Friday, March 24, 2017

Will palmitic acid give you cancer or fuel metastasis?

Again thanks to Mike Eades for the full text of this paper and to Marco for poking me about it.

Targeting metastasis-initiating cells through the fatty acid receptor CD36

The executive summary: Both feeding a high fat diet to mice then implanting a certain type of cancer cells or feeding palmitic acid to that certain type of cancer cells pre-implantation makes the cancer much more aggressive once implanted. Up-regulating CD36 (described as a fatty acid transporter) has the same effect.

So. The question is: Should we all abandon high fat diets because fat, particularly palmitic acid, appears to be a promoter of aggressive metastasis?

I have thee things I'd just like to discuss.

I suppose the first is CD36. This is long accepted as a fatty acid transporter which facilitates the entry of FFAs in to those cells which express it on their surface. As far as I was aware this was all it did. My bad. The authors do mention that it promotes the uptake of other substances, including oxLDL, as an aside (they didn't look at this) and they do cite Hale's study using glioblastoms, which is rather more explicit about what CD36 really is:

Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression.

"We confirmed oxidized phospholipids, ligands of CD36, were present in GBM [glioblastomas] and found that the proliferation of CSCs [cancer stem cells], but not non-CSCs, increased with exposure to oxidized low-density lipoprotein".

CD36 is a scaveneger receptor which promotes the uptake of all sorts of lipids and oxidised phospholipids. Of course you can't help but think of 13-HODE and all of the other oxidised omega 6 PUFA derivatives which might or might not have been available to be taken up using extra CD36 receptors. This was not the point of the study, the study was aimed at nailing palmitic acid, to which I will return.

The second point relates to the mice fed the high fat diet.

The mice were fed TD.06414, essentially the same as D12492. Scroll to the bottom of the page to see the metabolic effects!

Lard and sucrose/maltodextrin, designed to produce obesity, hyperglycaemia, hyperinsulinaemia and hyperleptinaemia. No one measured the linoleic acid content of the diet so we can assume, very safely, that the approximate 16% of PUFA in the fat suggested by the manufacturer, is a gross under estimate. No one would expect a diet like this to be anything other than cancer promoting. Throwing in a few extra CD36s will make it worse. Is palmitate the problem in these "high fat" fed mice or is it 13-HODE, other PUFA oxidation products, insulin or leptin?

Point three is the one I'm currently interested in.

Pre incubation of the CD36+ cancer cells with 400micromolar unadulterated palmitic acid, for just 48 hours pre-implantation, promotes markedly increased metastasis when they are injected in to the mouse model. No PUFA, no 13-HODE, no hyperinsulinaemia. Just palmitic acid.

This is undoubtedly the money shot for the research group.

Now, what is going on here? From the focus of my blogging at the moment it's clear that palmitic acid is the highest driver of FADH2 input in to the ETC short of stearic acid. What will 48 hours of high level, uncontrolled FADH2 drive do to reverse electron transport (RET) and the structural integrity of complex I?

This is a model. A concentration of 400micromol palmitate, with no other FFAs, just never happens in real life. This model of extreme palmitate induced RET will force mitochondria to disassemble a pathological amount of their complex I. That's pretty obvious from the work of Guarás. The function of complex I is to reduce the NADH:NAD+ ratio and so disassembling complex I will do the inverse and raise NADH per unit NAD+. I went through the relevance of changes in this ratio, specifically for the generation of aggressive metastatic cancer phenotypes, in 2013 when I posted about Hoffer and B3 therapy for cancer prophylaxis and the modern versions using all of the clever stuff we do nowadays.

Of course you have to wonder about point two above; how much of the cancer promoting effect of obesity might be from the pathology of concurrently elevated fatty acids (reducing complex I availability so NAD+ generation) combined with elevated glucose (supplying the maximum amount of NADH) acting via the NADH:NAD+ ratio, never mind 13-HODE etc. A double whammy.

Personally I'm not about to give up eating butter on the basis of this paper. But that's just me I guess.


BTW, will blocking CD36 be an anti-cancer adjunct? Quite possibly, especially if it blocks 13-HODE entry in to the cell. Or even if it blocks FFA entry when people can't be ars*d to avoid hyperglycaemia while ever they have chronically elevated FFAs.


Jill Grow said...

I've read your blog off and on for several years, and I just came back after a several-month break. Anyway, glad to see you're still at it - I learn a lot, vicariously, through your posts. Thanks!

Peter said...

You're very welcome Jill. I have no choice about blogging, it's just something which I do...


karl said...

There are a few papers about CD36 and macrophages and formation of foam-cells.

First - there is a correlation between Linoleic acid consumption and oxLDL levels.
(other dietary bits can also change oxLDL )

So if we drop the failed cholesterol narrative and move to a narrative about what might actually cause CAD - that the damage is actually done by inulin levels or some other growth factor - causing the initial thickening(I think of it as overgrowth) that leads to necrosis.

The body responds to the injury in the normal manner - turns on the immune systems - recruits cholesterol and macrophages. These macrophages apparently are stimulated by oxLDL - the oxLDL looks like a dead or dying bacteria and the oxLDL get engulfed - resulting in foam cells that eventually choke off the artery.

So lowering LDL slightly lowers oxLDL - so you can slow down the growth of foamcells - and slightly lower the rate of heart attacks - at a cost.

Wouldn't a better intervention be to prevent any further initial damage?

If insulin is doing the damage - curing T2D explains a lot - exercise helps reduce insulin and is correlated to help.

My concern is that I think LA looks to be the cause of the T2D pandemic - and thus elevated insulin levels. What started in the early 1960's of consumption of concentrated seed oils - a synthetic food - is still increasing - the 600day half life confounds research studies - and people trying to lose weight.

I wonder if I'm walking around with 5 stents in my chest in part because my mother was an early adopter of cooking with corn-oil?

Anyway - why do cancer cells share these receptors? How does taking in more oxLDL effect the mitochondria?

Kenneth Strain said...

"Anyway - why do cancer cells share these receptors? How does taking in more oxLDL effect the mitochondria?"

Thanks for the Fearon paper! Ca2+ mediated feedback loops are interesting.

Add that to the glutathione-related effects - e.g. among many papers: Paraphrasing from abstract: knockdown experiments against glutathione reductase and glutaredoxin showed that both enzymes are essential for the protection of macrophages against OxLDL. This is then linked directly to apoptosis.

Or on the CD36 topic: (also open access) includes some interesting material e.g. the paragraph starting "GSH is an abundant endogenous antioxidant" and mentions hyperpolarisation and glutathione reductase - indeed the whole paper is full of links among the components under discussion.

karl said...

Re: the glutathione-mediated protection from oxLDL paper.

I've dug into oxLDL quite a bit. My hunch (ungrounded narrative warning) is that the confusion about LDL is due to the confounding of oxLDL which statins don't lower. Thus - someone with lower LDL has lower oxLDL - thus slightly lower CAD. But that does not mean lowering LDL without lowering oxLDL is going to work.

BUT! there are other things one can do to lower oxLDL - don't eat linoleic acid is one.

I have some of my messy notes
here and I wonder if these interventions might have a better effect than the drugs they sell.

So if I buy into the narrative in the above comments - is lowering insulin and oxLDL a better approach than what the medical community is pushing?

Re CD36 -

From someplace in the piles of papers I've read: Some say that CD36 is 'intended' to detect dead or dying bacteria and signal the macrophage to engulf it. That it also stimulates the engulfing of oxLDL is accidental and not important unless oxLDL is high(from eating concentrated seed oils). It seems a narrative worth exploring - more interesting than the failing mantra that we have bad LDL that we evolved to cause heart disease.

Eric said...

Pete: here's an update on the high fat rodent diet containing higher PUFA than it should according to USDA data on lard

Karl, what do you mean by 600 day half life?

From the wikipedia article on 13-Hode

"ALOX15 is fully capable of metabolizing the linoleic acid that is bound to phospholipid[6] or cholesterol[7] to form 13(S)-HpODE-bound phospholipids and cholesterol that are rapidly converted to their corresponding 13(S)-HODE-bound products."

"In an animal model and in humans 13-HODE (primarily esterified to cholesterol, phospholipids, and possibly other lipids) is a dominant component of these plaques."

Do they mean that 13-HODE can be formed from cholesterol and into cholesterol? Or is it more that in can come bound to cholesterol?

Also from this arricle:
"These studies suggest that 13-HODE-producing metabolic pathways,[63] PPARγ,[64][65] CD36,[66] and aP2[67] may be therapeutic targets for treating atherosclerosis-related diseases. Indeed, Statins, which are known to suppress cholesterol synthesis by inhibiting an enzyme in the cholesterol synthesis pathway, 3-hydroxy-3-methyl-glutaryl-CoA reductase HMG-CoA reductase, are widely used to prevent atherosclerosis and atherosclerosis-related diseases. Statins also inhibit PPARγ in human macrophages, vascular endothelial cells, and smooth muscle cells; this action may contribute to their anti-atherogenic effect.[68]"

Does CD36 produce 13-HODE now??

The second half of this paragraph seems to suggest statins will reduce 13-HODE production, if not oxLDL.

karl said...

That is the number from a paper of the half life in adipose tissue. Thus - even if you stop consuming large amounts - the turn-over of FA in and out of adipose tissue would take about 2-years.


In early stuff I wrote I mentioned that this was from only one paper - there are others that are claiming that LA is preferentially retained.

I'm trying to find the original paper - I think it was from one of these:


Draper, H. H., et al., Lipids 21(4), 305-7, 1986, "Metabolism of MDA."

Peter said...

HI Eric,

Sorry I missed this one. They are saying that most of the LA which forms 13-HODE is esterified and that they are oxidised using PPARγ pathways. Statins might block this (the oxidation via PPARγ pathways). So yes, this is the suggestion. My guess is that 13HODE is a growth stimulant to strengthen damaged tissue while consuming a normal human diet (low but not zero PUFA content). Swallowing cardiological advice levels of vegetable oil simply ups the PUFA to the level where 13-HODE makes anything grow, especially cancers. I doubt the esterified vs FFA nature of the PUFA matters much.

Of course they are working from the premise that statins do actually cause some benefits, for which the evidence base is very limited to historical studies run by drug companies themselves.

CD36 is a transport molecule, it deals with what is presented to it.