Sunday, September 27, 2020

SARS-CoV-2 loves linoleic acid

I haven't posted much about the SARS-CoV-2 virus or COVID-19. Mostly because I don't do politics on the blog and watching the utter incompetence of the UK government has been painful but not unexpected. It's fascinating how by having a completely wrong approach, but doing it so badly, that you can actually end up with a functional approach leading to herd immunity. Sadly it includes appalling rule by decree from Bojo.

On a brighter note, here's a snippet from the end of a fascinating paper looking at the detailed structure of SARS-CoV-2 and its fatty acid binding sites:

Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein

"We hypothesize that LA [linoleic acid] sequestration by SARS-CoV-2 could confer a tissue-independent mechanism by which pathogenic coronavirus infection may drive immune dysregulation and inflammation (35–37). Our findings provide a direct structural link between LA, COVID-19 pathology and the virus itself and suggest that both the LA binding pocket within the S protein and the multi-nodal LA signaling axis, represent excellent therapeutic intervention points against SARS-CoV-2 infections."

I think it was Puddleg who made a very reasonable comment about what, should he find himself in the ITU and someone tried to hook him up to a linoleic acid based intravenous emulsion, he would try to do. I think strangling them was involved.

The virus is looking to help the virus to make more virus, not to kill the host. A good plan to generate anabolic substrate might be activating peroxisomes to get all of that peroxisomal acetyl-CoA and cytoplasmic malonyl-CoA. Like this:

Infection-Induced Peroxisome Biogenesis Is a Metabolic Strategy for Herpesvirus Replication

and if we wanted to be a bit more specific we could take a lesson from Cytomegalovirus:

Cytomegalovirus Infection Triggers the Secretion of the PPARĪ³ Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures

which uses good old 13-HODE derived from linoleic acid as well as 15-HETE from arachidonic acid to get what it needs. Both are potent peroxisome proliferation stimuli and are being used, probably also by most other enveloped viruses, to generate the lipid precursors needed to build more envelope. Hence their love affair with linoleic acid.

The fact that your cardiologist made you obese and diabetic as you become elderly (what ever your age) as a result of promoting hearthealthypolyunsaturates ties in neatly with the probability that linoleic acid might also markedly assisted viral replication in addition to triggering a cytokine storm.

The lipid hypothesis just never stops giving.



Tucker Goodrich said...

I'll add this.

"Does Consumption of Omega-6 Seed Oils Worsen ARDS and COVID-19?"

The answer is a definite "Yes", but it's not quite as simple or obvious as this paper makes it seem.

This isn't the first paper to note that SARS2 has LA in the spike protein (I'll try to post the other paper later...) but the other paper adds the perspective that other viruses also use other fats (like palmitoleic) in a similar manner.

So as much I would love to blame LA for all this, I don't find this paper compelling enough.

Interestingly, arachidonic acid seems to suppress SARS2...

Passthecream said...
This comment has been removed by the author.
cavenewt said...

There are many anecdotal reports that people who go low carb, and who (especially these days) tend to avoid vegetable oils, hardly ever get sick. This seems to, at least partly, explain why.

I haven't had a cold since beginning low carb in 2010, although I didn't completely stop using vegetable oil for several years after that. So it's not the only explanation.

Passthecream said...

Thanks Peter and Tucker for continuing to dig out this stuff and discuss it.

Cavenewt I suspect, not only the basic oily constituents but also the many other strange plant compounds in vegetable/seed oils cause problems. For instance sitosterol and other phytosterols in the soybean oil that's been discussed recently, and traces of gossypol in cottonseed derived oils. Very few foods are simple single things. I believe that about 25 years ago when I became convinced that it was a good idea to consume a lot of hearthealthypolyunsaturates together with a wide range of (supposedly) healthy grains, fruits, nuts and vegetables, many of my subsequent health problems started to build up. It has taken a long time to unwind them by low(ish) carb eating and avoiding those oils and complex plant foods as much as possible.

Eric said...

Cave, so is olive oil a vegetable oil in your book? Very curious because I never liked and used the other veg oils but find it hard to replace olive oil and use it in copious amounts.

On the down side, there can be a copious amount of LA in olive oil, and I probably wouldn't trust mass market Italian oils.

Peter, how do you strangle your caregivers if you need to be in the ICU?

Eric said...

Too lazy to go and read the linked papers. Does the virus sequester LA while floating about in the bloodstream to bolster its envelope or while hijacking the cell metabolism to make more envelopes for new viruses? And how does it screw up the immune response with the help of LA?

Tucker Goodrich said...

"Does the virus sequester LA while floating about in the bloodstream to bolster its envelope or while hijacking the cell metabolism to make more envelopes for new viruses? And how does it screw up the immune response with the help of LA?"

It doesn't appear to do anything uniquely different to other viruses that cause equivalent illness.

cavenewt said...

@Eric "Cave, so is olive oil a vegetable oil in your book? Very curious because I never liked and used the other veg oils but find it hard to replace olive oil and use it in copious amounts."

Technically olive is a fruit, so that would put it more in the camp of avocado oil. In my rudimentary understanding of the chemistry, olive oil, being a monounsaturated, has only one kinky double-bond connection while polyunsaturated fats have multiple ones and saturated fats are straight-line. This makes olive oil sort of an intermediate in terms of saturation. In a lot of studies, olive oil appears to be relatively benign in terms of obesogeneity and tumorogeneity, or in some cases only not as bad as polyunsaturates.

I did a lot of reading on the effect of different fats on cancer as I had a cancer blip over the winter. Especially in light of the fact that it can be difficult to find unadulterated olive oil, I have quit using it completely. There are other ways to make salad dressing. In perhaps an excess of caution, I also stopped eating chicken and pork, although Brad (of croissant diet fame) is now selling pastured, low-PUFA pork, so I might give that a try at some point.

I use coconut oil, cocoa butter, tallow, and butter.

Eric said...

Thanks Cave. I think its the range of 3 to 21% LA in olive oil that makes me nervous:

Will probably have to do some more research to find reliable data on unadultered olive oil.

The fats you mention are the obvious alternatives, but they have serious downsides:
- they are solid at room temperature
- they have a distinct taste that only goes with certain dishes, butter probably being the most flexible in terms of being able to replace olive oil in some dishes

I have even tried high oleic sunflower oil, and it doesn't do anything for me. Maybe if they started selling olive oil aroma?

Chris said...

One of the Ray Peat inspired guys had interesting related post recently. - COVID-19/SARS may be due simply to serum PUFA and its peroxidation. Peat of course hates PUFAs

Totally agree re the crazy UK approach to this virus.

Hope you are doing ok Peter.

Peter said...

Hi Chris, great to hear from you. I have to say that I would be very loathe to dismiss such an idea. The precedent is that acute radiation sickness can be markedly ameliorated by the prior removal of most PUFA from the lab animals’ diet and of course Tucker has an extensive review of the role of PUFA in determining who lives and who dies in the ITU with ARDS. At the moment I’m looking at the opposite, genuine PUFA deficiency and what that does…

Total aside. I love your Pentland Hills (hiked many of them in the past) photographs on Facebook. Makes me miss the Campsie Fells from our time in Glasgow! We’re all fine down here and I’m not expecting any family problems from COVID, the sooner the kids get it the better, then they can visit Nanna without worries about other more elderly in-contact relatives… I’ve told my Clinical Director at work that she can carve as my epitaph, should I pass away with COVID, as “He never remotely expected to get ill with it”. Would serve me right!


Passthecream said...

@ Eric, you can make butter less 'flavourful' by clarifying it ie removing the milk solids by gentle heating although if you do that with budget type butters you won't end up with much butterfat. I went through a period of harvesting my own olives and getting them turned into oil as virgin as it could possibly be, but I really don't like the stuff and when fresh it is completely unpalatable. Very nasty. It has to age for a while.

Tucker Goodrich said...

@Peter: "The precedent is that acute radiation sickness can be markedly ameliorated by the prior removal of most PUFA from the lab animals’ diet..."

OK, do you have a paper showing exactly that?

I've come across the following, and would assume what you claim to be correct, but I would of course love to see an actual demonstration.

1957: "Toxicity of Autoxid. Squalene & Linoleic Acid, and
Simpler Peroxides, in Relation to Toxicity of Radiation"

"Exposure of mice to whole body irradiation (WBI) causes cardiolipin (CL) oxidation and accumulation of its hydrolysis products in small intestine"

Peter said...

Hi Tucker,

I'm pretty sure I have had ownership of such an actual study but it was a very long time ago. Probably from a Ray Peat follower, but that was several hard drives ago and finding stuff under those circumstances is difficult. None-relatedly I've also lost any evidence that over expression of SCD1 in mice is grossly obesogenic (as it should be). I've spent months on and off hunting on Pubmed. I fear the radiation paper may be similar... I'll have a look.


Passthecream said...

Peter, this paper has a similar result from the knockout direction:

Passthecream said...

Maybe the one you're looking for is in their refs?

Tucker Goodrich said...

@Peter: I've lost papers on PubMed too, I know the feeling.

I'll take a look too and see what I can find.

The more I learn the more I appreciate Ray Peat. Every time I read his stuff I realize how much I didn't understand the previous go through, and how much I had missed. Sigh.

Eric said...

Interesting. So should patients receiving radiation therapy get lots of PUFA to have maximum effect on the tumor (peroxide release) at a small overall dose? Or should they avoid PUFA to avoid collateral damage?

Eric said...

Tucker Goodrich said...

@Eric: You're spot on. There's a better paper than this one showing that a ketogenic high n-6 diet combined with radiation is a good treatment for tumors, but I'll have to keep looking for it!

"Ketogenic Diets Enhance Oxidative Stress and Radio-Chemo-Therapy Responses in Lung Cancer Xenografts"

"Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA."

They get extra credit for this observation:

"Our model uses a soy based fatty acid composition which is relatively high in oleic (18:1), linoleic (18:2), and linolenic (18:3) acids with standard mouse chow as the control. Because unsaturated fatty acids are substrates for lipid peroxidation that may govern the formation of aldehydes such as 4HNE, this fatty acid composition may be influencing our results."

Eric said...

Tucker, I'll be looking forward to the other paper, even if this seems interesting enough.

Ideally, you'd want to sneak PUFA into cancerous cells while flooding everything else with SFA. But how to do it? Are cancerous cells much interested in anything other than glucose?

Tucker Goodrich said...

I went and looked, it turns out this was the paper I was thinking of. At least they recognize the confounder, even though I wish they would connect that it was n-6 and not "ketogenic" per se that was giving these results...

cavenewt said...

Well. I spent last December getting radiation, and focusing on ketosis and elimination of PUFAs.

I guess I'm doomed.


Peter said...

cave, no time for more but I would go for the role of stearate as a source of ROS to drive apoptosis of cancer cells rather than omega 6s to selectively drive ROS damage within a radiation field... I think you have this paper?

I would guess breaking LA to give 13-HODE might not be so good even within a radiation beam.


cavenewt said...

Hey Peter, thanks for the reassurance! I do find it hard to believe that it's preferable to trash the rest of your body just to attack one tumor. But of course it depends on the tumor. As it was, I got myself into a clinical trial so as to receive less than the standard amount of radiation. The standard treatment runs the risk of causing permanent radiation damage to lungs and heart. No thanks.

I can't help wondering how long it will take for researchers to absorb the idea that different fats behave differently and at least try to take those things into account in their experimental designs. That one comment Tucker pointed out was encouraging, but from our superiorly enlightened perspective didn't go nearly far enough.

cavenewt said...

Forgot to answer your question. Yes I totally have that article. It was much appreciated. That got me using cocoa butter and cacao nibs.

I've so successfully internalized the evil of HODE that it's led to conflicted feelings about the character Hodor in Game of Thrones—he's supposed to be a good guy, after all.

Tucker Goodrich said...

@cavenewt: "I can't help wondering how long it will take for researchers to absorb the idea that different fats behave differently and at least try to take those things into account in their experimental designs."

Don't hold your breath.

tldr: The answer is "yes".

"Does Science Advance One Funeral at a Time?"

Passthecream said...

Cavenewt, Eric - I wonder how many chemotherapy formulations contain some type of pufa or have them in their associated protocols such that the effect of the lipid is part of their 'benign' toxic action?

cavenewt said...

Pass—thankfully, for myself it's not an issue. I'm only taking an aromatase inhibitor which suppresses estrogen (which is worrisome enough). I go to the prestigious Huntsman Cancer Center in Salt Lake City where they're totally mainstream about things like low fat diets, and have absolutely no interest in approaching cancer treatment metabolically.

Peter said...

Tucker, my hunting for PUFA/radiation comes up in the next post. I'm just reading it through yet again, wondering what I might have missed......