Quick Study Analysis: Is It Oxidation or Omega-6 Fats That Is The Problem?

I've recently heard the claim that seeds oils are not the problem, it's just oxidization. Is this correct?

Is is just oxidation? Does Ω-6 really not matter?

I’ve heard this claim made recently (we’ll get to where the claim comes from some other time).

I think it’s a pretty straight-forward question, and serendipity led me to a pretty good demonstration of the truth or falsity of this claim.

Background

All unsaturated fats are subject to oxidation, to some degree. This paper from 1987 looks at how different fats oxidize during heating:

(Yoon, 1987)

You can see that saturated fats (SFA) are the most resistant (this is at 356F, 180C, so they are not burning), monounsaturated fats (MUFA) begin to show susceptibility, and polyunsaturated fats (PUFA) are the most susceptible to oxidation. Close observation will reveal that there’s a further distinction to be made.

The Ω-3 are reduced by ~50% more than the Ω-6 fat. They’re significantly more susceptible to oxidation.

This must be bad, right?

One more bit of background, and then we’ll get into today’s paper.

When PUFAs oxidize, they breakdown into a dizzying array of other molecules, known as oxidation products. Many of them are highly reactive with other molecules, and thus are hard to track in the body.

The best-studied is an Ω-6 oxidation product, 4-HNE. 4-HNE is highly reactive, and highly toxic. It’s toxicity is due to the fact that it can bind to and alter many other molecules in a cell, including proteins, other fats, and DNA. The Ω-3 version of 4-HNE is 4-HHE.

There’s one very notable difference between 4-HNE and 4-HHE:

“In this context, it is noteworthy that HNE, which is a product of omega-6 PUFA oxidation, promotes both membrane association and Aβfibril formation, while 4hydroxy-2-hexenal (HHE), an omega-3-derived analogue of HNE, has neither effect.

“Therefore, the tendency for oxidative stress to induce Aβfibril formation may depend on the relative availability of omega-3 versus omega-6 substrates.” (Furman, 2016)

That looking at a mouse model of Alzheimer’s disease. In heart failure (HF), Stanley et al. note (“n-” is Ω-):

“The main metabolite formed upon peroxidation of n-6 PUFA is 4- hydroxy-2-nonenal (HNE), while n-3 PUFA generate 4-hydoxy-2-hexanal (HHE)…. On the other hand, HHE is less reactive and does not exert the toxic effects observed with HNE.

“This has major implications for the impact of dietary lipids, as a high intake of n-3 PUFA, particularly DHA and EPA, will increase DHA and EPA in mitochondrial membranes in exchange for a decrease in n-6 PUFA (arachidonic acid and linoleic acid). This would result in a decrease in HNE and greater HHE, and thus less cytotoxicity for a given rate of lipid peroxidation.” (Stanley, 2012)

So Ω-6 4-HNE is significantly more toxic and damaging than 4-HHE. Additionally, in an industrial diet context, we have much more Ω-6 than Ω-3 in our diet. The natural proportion may have been 3:1, the industrial proportion is up to 30:1. Oxidation of PUFA is inevitable, and we have very important systems to cope with it. Up to a point.

Human effects of Ω-6 and Ω-3

"Lipid Aldehydes 4-Hydroxynonenal and 4-Hydroxyhexenal Exposure Differentially Impact Lipogenic Pathways in Human Placenta" (Rasool, 2023)

Overly-complicated diagram from (Rasool, 2023)

This is an interesting paper. Omega PUFA fats have a major impact on development during pregnancy, and there has a been a lot of research into the varying fats. For instance, Ω-3 fats are now required to be added to infant formula after it was discovered that deficiency led to neurological deficits.

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Rasool et al. look at the effect of these two oxidized Ω-3 and -6 PUFAs on lipid metabolism, to see the effects on gene expression affecting obesity and development, as we are currently suffering an epidemic of over-fat babies.

Why the placenta?

“Although the placenta plays a key role in mediating the consequences of oxidative stress on the fetus, long-term programming can occur, not only in the feto-placental unit, but in alterations of physiologic systems such as heart and blood vessels, which can ultimately lead to cardiovascular disease in later life.”

(All quotes are from Rasool, 2023, unless otherwise noted.)

“Within the first trimester of pregnancy, a burst of oxidative stress occurs during the establishment of maternal blood flow as part of normal placental development; however, it is proposed that a lack of antioxidant defense may lead to preeclampsia or even early pregnancy failure.”

“Therefore, it is highly important to understand the consequences of placental exposure to oxidative by-products such as 4-HHE and 4-HNE.”

“We measured the effect of increasing the concentrations of two well-known lipid aldehydes, 4-hydroxynonenal [4-HNE] and 4-hydroxyhexenal [4-HHE], on lipid metabolism genes in placental tissue.

“We found that they differentially impact fatty acid synthesis and uptake pathways in human placenta, which may have implications for the efficacy of Ω-3 fatty acid supplementation in environments of oxidative stress.”

“4-HNE increased gene expression associated with lipogenesis and lipid uptake (ACC, FASN, ACAT1, FATP4), and 4-HHE decreased gene expression associated with lipogenesis and lipid uptake (SREBP1, SREBP2, LDLR, SCD1, MFSD2a).

“These results demonstrate that these lipid aldehydes differentially affect expression of placental FA metabolism genes in the human placenta and may have implications for the impact of LCPUFA supplementation in environments of oxidative stress."

This is surprising.

Unlike the examples above, where 4-HNE is harmful and 4-HHE is innocuous, here they seem to have opposite effects. Ω-3 is considered anti-obesity, and Ω-6 pro-obesity, in accordance with this data, and indeed this is what we see in this data even in the oxidative products.

“We have further shown that supplementation with n-3 LCPUFA in the form of fish oil reduces placental lipid storage and lowers expression of lipogenic pathways such as PPAR-γ and its targets in the placentas of patients considered overweight and obese.”

Not just the lipid pathways, but the actual amount of lipid in the placenta.

“We found that randomizing obese women to n-3 supplementation during pregnancy led to a 30% decrease in placental lipid content, consistent with an inhibition of esterification pathways.”

There’s a lot more to this paper, so do read the whole thing. It’s not an ideal model, but as a means of seeing grossly what effects these different fats might have it’s an interesting start.

4-HNE is thought to be a major driver of obesity—in all species. And it seems that correcting Ω-3 deficiency is protective.

Conclusion

Clearly (Rasool, 2023) and the examples given above show that the type of fat oxidized matters more than the fact of oxidation, and even outweighs the susceptibility of the fat to oxidation. These oxidation products have drastically different effects on the body.

The best option is to reduce your consumption of Ω-6 fats as the first step in fixing your diet.

We discussed another paper looking at 4-HNE and obesity in this episode.

P.S.

“I’ve heard this claim made recently (we’ll get to where the claim comes from some other time).”

Link to X post. (Shanahan, 2024)

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References

Furman, R., Murray, I. V. J., Schall, H. E., Liu, Q., Ghiwot, Y., & Axelsen, P. H. (2016). Amyloid Plaque-Associated Oxidative Degradation of Uniformly Radiolabeled Arachidonic Acid. ACS Chemical Neuroscience, 7(3), 367–377. https://doi.org/10.1021/acschemneuro.5b00316

Rasool, A., Mahmoud, T., & O’Tierney-Ginn, P. (2023). Lipid Aldehydes 4-Hydroxynonenal and 4-Hydroxyhexenal Exposure Differentially Impact Lipogenic Pathways in Human Placenta. Biology, 12(4), Article 4. https://doi.org/10.3390/biology12040527

Shanahan, C. (2024, October 17). Harvard dietitian defends seed oils...big surprise. She gets my list of the Hateful Eight correct. But some of the facts she misses here include: I’m not a “social media wellness influencer,” I’m an MD The main toxicity issue has nothing to do with hexane. The reason the https://t.co/1dRL9j0A8x [Post]. X. https://x.com/drcateshanahan/status/1846912572714320159

Stanley, W. C., Dabkowski, E. R., Ribeiro, R. F., & O’Connell, K. A. (2012). Dietary Fat and Heart Failure: Moving from Lipotoxicity to Lipoprotection. Circulation Research, 110(5), 764–776. https://doi.org/10.1161/CIRCRESAHA.111.253104

Yoon, S. H., Kim, S. K., Kim, K. H., Kwon, T. W., & Teah, Y. K. (1987). Evaluation of Physicochemical Changes in Cooking Oil During Heating. Journal of the American Oil Chemists’ Society, 64(6), 870–873. https://doi.org/10.1007/BF0264149-6