Wednesday, February 15, 2017

Linoleic acid and Tuberous Sclerosis

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TLDR: I don't like linoleic acid much.
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Tuberous Sclerosis (TS) is a genetic disease which affects mTOR signalling and predisposes to many problems, one of which is early onset kidney tumours. People with TS also have a tendency to suffer from intractable epilepsy so, almost by accident, a number of them have had their tumours closely monitored while eating a deeply ketogenic diet for the epilepsy. Does the KD help slow tumour growth?

No.

To look at this in more detail a group in Poland has used a TS rat model and tried to manage the disease with a KD. This is the study:

Long-term High Fat Ketogenic Diet Promotes Renal Tumor Growth in a Rat Model of Tuberous Sclerosis

It is a very interesting paper. All rats were euthanased at 14 months of age, having spent differing periods of time eating a close derivative of the F3666 ketogenic diet. The longer the rats had spent on this diet, the more aggressive the renal tumour progression was found to be, especially in the rats which ate it for eight months (the longest duration).

Other than this there were some additional interesting findings. Insulin and glucose did (almost) exactly what you would expect:






   


















What is more interesting is that growth hormone increased progressively with duration of time spent on the KD:




















This was noted by the authors and was considered as one of the potential explanations of the increase in tumour burden after 8 months on KD:

"Likewise, it has been shown that the growth hormone activates the MAPK pathway, thus its overproduction in the ketogenic groups may also boost ERK1/2 phosphorylation. We believe that HFKD induced the ERK1/2 activation results as a cumulative effect of the renal oleic acid accumulation and the systemic growth hormone overproduction".

I'm not convinced by the oleic acid idea but no one would argue against identifying elevated growth hormone as a stimulant for tumour growth.



Overall we have progressively falling levels of both glucose and insulin, with a progressively rising growth hormone concentration, over the eight months of a ketogenic diet. I asked myself if there might be an explanation for the nature of these reciprocal changes, before thinking about the tumour growth.

Looking at the insulin-glucose levels we can say that insulin sensitivity increased with time on the ketogenic diet, using the surrogate HOMA score based on the product of insulin and glucose. That's despite a concurrent tripling of GH levels, which should induce insulin resistance.

The obvious concept is that GH was being used to maintain normoglycaemia in a set of rats which were developing progressively increasing (pathological) insulin sensitivity and might, theoretically, have become hypoglycaemic on a very low carbohydrate, very low protein diet. That is, despite having been on a high fat diet, they failed to maintain adequate (ie physiological) insulin resistance to spare glucose for the brain.

Does GH sound like a metabolic solution for the problem of pathologically increasing insulin sensitivity? Pathological insulin sensitivity: Is anyone thinking linoleic acid? Well, I am (now there's a surprise).

The rats were raised on a standard chow of un-stated composition before switching to their KD. It seems a reasonable assumption that the chow was relatively low in fat. Exactly how much linoleic acid was supplied is unknown but other rodent chows I've seen described or analysed tend to provide about 2% of calories as linoleic acid.

The F3666 derived diet looks, depending on the lard composition, to be in the region of 18% omega 6 PUFA. That's high (yes, another rodent study has shown that mice develop NASH on this diet, no surprise there).

The rats were raised initially on a starch based diet so their juvenile adipose tissue would probably be composed of DNL derived saturated and monounsaturated fats, supplemented by a little PUFA from the diet. Transition to F3666, which provides approximately 18% of calories in the form of linoleic acid, generates a metabolism much more dependent on linoleic acid. The younger the rats were when they switched to F3666, the less "normal" adipose tissue they would have had available and the more rapidly they would end up with adipose tissue (and plasma) high in linoleic acid.

Rats on true ketogenic diets do not become obese, even on F3666. So we have slim, omega 6 fed rats. Small adipocytes, no excess FFA release, no insulin sensitivity differential between adipocytes and the rest of the body. There is nothing to over-ride the insulin sensitising effect of linoleic acid. Both adipocytes and the rest of the body become progressively more insulin sensitive mediated through linoleic acid. They don't become obese because insulin stays so low due to the lack of carbohydrate and protein. The excess insulin sensitivity only kicks in gradually because their pre-stored, chow derived adipose tissue provides a supply of physiological FFAs which can act as a buffer to the sensitising effect of 18% linoleic acid for a while.

Glucose falls progressively due to the development of progressively increasing pathological insulin sensitivity, linoleic acid induced. GH may well be a stress response to maintain normoglycaemia under these conditions. The GH may or may not be acting as a tumour promoter, but we cannot ignore the role of linoleic acid in its elevation.


Now the tumours.

We all remember Sauer's rats with their xenografts which grew like wildfire as soon as he starved them? Yes. The tumours grew because they were exposed to linoleic acid released from their adipocytes under starvation. Linoleic acid is a precursor for 13-hydroxyoctadecadienoic acid, better known as 13-HODE. Sauer demonstrated that this was the problem very neatly, at the cost of extensive vivisection. I doubt anyone would be allowed to replicate his work today.

We have no idea of either the linoleic acid or the 13-HODE concentration in the plasma of the F3666 fed TS rats. It would be interesting to know. It might matter...

I particularly think it might matter because F3666 is going to be the "off the shelf" KD that a lot of researchers are going to use.....



At the end of the last post I mentioned that fact that any person who is currently obese through following conventional advice to replace healthy saturated fats with 13-HODE generating linoleic acid is probably carting around kilos of a tumour growth-promoting precursor. In Sauer's study all that was needed to release the linoleic acid was starvation. I would suggest that ketogenic eating might do the same, especially if it is based around saturophobic stupidity (think of kids in the USA with tuberous sclerosis on a "medical" ketogenic diet, or the rats in the above study). There is also anecdote on tinternet that patients of Dr Atkins did fine if they had CVD but those with cancer did badly. I find this plausible. They were obese because they were loaded with linoleic acid and they may well have followed an Atkins diet high in hearthealthypolyunsaturates. That's a good way to grow a cancer.

Sauer found a solution in the form of fish oil to limit tumour growth in his rats, most especially EPA. The very long chain omega 3 PUFAs activate g-protein coupled receptors to reduce lipolysis from adipocytes and activate fatty acid oxidation from the diet. VLC omega-3 fatty acids do not promote excessive insulin sensitivity via the Protons based FADH2:NADH ratio concept because they are specifically oxidised in peroxisomes, not mitochonria. The peroxisomes shorten them to C8 length and then pass this to mitochondria as caprylic acid which has a "palmitate-like" FADH2:NADH ratio of 0.47 which is fine for maintaining physiological insulin resistance.

You do have to wonder whether the benefits of fish/oil in a population loaded with linoleic acid might stem largely from this effect of limiting adipocyte release of that linoleic acid. An interesting idea.

I still find it breathtaking how much the lipid hypothesis of heart disease might have done to injure individual people exposed to its recommendations. Which includes much of the world.

Peter

19 comments:

Eric said...

Except fish oil, especially if oxidized, seems to promote cancer:
http://perfecthealthdiet.com/2011/04/omega-3-fats-angiogenesis-and-cancer-part-i/
http://perfecthealthdiet.com/2011/04/omega-3s-angiogenesis-and-cancer-part-ii/

What do you make of this?

Peter said...

Loading yourself with linoleic acid puts you in a place which is quite hard to get out of. Personally I'm free of trying to make specific recommendations, no Peter Diet here. Read what Sauer did and have a think about it...

Peter

DLS said...

thoughts: Im not a caged rat eating rat chow ad lib. im a free humanb eating large amount of peanuts ( they have extra goodies like... aflotoxins lols)+ other things (what else did the rats eat besides pufa? meat cheese eggs butter? ) only 18% ??? ...at 100gr o day im - doing 37% cals of plutonium, i mean linoleic acid, i think this applies to my dear friends eating ad lib french fries reheated 10 million times w the same oil... no vitamin E, niacin, folate, protein manganese, resveratrol and mono fats there... human studies shows that eating peanuts. lol no. i might get cancer when im 90... now with 39 i atill look like a 30yr old guy. 18 of ifing didnt starve me to dead. still... im going to reduce my peanut intake to ..100gr a day,. edit. peter diet! peter diet! food is info, share the knowledge . heal the world, dont let ancel keys win.

Peter said...

DSL, they ate lard, butter, corn oil, m-vits and just a little casein.

Peter

DLS said...

so shit basically edit Mark Sisson is on board with the peanuts! i feel so relieved (lol) btw the Australian Aboriginals, Kung San from southern Africa, tribes of the American Southwest, and even The Neanderthals ate legumes... maybe the rats need more time? (J/K)

Samuel William said...

Thank you! In reference to the oleic acid I've come across a few papers that show higher oleic acid than normal in cancer cell lines. Example: http://prhsj.rcm.upr.edu/index.php/prhsj/article/view/466/330

Peter said...

Hi San, thanks, hard to see the significance of the oleic acid from my rather limited perspective...

Peter

William Eden said...

Since we're on the subject of LA... I'd be curious to get your take on these papers:

http://ajcn.nutrition.org/content/95/5/1003.long
http://diabetes.diabetesjournals.org/content/early/2014/02/11/db13-1622

Basically, when eating a CIAB diet under hypercaloric conditions, if you substitute SFA for LA you gain less visceral fat and hepatic fat, and maybe you convert more of that excess into lean mass.

Under hypocaloric conditions this differential disappears: https://www.ncbi.nlm.nih.gov/pubmed/27903520

Naively, shouldn't the high LA content be causing the liver not to release its lipoproteins, and store lots of excess triglycerides from all the fructose in the diet? Something seems fishy here... and I'm not talking about omega-3s.

DLS said...

aja! o wait sFA from... palm oil, wtf scientists? is butter to expensive?... edit in the meantime im doing 100+gr of crunchy peanuts or 13g linonium per day. im bored of sugary chocolate. maybe i will make my own choco using regular butter and cream...
mmm this!
https://www.youtube.com/watch?v=JzYVs_G9Knw

Peter said...

Hi William,

The liver fat is a very interesting issue. It all depends on where the liver fat comes from. If we have adipocytes which are hanging on to lipid due to the linoleic acid effect, then removing the supply of linoleate and replacing it with saturated fat would allow loss of FFAs from those adipocytes at a given level of insulin. If nothing is done with those FFAs (as per study protocol, no increased exercise allowed) then they end up in the liver and eventually show up as the small increase in triglycerides noted in Table 1. This is probably what happens in a small percentage of people who go to ketogenic diets and raise their triglycerides.

This liver fat would be enough to induce (more) hepatic insulin resistance with associated appearance of insulin in the peripheral circulation without needing any extra to be secreted. The proinsulin increased by the same amounts in both groups but the systemic insulin increased by 12pmol/l in the sat group vs 2.2pmol/l in the PUFA group. The systemic hyperinsulinaemia would then limit the rate of fat loss.

All study participants were encouraged to weigh themselves weekly “to avoid weight loss”. Implicit in this is that, if they were losing weight, they should eat more. Anyone who is eating more than they feel they need to, i.e. is overfeeding themselves, will maintain or gain weight at the cost of elevated insulin, especially if the extra calories are starch or sugar. We don’t know how it happened but both groups increased their calorie intake. Was this over-eating to maintain a number on the scale or was this spontaneous eating because the diet increased hunger? Was it the same in both groups?

We’ll never know.

Once you start controlling calories, either higher or lower than appetite dictates, you can’t really say anything about the sequestration or liberation of calories secondary to changes in insulin sensitivity and their effect via appetite on bodyweight. Especially if some effort is made to control exercise too.

Liver fat and elevated FFAs are a subject I have a couple of posts planned on but I’ve been a bit side-tracked of recent days. Good old Lisanti and growing cancers on ketones ’n’ lactate…… And Nick Lane has added Loki to Luca and Leca. Loki is interesting as it’s a strange archaeon which is still alive in deep sea hydrogen rich anaerobic mud today. It appears to be derived from the lineage of the archaeon which teamed up with the alpha proteobacterium to give Leca, but didn’t do so itself. It doesn’t appear to have a functional ATP synthase (it has some subunits, which must do something, but it doesn’t appear be complete enough to generate ATP chemiosmotically), it seems to run on soluble hydrogenases and electron bifurcation…

Peter

DLS said...

sooo Visiting my folks.boring 12hr car trip.(not driving) just sitting my ass off. at 9:30 AM ate in 15 secs... 100+ gr of tasty peanuts ( linoooou) then at 10:30... 3 huge boiled eggs , 100+gr pategras cheese, 4 leftover extra lean meats, 4 slices of -sugary?- ham. a bit of chocolate. i was FULL. at 11:00 pm ( home) I pricked my finger using 1 -one thouch ultra- ... 63 mg/dL. oh also weighed myself (docs scale) ... 62 kg ( im 175cm, muscular) mmmm i dont think i have diabetus peter... tomorow i will eat again at 9a large proper meal. ( with peanuts AND almonds) i will be interesting to see the results after 2 hrs.

salix said...

This blog is the only place I can read about "pathological insulin sensitivity". Do you know of any other writer/researcher/individual who regards insulin sensitivity as other than always and forever beneficial?

Stan Bleszynski said...

Hi Peter,

Just noticed your comment: "And Nick Lane has added Loki to Luca and Leca. ..."

I find this to be a fascinating topic, please continue. When I looked into that and did some investigation, I came into a conclusion that a lot more surprises are awaiting us in the domain of the deep underground microbial lifeforms. Regards,
Stan (Heretic)

Peter said...

salix, I don't know. I just look at the data and have to have a name for what I see....

Stan, yes, it's fascinating. At the moment, when I get chance, I'm trying to see what Loki's partial ATP synthase might do. No prokaryote carries genes without using them. The hydrogenases are really interesting from the origin of life basis. Appears to have CODH/ACS if I recall correctly...

Peter

Peter said...

Correction, the 90% of the Loki genome which we have doesn't include CODH/ACS. It will be in the last 10%...

Peter

karl said...

@William Eden

From the first paper:

Downregulation of PCSK9 could be a novel mechanism behind the cholesterol-lowering effects of PUFAs


So they are floating a new narrative -that fish-oil may act as a poor-mans PCSK9 inhibitor..


There is some evidence that high-dose fish oil can reduce Lp(a) ( Associated with rather sever CAD ) - From the papers I've read it appears that PCSK9 inhibitors - unlike statins - reduces Lp(a) and oxLDL (and thus quite likely oxLP(a) ).

Of course we are already awash with ungrounded narratives (some based on a tower of other ungrounded narratives).

One narrative is that long chain O-3 block the production of inflammatory prostaglandins by competing for the metabolic pathway. I'm not so sure it is on solid ground.

Seems there are at least 4 potential negative effects that LA(Linoleic Acid)(Linoleic Acid) does:

- Inappropriate insulin sensitivity in adipose tissue - producing weight gain.(protons)
- Increase in production of protacyclin and thromboxane (what fish oil is supposed to block)
- Production of HNE causing insulin resistance.
- Increases oxLDL

There is an interesting graph at:

http://nut.sourceforge.net/LandsHUFA.jpg

A few more graphs here

Peter said...

Some nice graphs there karl!

Peter

Ellie said...

Hi Peter! I'm a longtime reader of many years but have rarely if ever commented on your blog. However, I thought of you when I came across this study. As a type one diabetic it was very interesting to me. But when I read the full study text in Cell, I couldn't figure out what they actually did.
http://www.cell.com/fulltext/S0092-8674(17)30130-7
The PDF that listed diet components made it seem like the first day had some fat and the last three days were all water, but the graphs in Figure 1 showed that the caloric intake was more consistent than that over the four days of the diet, while the water intake dropped to almost nothing over those four days. Either their graphs are weird or I don't know how to read this information. Guess I won't be running human trials on myself anytime soon!

I'm not by any means demanding that you comment on this, but if you do have the time and inclination, any help you could give me to understanding this FMD they gave the mice would be very much appreciated. I don't like being confused, ha ha!

Peter said...

Ellie, yes, the water in take dropped to zero in part because the "broth" was suspended in Hydrogel so was 95% water by weight and possibly because their blood glucose fell below their renal threshold for glycosuria, which is very high in rats. But, fundamentally, the study results are fully incompatible with their methods. And where, in the methods, is there any reference to the short term starvation graphs? And how do you get ANY food intake during short term starvation? And how do you get about 50% of caloric intake in FMD when they were only offered 10% of normal calories? You have to ask whether there has been a complete mix up of the results from this and a different study!

I was underwhelmed by Longo's first study so certainly didn't waste any time on this one. Sadly, no one will ever get back the hours of their life they have spent on this. Are any of the other results valid? Who knows.........

Peter