FrFO7 (n = 8) receiving 63% fructose and 7% FO. Animals were fed these diets for 30 days.
  

  

  Figure 1: The effects of fish oil on the lipids and lipoproteins was clearly dose-dependend, but more didn't help more. Quite in contrast, the high dose fish oil (FO) supplementation lead to minimal increases in liver fat compared to the 5% FO diet - an effect that may be explained by an increase in inflammation (Salim de Castro. 2015).

  Fructose led to an increase in liver weight, hepatic and serum triacylglycerol, serum alanine aminotransferase and HOMA1-IR index. These alterations were reversed by 5% and 7% FO. FO had a dose-dependent effect on expression of genes related to hepatic β-oxidation (increased) and hepatic lipogenesis (decreased).
  

  

  Figure 2: We've seen similar pro-inflammatory effects with much lower doses of fish oil before: In human athletes, do you remember? It appears clear that "too much of a good thing" can, once again, become a "bad thing".

  Much to the fish oil worshippers', surprise, though, the group receiving the highest FO amount had increased markers of oxidative stress. So, "n-3 fatty acids may be able to reverse the adverse metabolic effects induced by a high fructose diet", but too much of them will make your body vulnerable to inflammation and may have negative effects on your liver (learn more | cf. Zugasti. 2015).
  
  What needs to be studied further, though, is whether these effects are due to interactions with the pro-inflammatory high fructose diet. If that's the case, the increase in TNF-alpha may be a consequence of increased oxidation of the omega-3s from fish oil in an already highly inflammatory scenario. If we think of fish oil as gasoline, this would also imply that the same effects may be absent in a scenario where the baseline inflammation is low.

More is not necessary, either: Whether the effects depend on an inflammatory diet or not may not be relvant in view of the fact that a  recent review in which scientists from the Università Cattolica set out to identify the optimal amount of DHA+EPA to reduce the risk of prostate and breast cancer shows that 2g/day of EPA+DHA is enough to produce "a tissue enrichment in these fatty acids comparable to that observed in plenty of the animal studies, where clear antineoplastic effects of these FA were reported" (Fasano. 2015). Studies on beneficial cardiovascular effects used even lower doses of fish oil, so why would you still want to superdose, anyway?

• Bioavailability of Fatty Acids From Krill Oil, Krill Meal and Fish Oil in Healthy Subjects-A Randomized, Single-Dose, Cross-Over Trial.
  You've read about potential differences between krill and fish oil on the SuppVersity, before (reread it). Thus, you will also be aware that krill contains two marine omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mainly bound in phospholipids, while fish oils contain EPA and DHA predominantly bound in triglycerides. As Köhler et al. point out in their latest study, "[t]he difference in the chemical binding of EPA and DHA has been suggested to affect their bioavailability, but little is known on bioavailability of EPA and DHA in krill meal" (Köhler. 2015).
  

  

  Table 1: Overview of the supplements used in the study at hand (Köhler. 2015).

  Accordingly, Köhler et al. undertook a randomized, single-dose, single-blind, cross-over, active-reference trial to compare the acute bioavailability of two krill. Each of the supplements contained containing approx. 1 700 mg EPA and DHA and was thus significantly below the 7% human equivalent (approx. 5.5g of combined EPA + DHA) that was used in the previously discussed study by Salim de Castro et al. (2015).
  

  

  Figure 3: Incremental area under 72 h response curve of EPA and DHA in plasma phospholipids after ingestion of different study products (krill oil, fish oil and krill meal) in 15 study subjects (Köhler. 2015).

  The main study outcomes were the fatty acid compositions of plasma triglycerides and phospholipids, which was measured repeatedly for 72 hours. The analysis of the respective data revealed a larger iAUC [incremental area under the curve = measure for total uptake] for EPA and DHA in plasma phospholipid fatty acids after krill oil (mean 89.08 ± 33.36% × h) than after krill meal (mean 44.97 ± 18.07% x h, p < 0.001) or after fish oil (mean 59.15 ± 22.22% × h, p=0.003).
  
  Since the mean iAUC's after krill meal and after fish oil were not statistically significantly different, the results Köhler et al. present in their latest article in Lipids in Health and Disease underline the significance of previous rodent studies (learn more). What remains to be seen, though, is how relevant these effects actually are in terms of the purported health benefits of fish oils.

Rancif Fish Oil = Ill Effects - Plus: 3 Tips to Help You Make the Right Fish Oil Choices | read more

Bottom Line: Next to the previously raised question, whether the increased bioavailability of krill oil is physiologically relevant in terms of the desired health benefits of omega-3 supplementation, it would also be interesting to find out, whether higher doses of krill oil, due to not being triglyceride bound and thus possibly less prone to being stored as liver fat, would have similar pro-fatty-liver effects as high doses (5g+ of EPA + DHA / day) of fish oil.

In the mean time, the benefits of low dose fish oil supplementation appear to be too well-established to warrant questioning the beneficial effects of ~1g and not 5-10g (as some "experts" suggest) of EPA and DHA per day.

In that, studies appear to suggest that the former is geared more towards improvements in lipid metabolism, while the latter is the more important omega-3 fatty acid for cell and, more specifically, brain health. Against that background it does not appear to make sense to take isolated DHA supplements, even if those are touted as "superior" by their vendors | Comment on Facebook!

References:

• Fasano, Elena, et al. "Long-Chain n-3 PUFA against breast and prostate cancer: which are the appropriate doses for intervention studies in animals and humans?." Critical Reviews in Food Science and Nutrition just-accepted (2015): 00-00.
• Köhler, Anton, et al. "Bioavailability of fatty acids from krill oil, krill meal and fish oil in healthy subjects–a randomized, single-dose, cross-over trial." Lipids in Health and Disease 14.1 (2015): 19.
• Salim de Castro, Gabriela, et al. "Dietary Docosahexaenoic Acid and Eicosapentaenoic Acid Influence Liver Triacylglycerol and Insulin Resistance in Rats Fed a High-Fructose Diet." Marine drugs 13.4 (2015): 1864-1881.
• Zugasti Murillo A, Petrina Jáuregui E, Elizondo Armendáriz J. "Exclusively based parenteral fish-oil emulsion (Omegaven(®)) in the treatment of parenteral nutrition associated liver disease: Report of a case." Endocrinol Nutr. (2015): pii: S1575-0922(15)00088-1.