Guest Post: Prof. Hulbert's Response to "Beneficial Effects of Linoleic Acid on Cardiometabolic Health: an Update"
tldr; A response to the recent OmegaQuant paper on how seed oils are good for cardiovascular disease. A guest post by Prof. A.J. Hulbert, author of "Omega Balance."
Introduction
I recently came across this paper:
“Beneficial Effects of Linoleic Acid on Cardiometabolic Health: An Update” (Jackson, 2024, not paywalled.)
They wrote: “All in all, the use of the n-6 to n-3 PUFA ratio, dietary or otherwise, should be discontinued.” I thought that would be of interest to Prof. Hulbert, and sent it along to him.
Why would we (or you) care about this paper?
The five authors, in order, are:
Kristina H. Jackson
William S. Harris
Martha A. Belury
Penny M. Kris-Etherton
Philip C. Calder
Dr. Harris is a preeminent researcher of Ω-3 fats, was first author of the American Heart Association’s 2007 paper, “Omega-6 Fatty Acids and Risk for Cardiovascular Disease: A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention” (Harris, 2007), and is the founder of the OmegaQuant company, which sells a well-regarded testing service for polyunsaturated fats. He was also a co-author of the International Society for the Study of Fatty Acids and Lipids statement, “Intake of PUFA in Healthy Adults” (ISSFAL, 2004).
Dr. Kris-Etherton was a co-author of (Harris, 2007), and of the AHA’s 2017 follow-up: “Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association” (Sacks, 2017).
Dr. Jackson is Dr. Harris’ daughter, and is director of research for OmegaQuant.
Drs. Belury and Calder are both involved in research involving polyunsaturated fats.
Dr. Calder wrote a commentary on Harris 2007, titled, “The American Heart Association Advisory on n-6 Fatty Acids: Evidence Based or Biased Evidence?” (Calder, 2010).
So one can see this as a follow-up, of sorts, to the AHA’s prior work in this area. Having Calder join as senior (last) author is notable.
(I’ll do my own response to this paper later, and discuss their backgrounds a bit further there.)
Prof. Hulbert published Omega Balance (Hulbert, 2023) last year, and we interviewed him:
Hulbert’s book is a review of the effects of polyunsaturated fats on human and animal health.
The Omega Balance is Ω-3 fats as a percentage of total polyunsaturated fat. The n-6:n-3 (or Ω-6:Ω-3) ratio expresses the same information (the amount of the two fats in the diet) in a different format. So while I figured Prof. Hulbert would agree with their point regarding the ratio specifically; their larger argument, that the proportions of the two fats aren’t important, is something he would disagree with.
So Prof. Hulbert wrote this email to Dr. Jackson, and she responded suggesting he submit it as a letter to the editor of the journal. Prof. Hulbert declined to do so, and had already agreed to my request that we publish it here, where hopefully it will get a larger audience.
I present it in full, unedited except for minor typographical corrections; for readability, to add citations—any errors are mine, and to reformat his emphases. He highlighted some sentences in red, those are bold & italic here. The attachments are hosted in my Drive account, hopefully those will be accessible to all.
26 September 2024
Subject: Comments on your recent paper in Lipids in Health and Disease
Dear Kristina,
Your paper "Beneficial effects of linoleic acid on cardiometabolic health: an update" (Lipids in Health and Disease 23:296, 2024) was recently brought to my attention. The last section of this paper is titled "Is there any utility to the n-6 to n-3 PUFA ratio?" and it is this section that has provoked my email to you.
Ironically, I agree with your conclusion "All in all, the use of the n-6 to n-3 PUFA ratio, dietary or otherwise, should be discontinued" but not for the reasons you suggest. Although conceptually popular with a general audience, mathematical literacy shows ratios have a very non-linear distribution and thus can sometimes be dangerous, if not considered properly. This is because the values of a ratio of any two things ranges from "0" to "∞" and the midpoint (when both things are present in equal amounts) of this range is "1". This means they cannot be averaged or easily statistically analysed (e.g. used in regression analyses). This may seem a pedantic quibble but it is better to use a proportion when considering the balance between two things (e.g. n-6 as a percentage of total PUFA). Elsewhere, I have argued that n-3 as a percentage of total PUFA ("Omega Balance") is a better quantitative indicator of the balance between n-6 and n-3 than is the "n-6 to n-3 ratio" (see attachment #1 ....p17 from Omega Balance book).
In the following text, I will often use the word 'omega balance' to refer to 'n-6 to n-3 ratio' (a high 'n-6 to n-3 ratio' is analogous to a low 'omega balance')
However this is not my main concern. It is your dismissal of consideration of the balance between n-6 and n-3 in the diet when considering the effects of the two essential types of fats. It seems to me that you have set up a series of straw-man assumptions to come to this conclusion. My answer to your question is "yes there is much utility in considering the balance between omega-3 and omega-6 in the diet".
To ascribe your first two assumptions:
(1) all n-6 PUFAs are “bad”, that all n-3 PUFAs are “good” and that all n-3 PUFAs oppose the action of all n-6 PUFAs;
(2) all n-6 PUFAs are functionally equivalent, as are all n-3 PUFAs;
to investigators analysing the influence of diet omega balance on health and metabolism is wrong, simplistic and condescending to serious investigators.
Assumption (3): all ways of changing the ratio are equivalent,
To recognize that there are many ways to change the ratio does not negate the fact that diet omega balance may influence metabolic health.
I will deal with assumption (4) shortly.
Maybe we can agree on some assumptions?
(a) that omega-3 and omega-6 are separate classes of essential fats (they cannot substitute for each nor be interconverted), and
(b) that they are converted to other individual omega-3 and omega-6 in the body and compete with each other for these modifications by desaturase enzymes, and
(c) they also compete with each other for incorporation into membrane lipids via the activity of acyltransferase enzymes (from Bill Lands’ research).
Assumption (b) is often described in various reviews, while assumption (c) is rarely considered in such reviews, but in my own opinion, is the most significant competition between these two types of essential fats, and in this particular competition the individual omega-3 and omega-6 fatty acids will be significant (i.e. not all omega-3 nor all omega-6 will compete identically).
For me, one of the problems with interpreting the results of diet experiments confined to humans is that blood parameters are often the only parameters measured. Plasma values need not be indicative of tissues levels and red blood cells are not necessarily typical cells. The fact that in some previous articles criticizing the use of the n-6:n-3 ratio, it is pointed out that the ratio differs significantly between different lipid pools in the blood just describes the situation that metabolic pathways treat different omega-3 and omega-6 fats differently and it doesn't negate consideration of the balance between these types of essential fats in the diet.
Another problem with human studies is that many investigators do not appreciate that metabolic "time" is different in different species. For example, a 6-month diet experiment in humans is equivalent to a 4-week diet experiment in a rat (a 7-week diet experiment in a human is equivalent to a 1-week experiment in a rat). That there are no significant changes in many human diet experiments is because they are often performed for only relatively short periods. This was manifest right from the beginnings of essential fatty acid research. The early proposal that, unlike rats, PUFA were NOT essential in humans was due to the fact that the 6-month human experiment was not long enough for deficiency symptoms to appear (George and Mildred Burr showed that it took 15 weeks for rats to show deficiency symptoms (equivalent to ~2yr in humans) [(Burr, 1930)].
Assumption (4) that higher LA [linoleic acid] intakes lead to higher ARA [arachidonic acid] levels.
What ARA levels are we talking about? It is the ARA content of membrane lipids that is the pool we should be concerned with, as it is this pool that is the source of various second messengers (both eicosanoids and endocannabinoids) and I will assert that experiments in rats show that although greater dietary omega-6 (LA) results in greater membrane ARA content that omega balance (ALA [alpha-linolenic acid] as % total PUFA) is a much stronger determinant. In this rat experiment (see attachment #2), although variation in diet LA content could predict on average 37% of the variation in membrane ARA content (average of brain, heart, liver & skeletal muscle), in comparison however, diet omega balance (ALA as percent of total PUFA) could predict on average 90% of the variation in membrane ARA content.
A much better predictor.
Although these results were for a diet with a fat content as 25% energy, it is also true for very low-fat diets (<1% energy). When we analysed data [(Abbott, 2011)] from Mohrhauer & Holman’s 1963 papers for liver, heart and brain we found almost identical values (see attachment #3) [(Mohrhauer, 1963a, 1963b, 1963c)].
My conclusion from these studies and analyses is that diet omega balance (analogous to diet n-6:n-3 ratio) is extremely important in determining membrane ARA content.... indeed much more important than diet LA content.
Additionally, two brief comments about the earlier part of your paper.
I note that although you cite the observational studies relating increased diet omega-6 with better cardiovascular health you do not cite or discuss the results of the Sydney Diet Heart Study [(Woodhill, 1986)]. A human experiment where diet omega-6 intake was increased over a considerable time (but with no change in omega-3 intake) resulted in worse cardiovascular health (an increased mortality) was surely worthy of discussion. Along with many other scientist, my opinion is that experimental evidence should be considered more strongly than observational correlations.
Secondly, there are a series of experiments from 30-40 years ago that clearly demonstrate that insulin-resistance is strongly related to diet omega balance. Storlien first showed that rats fed a high omega-6 fat diet were insulin-resistant but not insulin-resistant when he replaced some of the omega-6 with omega-3. Furthermore, a series of later diet experiments by Storlien and others showed that it was not the presence of omega-3 per se but it was the relative balance of omega-3 and omega-6 in the diet that determined whether tissues are responsive to insulin. [(Storlien, 1986 and 1991)] Later experiments on a range of human subjects showed similar results. Insulin-sensitive humans had muscle membrane fats with an omega-balance above ~15%. Humans with muscle omega balance values less than ~15% were increasingly insulin-resistant. Those and other studies are evidence that type 2 diabetes is strongly influenced by the balance in the diet between omega-6 and omega-3 essential fats (see appropriate section in Omega Balance book).
Finally, although there are no definitive suggestions as to what the balance between omega-6 and omega-3 in the diet should be, of course one can be calculated from the ISSFAL recommendations of an adequate intake of n-6 and a healthy intake of ALA and the suggested minimum intake of EPA & DHA. This proposes a diet omega balance of about 30%, well above the median intake in the U.S. (and Australia) of ~9%.
Please feel free to share these comments with your other authors and also to respond to any of them. I obviously believe your dismissal of the importance of the n-6 to n-3 ratio of the diet is misguided and have described in some detail why I regard it as very important, in a recent book published by Johns Hopkins Press (https://www.press.jhu.edu/books/title/12823/omega-balance)
Yours sincerely,
Tony Hulbert
A. J. Hulbert PhD DSc
Emeritus Professor
University of Wollongong
Conclusion
My thanks to Prof. Hulbert for allowing me to reproduce this email here.
If you have any questions or thoughts for Prof. Hulbert, Dr. Jackson or her co-authors, or myself, please let me know in the comments.
Prof. Hulbert will be forwarding this post along.
(Normally a post like this would be paid-subscriber only, this is free for all.)
References
Abbott, S. (2011). The Influence of Dietary Fatty Acid Profile on Membrane Fatty Acid Composition in the Rat and Its Metabolic Implications [Doctor of Philosophy, University of Wollongong]. University of Wollongong Thesis Collection 1954-2016. https://ro.uow.edu.au/theses/3260
Abbott, S. K., Else, P. L., Atkins, T. A., & Hulbert, A. J. (2012). Fatty Acid Composition of Membrane Bilayers: Importance of Diet Polyunsaturated Fat Balance. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1818(5), 1309–1317. https://doi.org/10.1016/j.bbamem.2012.01.011
Burr, G. O., & Burr, M. M. (1930). On the Nature and Rôle of the Fatty Acids Essential in Nutrition. Journal of Biological Chemistry, 86(2), 587–621. https://doi.org/10.1016/S0021-9258(20)78929-5
Calder, P. C. (2010). The American Heart Association Advisory on n-6 Fatty Acids: Evidence Based or Biased Evidence? British Journal of Nutrition, 104(11), 1575–1576. https://doi.org/10.1017/S0007114510004253
Harris, W. S., Mozaffarian, D., Rimm, E., Kris-Etherton, P. M., Rudel, L. L., Appel, L. J., Engler, M. M., Engler, M. B., & Sacks, F. (2009). Omega-6 Fatty Acids and Risk for Cardiovascular Disease: A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation, 119(6), 902–907. https://doi.org/10.1161/CIRCULATIONAHA.108.191627
Hulbert, A. J. (2021). The Under-Appreciated Fats of Life: The Two Types of Polyunsaturated Fats. Journal of Experimental Biology, 224(8), jeb232538. https://doi.org/10.1242/jeb.232538
Hulbert, A. J. (2023). Omega Balance: Nutritional Power for a Happier, Healthier Life. Johns Hopkins University Press. https://amzn.to/3uC2igY
International Society for the Study of Fatty Acids and Lipids, Cunnane, S. C., Drevon, C. A., Harris, W. S., Sinclair, A. J., & Spector, A. A. (2004, June 8). Statement 3: Intake of PUFA in Healthy Adults. https://www.issfal.org/statement-3
Jackson, K. H., Harris, W. S., Belury, M. A., Kris-Etherton, P. M., & Calder, P. C. (2024). Beneficial Effects of Linoleic Acid on Cardiometabolic Health: An Update. Lipids in Health and Disease, 23(1), 296. https://doi.org/10.1186/s12944-024-02246-2
Mohrhauer, H., & Holman, R. T. (1963a). Alteration of the Fatty Acid Composition of Brain Lipids by Varying Levels of Dietary Essential Fatty Acids. Journal of Neurochemistry, 10(7), 523–530. https://doi.org/10.1111/j.1471-4159.1963.tb09855.x
Mohrhauer, H., & Holman, R. T. (1963b). The Effect of Dose Level of Essential Fatty Acids Upon Fatty Acid Composition of the Rat Liver. Journal of Lipid Research, 4(2), 151–159. https://doi.org/10.1016/S0022-2275(20)40341-4
Mohrhauer, H., & Holman, R. T. (1963c). Effect of Linolenic Acid Upon the Metabolism of Linoleic Acid. The Journal of Nutrition, 81(1), 67–74. https://doi.org/10.1093/jn/81.1.67
Sacks, F. M., Lichtenstein, A. H., Wu, J. H. Y., Appel, L. J., Creager Mark, M. A., Kris-Etherton, P. M., Miller, M., Rimm, E. B., Rudel, L. L., Robinson, J. G., Stone, N. J., Van Horn, L. V., & on behalf of the American Heart Association. (2017). Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association. Circulation, 136(3), e1–e23. https://doi.org/10.1161/CIR.0000000000000510
Storlien, L. H., James, D. E., Burleigh, K. M., Chisholm, D. J., & Kraegen, E. W. (1986). Fat Feeding Causes Widespread in Vivo Insulin Resistance, Decreased Energy Expenditure, and Obesity in Rats. American Journal of Physiology-Endocrinology and Metabolism, 251(5), E576–E583. https://doi.org/10.1152/ajpendo.1986.251.5.E576
Storlien, L. H., Jenkins, A. B., Chisholm, D. J., Pascoe, W. S., Khouri, S., & Kraegen, E. W. (1991). Influence of Dietary Fat Composition on Development of Insulin Resistance in Rats: Relationship to Muscle Triglyceride and ω-3 Fatty Acids in Muscle Phospholipid. Diabetes, 40(2), 280–289. https://doi.org/10.2337/diab.40.2.280
Woodhill, J. M., Palmer, A. J., Leelarthaepin, B., McGilchrist, C., & Blacket, R. B. (1978). Low Fat, Low Cholesterol Diet in Secondary Prevention of Coronary Heart Disease. Advances in Experimental Medicine and Biology, 109, 317–330. https://doi.org/10.1007/978-1-4684-0967-3_18