Do Polyunsaturated Fats Block Glycolysis?

Definitely in the Liver, Likely in the Breast and Cervix, Probably Everywhere

Attentive readers may have noticed that I have become interested in the idea that polyunsaturated fats might block glycolysis.

This idea explains everything. At the moment I could be convinced that polyunsaturated fats explain the fall of the Roman Empire. (And Macedon before it, bloody olive oil....). Their evil is boundless, unlimited.

Or so it would seem, if polyunsaturated fats actually blocked glycolysis.

And the devil on my left shoulder is saying "Trace more implications! Find more consequences!"

And the angel sitting on my right shoulder is saying "Remember that you are subject to confirmation bias".

And so I think it's time to step back from tracing all the fascinating implications, which basically pin all the diseases of modernity and various other surprising things on polyunsaturated fats, and start wondering if the basic fact is true.

I want to point out, if anyone is taking me seriously because I am using long words, that I do not know what I am talking about, and am very unsure of my interpretation of the following two papers. But here goes.

---

So, Do Polyunsaturated Fats Block Glycolysis?

My prize article, and bedtime reading for the last week or so, has been:

Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation

https://www.jci.org/articles/view/25256

published in 2005

This looks as solid as a rock.

Even the abstract of this paper is intimidatingly complicated, go and read it if you like reading that sort of thing.

I may have misinterpreted the paper (I am learning biochemistry at a furious rate but there is a lot to learn and I am starting from scratch)

But my summary of it is:

---

They're tracing the actual mechanism for a known effect, and they seem to have nailed it.

They tested five different fatty acids

eicosapentanoic acid (C20:5) EPA, an omega-3 polyunsaturated fat

docosahexaenoic acid (C22:6) DHA, an omega-3 polyunsaturated fat

linoleate (C18:2) linoleic acid, omega-6 polyunsaturated

oleate (C18:1) a mono-unsaturated fat

stearate (C18) a saturated fat

and they found the mechanism by which all three polyunsaturated fats block glycolysis (and lipogenesis), and they checked that the saturated and the monounsaturated fat do not do this.

In particular, linoleic acid (C18:2) the principal polyunsaturated fat in seed oilz, blocks glycolysis in liver cells.

---

I think I can take this paper to the bank, it's just one of the things that is known. It's an established fact in cancer research. Cancers love glycolysis, and being able to stop it is obviously a good thing if you're trying to kill off a cancer.

Why it's never occurred to anyone that blocking glycolysis might not be terribly good for the rest of the body is beyond me. Obviously cancer people don't care, they have something important and urgent to do and who cares about the side effects?

But really, the rest of medicine, you should notice when you are recommending people eat something that blocks the main metabolic pathway! There might be consequences.

But this paper is only talking about liver cells.

In particular, one of the effects is to block the enzyme Pyruvate Kinase (which is not a kinase), which catalyses the last step of glycolysis.

And Pyruvate Kinase comes in four forms, one for the liver, one for the red blood cells, one for the muscles and the brain, and one for everything else. And it looks like the mechanism that this beautiful paper traces applies only to the liver form.

So this effect may happen only in the liver. It would still be an extremely bad idea to block glycolysis in the liver, but it's not the all-body systemic catastrophe that blocking glycolysis generally would be.

In particular, it wouldn't straightforwardly explain why ketosis seems to be a panacea for all mental illnesses.

---

Relatedly, experimental subject #001 reports that ex150ish appears to have fixed his severe life-wrecking treatment resistant bipolar disorder that he has been suffering from for decades, and that he’s been feeling fine for nearly four weeks now, and he is looking for a more sustainable way of staying in ketosis permanently.

And also relatedly, the internet seems to be black with anecdotes of keto diets fixing all manner of mental illnesses.

Even psychiatry has noticed, and may even get round to investigating at some point when they have finished doing whatever it is they do all day.

---

The other paper I found, investigating whether and how omega-3 PUFAs block glycolysis in other cells, looks less gears-level, and I frankly don't understand what they did or why, but it's still biochemistry, still a proper experiment that might tell us things, and I take it seriously:

Omega-3 polyunsaturated fatty acid promotes the inhibition of glycolytic enzymes and mTOR signaling by regulating the tumor suppressor LKB1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925660/ (pubmed seems to have slightly garbled the paper, read the original pdf instead or it will be confusing)

published in 2013

---

They're attempting to explain the following fact:

Many studies revealed that mice fed a diet rich in ω3PUFAs display reduced risk of developing cancer while mice fed diets rich in ω6PUFAs have the opposite effect. These studies concluded that the fatty acid composition of a given diet significantly impacts the risk of developing cancer.

So they think that omega-3s suppress cancer but omega-6s cause it.

(You would think omega-6 PUFAs cause cancer would be fairly big news on its own, right??)

They are not testing liver cells, they are testing HeLaS3, which is a line of cervical cancer cells left to us by Henrietta Lacks. And they are also testing MCF-7, which is another immortalised line of cancer cells, this time the descendants of Frances Mallon's breast cancer.

I think that implies that the Pyruvate Kinase in HeLa cells and MCF-7 cells is the standard form which is found everywhere except liver, muscles, brain and red blood cells, and which is probably not subject to the effect in the first paper.

And they tested

arachidonic acid (C20:4) AA, an omega-6 PUFA

docosahexanoic acid (C22:6) DHA, an omega-3 PUFA, also tested in the first paper

And they say that omega-3 PUFAs suppress glycolysis but omega-6 PUFAs don't.

And they think that the mechanism is something to do with LKB-1, which suppresses mTOR, which is a master metabolic regulator.

And they say that they found that the omega-3 acid DHA acts on LKB-1, but the omega-6 AA doesn't. And this is borne out by the Western blot images in the paper.

But it also seems that both AA and DHA reduce the amount of ATP generated by the cells. It's just that DHA does it more.

AA and DHA both reduce the amount of ATP that cancer cells generate

The mechanism they trace out here seems to be that DHA somehow enhances the expression of liver kinase B1 (LKB1), also known as Serine/threonine kinase 11 (STK11)

LKB1/STK11 seems to be a sort of master regulator enzyme, in control of the cell cycle. i.e. it controls whether cells divide or not!

No wonder it's a tumour suppressor.

But it will also suppress any other sort of cell division.

No wonder DHA is an anti-inflammatory. It's literally turning off your immune system by stopping cells replicating. And doubtless causing all sort of other chaos.

Again, if you're trying to treat cancer, you can probably ignore the side effects in favour of killing the cancer.

But messing with LKB1/STK11 is going to be a very very bad idea in general. If you're not trying to kill off a cancer, you do not want anything messing with LKB1/STK11.

---

It looks like the LKB1/STK11 acts on mTOR, the same mechanism of action as Rapamycin.

Rapamycin is an anti-fungal, immunosuppressant, anti-cancer drug, a poison that bacteria make to kill their enemies.

Rapamycin is also supposed to extend life in mammals, which it does by slowing down metabolism.

Perhaps it does extend life in sterile lab conditions. I very much doubt that it extends life if there are diseases around. Because it is turning off your immune system.

And would you really want to live longer if the price was a screwed metabolism?

DHA affects LKB1 which affects mTOR, and glycolysis is blocked.

Rapamycin (also called Sirolimus these days) is a drug used to treat lymphangioleiomyomatosis (LAM), a rare cancer-like disease.

Wiki says: https://en.wikipedia.org/wiki/Sirolimus

The most commonly reported side effects of sirolimus [Rapamycin] treatment of LAM were mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol.

We can probably infer that it causes all the other 'slowed metabolism' effects as well.

Personally, if I did not have an actual active cancer, I would not touch Rapamycin with someone else's bargepole. It is a poison.

---

So, this is what I get out of these two papers:

In the liver, polyunsaturated fats (at least DHA, EPA and linoleic acid) directly block glycolysis through a well understood mechanism.

In the non-liver cancer cells, DHA not only blocks glycolysis, it blocks the entire cell replication cycle, by interfering with the master regulator of the cell cycle, mTOR.

And in two lines of non-liver cancer cells, which are mainly making ATP through glycolysis, both DHA and AA reduce the amount of ATP generated. DHA does this more than AA, but both do it.

So there is some weak evidence here that AA is also blocking glycolysis in these cancer cells, and by extension in all cells.

---

At any rate, these two papers together convince me that I should never touch any sort of polyunsaturated fat ever again.

I would like more papers to read. Can anyone find any more papers that bear on whether polyunsaturated fats block glycolysis? Particularly in the brain.