Thursday, March 16, 2017

Stearic acid, FADH2, complex I and cancer

Just a quick aside:

George cited this study in the comments of the last but one post:

Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

While I think it is possible that metformin might inhibit mtG3Pdh at levels below those which inhibit complex I, the complex I effect may well still be equally real.

He goes on to say:

"Remodelling the ETC - I like that. The idea of the ETC as a modular assembly that will be reconfigured as the substrate balance shifts. Directly by the effects of the substrates on its outputs".

Remodelling the ETC using RET from FADH2 inputs might be antineoplastic too ie, less complex I would then be available for whatever ox phos the cancer is capable of…

Now: What normal food will generate the highest FADH2 input to the ETC per unit NADH? Correct, stearic acid will.

So what does stearic acid do to breast cancer cells in culture?

Stearate preferentially induces apoptosis in human breast cancer cells

Does it work in a rodent model?

Dietary stearate reduces human breast cancer metastasis burden in athymic nude mice

Do people with breast cancer have low stearate levels in their cell membranes?

Erythrocyte membrane fatty acid composition in cancer patients

Does stearate-driven RET down regulate complex I availability in cancer cells which are partially dependent of glucose derived NADH oxidation via said complex I? And so kill them?




Tucker Goodrich said...

"Erythrocyte Membrane Fatty Acids and Subsequent Breast Cancer: a Prospective Italian Study"

"Results: Oleic (highest versus lowest tertile of percentage of total fatty acids, odds ratio [OR] = 2.79; 95% confidence interval [CI] = 1.24 to 6.28) and monounsaturated fatty acids (highest to lowest tertile, OR = 5.21; 95% CI = 1.95 to 13.91) were positively associated with breast cancer risk. The SI (highest to lowest tertile, OR = 0.29; 95% CI = 0.13 to 0.64) was inversely associated with breast cancer risk. The analysis suggested an inverse association between total polyunsaturated fatty acids and breast cancer risk, but individual polyunsaturated fatty acids behaved differently. There was no association between saturated fatty acids and breast cancer risk."

Tucker Goodrich said...

This throws a wrench in it... From the paper above:

"A diet high in MUFAs is probably one determinant—but not the major one—of erythrocyte membrane MUFAs (8,29,30), which are extensively synthesized in the body (7,31). Therefore, the association of high levels of membrane oleic acid and low SI with increased breast cancer risk might be related to factors other than diet. Most oleic acid in mammalian tissue is derived from the saturated stearic acid residue (7,32). This key conversion is controlled by the enzyme Δ9-d...

"Δ9-d is activated by carbohydrate administration (37), and it is well established that insulin enhances Δ9-d activity (39–44). The possible relationships among dietary carbohydrate, insulin resistance, and breast cancer risk is receiving increasing attention."

Peter said...

Tucker, I was looking at "Our research study demonstrated a lower level of stearic acid and an increased content of oleic acid in RBC of cancer patients in comparison with control and non-cancer patients." I agree you could view this differential as indicative of insulin action and so of carbohydrate intake. Or, conversely, as differential intake, part of the war on saturated fat. Just epidemiology, rodents and cell cultures laced with confirmation bias........


Tucker Goodrich said...

"Just epidemiology, rodents and cell cultures laced with confirmation bias........"

Agree 100%. Looked cool at first, though!

I also don't think looking at RBC for guide to specific tissue levels works very well. AA is pretty tightly controlled in serum, for instance, but tissue levels can vary widely.

invent-a-name said...

Hi. This isn't exactly related to any one entry on your blog, but I thought you'd be interested to read this study (if you haven't already), and I'd be interested to hear your thoughts on it:

They used C57BL/6N mice, which I think (though I'm not sure) are slightly distinct from the mutated ones mentioned in your previous post. Before subjecting them to differing diets, they maintained the mice on uniform puritan diets providing two-thirds of calories from uncooked cornstarch (chow), and injected them all with a carcinogen called diethylnitrosamine (DEN).

After carcinogen exposure, they divided the mice into 5 groups: (1) same chow-based diet as before; (2) a high-sugar diet with sucrose (31% of total calories) and fructose (15% of total calories) replacing cornstarch; (3) a "western" diet with lard (23% of calories) and sucrose (21% of calories) replacing cornstarch; (4) a "western" diet with coconut oil (23% of calories) and sucrose (21% of calories) replacing cornstarch; (5) a ketogenic diet with 71% of calories from lard, 16% from casein and 6% from safflower oil (the other 7% of calories aren't mentioned and may or may not have been from cornstarch). All the diets contained 16-18% casein, 3-6% safflower oil and (with the probable exception of the ketogenic one) 5-6% wheat bran.

All the diets were given ad libitum. All the groups given some fat in replacement of cornstarch thought that their food was tastier and accumulated body fat, whereas the ones given sucrose and fructose tended to have less body fat overall (even though their food presumably tasted nicer than the cornstarch control), but the lean high-sugar mice still accumulated lots of liver fat and showed strong tumour growth, whereas the ketogenic mice (despite being fattest overall and despite a not-insignificant quantity of linoleic acid from safflower oil and lard) didn't accumulate any liver fat and showed minimal tumour growth. Post-prandial insulin seemed to be the best correlate of tumour growth.

However, the "western" diets with fat and sucrose jointly replacing cornstarch fared about as badly as the fructose/sucrose diet, with the very greatest degree of cancer growth coming from the diet co-enriched with coconut oil (with all its lovely lipogenic MCTGs) and sucrose.

Peter said...

I’ve had a quick look at the study and it’s interesting in that the ketogenic diet isn’t ketogenic at all. Putting 16-18% protein in to the diet of a mouse will simply not induce ketosis. You can search the document for “ketones”, BHB, AcAc etc and these weren’t measured. So whatever the diet effect, it wasn’t ketosis induced…

So high fat, low carbohydrate, lard based diet is no worse than chow for facilitating tumour growth. All DEN treated mice appear to have developed tumours, just the chow and “KD” were similar and better than the fructose supplying diets.

Perhaps avoiding a) DEN and b) fructose might well be a good idea……….

BTW I think all Bl/6 six mice lack SCAF1 from the phraseology in the CoQ as a metabolic control paper and its references. They cope but they’re not normal.

All the best