Wednesday, February 15, 2017

Linoleic acid and Tuberous Sclerosis

TLDR: I don't like linoleic acid much.

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?


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.



Eric said...

Except fish oil, especially if oxidized, seems to promote cancer:

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...


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% ??? 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.


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:

Peter said...

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


William Eden said...

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

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:

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!

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…


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 said...

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


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:

A few more graphs here

Peter said...

Some nice graphs there karl!


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.
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.........


Ellie said...

Thanks, Peter! I'm sorry the reports are so muddled, but at the same time glad to know it's not just me being thick.

NY said...

Longo says in an interview, "I don’t think severe calorie restriction is appropriate since, in addition to many beneficial effects, it also causes severe weight loss. I believe that for now, a high micronourishment, mostly plant-based diet with some fish that allows a BMI of 21–23 and low waist circumference is the ideal diet. "

Sounds like BOO-BOO...

Peter said...

Doesn't seem to help him write a self-consistent paper. Back to the drawing board I think...


SoVeryLippy said...

Pardon me if I digress or propagandize:

Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Studies
Maryam S. Farvid, Ming Ding, An Pan, Qi Sun, Stephanie E. Chiuve, Lyn M. Steffen, Walter C. Willett, Frank B. Hu
Download PDF
Circulation. 2014;CIRCULATIONAHA.114.010236
Originally published August 26, 2014

Conclusions—In prospective observational studies, dietary LA intake is inversely associated with CHD risk in a dose-response manner. These data provide support for current recommendations to replace saturated fat with polyunsaturated fat for primary prevention of CHD.

Robert Andrew Brown said...


Thank you for posting this.

The first paper I looked at "Dietary Fiber and Saturated Fat Intake Associations with Cardiovascular Disease Differ by Sex in the Malmö" "data from 8,139 male and 12,535 female participants (aged 44–73 y) of the Swedish population-based Malmö Diet and Cancer cohort. The participants were without history of CVD and diabetes mellitus, and had reported stable dietary habits in the study questionnaire" said . . .

"Strictly speaking, the SFA-CVD hypothesis is thus not fully testable in this population."

and concluded;

"In this well-defined population, a high fiber intake was associated with lower risk of iCVD, but there were no robust associations between other macronutrients and iCVD risk. Judging from this study, gender-specific nutrient analysis may be preferable in epidemiology."

No mention of linoleic acid in the conclusion, and from a quick skim of data I struggle to see how this cited study supports the contention advanced.

Being Swedish they were very likely not eating fried 'junk' food, and likely active health conscious and not obese - based on a week in Sweden three years ago, chats with locals, attitudes to health, use of supermarkets, general size of people etc.

The Omega Six issue is high intakes of Omega 6 combined with a nutrient depleted, oxidant rich, anti oxidant pathway poor, diet.

If you are a Kung! tribes person eating nose to tail, working for your food, with a high omega 6 intake from nuts (which also contain an uncommon Omega 3) then you will not exhibit western communicable diseases.

So in health conscious higher income people, consequences of high linoleic acid rich nut intake etc. will be very different to those on highly processed Omega 6 linoleic processed vegetable oil rich, industrial foods, including particularly fried foods such as linoleic acid rich industrial chicken.

So population selection will have a massive impact on results.

Is this study an exception or would deeper reading highlight other papers where the results were not as clear the conclusion would suggest.

Robert Andrew Brown said...

^ re my comment above this is the link to a paper referred to in that cited by SoVeryLippy "Dietary Linoleic Acid and Risk of Coronary Heart Disease: A Systematic Review and Meta-Analysis of Prospective Cohort Study"

My final comment above related to the paper cited by Lippy not the Malmo study.

Peter said...

SoVeryLippy and Andrew,

I look at this very simply. Let's assume, at the most basic level, that fructose generates insulin resistance via mtG3Pdh driving reverse electron transport through complex I to shut down insulin signalling (ignoring higher level stuff like uric acid). Linoleic acid fails to generate reduced electron transporting flavoprotein at step one of beta oxidation so cannot, when it needs to, drive ETFdh to reduce the CoQ couple and drive reverse electron transport through complex I, i.e. it fails to generate the correct insulin resistance signal when a saturated fat would do so.

So linoleic acid's pathological insulin sensitivity offsets fructose induced insulin resistance. i.e. linoleic acid delays the onset of fructose induced insulin resistance. At least until adipocytes distend enough that the LA effect becomes one of inappropriate fatty acid release from distended adipocytes.


That's ignoring a whole load of super complier effects and the effects of pharmacological doses of LA as seen in the Sydney and Minnesota studies which had to be buried for decades.

SoVeryLippy said...

Peter, thanks for the comments.

Andrew, yes the results are not clear to me so I keep reading; for example:

Conclusions—High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.

Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality
The Cardiovascular Health Study

Jason H.Y. Wu, Rozenn N. Lemaitre, Irena B. King, Xiaoling Song, Bruce M. Psaty, David S. Siscovick, Dariush Mozaffarian
Download PDF
Circulation. 2014;130:1245-1253
Originally published August 14, 2014

Robert Andrew Brown said...
This comment has been removed by the author.
Robert Andrew Brown said...

HI Peter

I wish I had your understanding of mitochondrial energetics; still struggling I am afraid; more reading required.

Hi SoVeryLippy

I am short on time at the moment but a quick skim on your reference;

They adjusted for everything in sight including Omega 3s - more information required.
"Multivariable hazard ratios of plasma phospholipid linoleic acid with risk of total mortality, evaluated by restricted cubic splines from Cox models adjusted for age, sex, race, enrollment site, education, smoking status, prevalent diabetes mellitus, atrial fibrillation, and hypertension, leisure-time physical activity, body mass index, waist circumference, alcohol use, and plasma phospholipid long-chain n-3 polyunsaturated fatty acid levels."

One measurement at baseline
"Potential limitations should be considered. n-6 PUFA biomarkers were measured once at baseline, and expected variation in circulating levels over time would cause misclassification over follow-up, causing underestimation of true associations. The 13-year within-person correlation for circulating n-6 PUFAs was comparable with such correlations for other major CVD risk factors such as blood pressure.52 These data suggest the single baseline fatty acid measurement provides an adequate, but not perfect, approach to estimate long-term n-6 PUFA concentrations. Residual confounding attributable to imprecisely measured or unmeasured factors cannot be excluded. The association with specific CVD outcomes should be regarded as descriptive because a competing risk model was not used."

Plasma phospholipid was the measure.

"The clear association between estimated dietary and plasma phospholipid LA confirms the role of the latter as a biomarker of consumption. However, our data indicated a nonlinear relationship, with greatest dose–response up to ≈8% energy from LA,"

Non linear above 8% - most eating western diets have higher intakes so what it it telling us about those with higher intakes.

Also probably key and something that is not considered if you have higher oxidative stress level more phospholipids will be oxidised, which will logically reduce measurable linoleic acid; so in phospholipids where accumulation is non linear higher linoliec acid could be a marker for lower oxidative stress viz less membrane HODE; which would explain the results in terms of long term cardiovascular risk, and have interesting implications that the effects of excess linoleic acid and oxdidative stress have very long term potential implications; so an interesting area for blood marker development.

It would be consistent with the problem being oxidised LA my hobby horse See my chapters in Omega-3 Fatty Acids: Keys to Nutritional Health

This study illustrates effect of oxidative stress on blood markers, and diabetes. HODE up Linoleic acid down - are HODEs taking the place of LA in plasma phospholipids - and we measure LA not LA and HODE - so is is high la in phospholipids a maker of low oxidative stress in those on an average western diet rather than a true measure of intake??

I am afraid I have stacks to do so will not be able to come back for a bit, and the above is very much off the cuff thinking, but nonetheless has interesting and widespread potential implications if in any sense grounded.

Many thanks to Peter for this excellent blog.

Robert Andrew Brown said...

^ just for clarification - (I was very tired and firefox was on go slow which did not help - and still have way to much to do - but I woke up thinking about this and driven to clarify.)

Linoeleic acid and its oxidised products are actively stored in and released from adipose tissue, and so will reflect in blood lipids, albeit to differing levels depending on measurement medium.

As Peter points out the time taken to change LA adipose lipid composition in a major way is potentially years. So it is not implausible that adipose stored oxidised and unoxidised LA will have long term metabolic implications,so results of one draw might have significant longer term predictive capacity.

The oxidised products of LA are by a very long way the most prevalent oxylipins in blood.

If oxidised LA content of blood lipids are high logically they are displacing something else likely LA or ALA (and more so in membranes which have 'rules' as to content ratios ceilings etc), so if you measure LA only, particularly in the fasting state, you likely also actually be getting a reflection of the levels of oxidized LA in blood products.

If you measured both LA and 13HODE at the same time, and their ratio, maybe that would be a useful blood marker as it would reflect both oxidative stress and LA intake, and so give a more nuanced reflection of both, particular in those with higher intake already reaching tissue membrane saturation.

The relevance of oxidized LA is highlighted for example here

Re the study referenced by Lippy

Which phospholipds exactly were being measured RBC or wider "Plasma phospholipid fatty acids were measured in 3941 study participants with available blood samples collected and stored from the 1992 to 1993 study visit, which we considered the baseline for this analysis."

My guess there will be some sort of reciprocal relationship between LA and oxidised LA products in phospholipds (and also in wider blood lipids eg LDL content, cholesterol esters etc), which will depend on which ones are considered etc. and that figure will become more relevant once LA membrane tissue level is approaching saturation, and be a better long term measure in the fasting state or from RBC.

If the case, then when measuring LA you are also measuring oxidised content, and particularity so once the membrane or wider capacity is approaching 'saturation', once the membrane response /change with dietary intake diminished, and when you are comparing that figure across groups all with high LA intake the relevance of the ratio of oxidised to unoxidised LA will increase, which will often be the case given many in the west have more than 8% LA in their diet.

There are lots of indications that oxidised plasma / tissue LA product levels as a basket will reflect risk of a wide range of conditions, and the biology says they will and do.

Lots of question raised.

I rumble on about related matter in chapters 27-32 which your library may have.

I have no vested interested in linking it as I get no reward beyond the honor and my free copy.

donny said...

The supplementary for the paper gives the vitamin and mineral mix added to the ketogenic chow, I don't see choline or betaine in the mix. They mention an initial false start, the original ketogenic chow, with cellulose, was killing the animals young. Switching to wheat bran allowed the animals to live long enough to actually do the experiment. Wheat bran isn't a great source of choline, but it's a source. Probably other stuff in there, no way of knowing what might be relevant.

Also, the amino acid profiles are quite different, the ketogenic diet used caseine, the standard diet used something else.

Besides choline, methionine might be relevant.

"Methionine and choline regulate the metabolic phenotype of a ketogenic diet"

In this study, methionine and choline were used to prevent the fatty liver that developed in mice on this ketogenic diet with five percent protein. From what I've read, it seems like methionine promotes fatty liver by increasing free fatty acids--interfering with adipocyte fat-trapping. Maybe not much of a factor with a ketogenic diet, free fatty acids are supposed to be high. The initial ketogenic diet that induced fatty liver had about 2 grams per kilogram methionine, they tripled this to 6 grams per kilogram in this experiment. The kidney cancer experiment had 3 grams per kilogram methionine. I have no idea whether this would have anything to do with elevated oleic acid in the kidneys of these animals

Okay, here's the ingredient/nutrition of the formula they say their ketogenic diet recipe came from;

.274 milligrams of choline per kilogram, that's the amount of choline in the ketogenic diet that caused fatty liver in the choline and methionine supplementation study. The non-ketogenic chow in that study had 2 grams of choline per kilogram. So it's not so much a matter of the ketogenic diet increasing choline requirements, maybe, as it is needing normal amounts of choline. They added 2 grams more choline per kilogram. That cut fat in the liver by roughly half. I do wonder if a different fat source would have made up the difference, but in a purified diet, there's no telling what other factor might be missing.

Samuel William said...

??? Unrelated to post but it seems negative to take in a fuel like high oleic that bypasses desaturase. We wouldn't have had it in evolution before olives and other recent foods like peanuts, relative to saturated, It also feeds yeast as their peroxisomal favorite fuel is oleic acid.(thinking of greeks, wine, yeast fermenting, love of olives, yeasty people)

Angela A Stanton PhD said...

I am reading the original article linked to this and find the following mix of fat for the rats as "ketogenic" fats: "lard, butter, corn oil, casein, wheat bran, a mineral mix, a vitamin mix and dextrose"... note "corn oil" is definitely NOT a ketogenic oil since it is of the bad high PUFA kind vegetable oil that is avoided everywhere.

Keto also doesn't eat wheat bran, and dextrose (glucose)....

while I understand that these are rats and their diets differ but there is where I also say "their diets differ" so when we introduce "equivalents," that reminds me of some of the experiments from the Ancel Keys' era when they made "saturated fat" from hydrogenated fats and milk equivalent from hydrogenated fats... these substitutions just don't work. In the ketogenic diet no one in his or her right mind will reach for corn oil... Also, most lard types are hydrogenated--unless those dear rats received organic high priced lard... therefore, I am having a very hard time accepting the findings.

While they may be right in that long-term deep keto can increase tumor growth, we so far have had the chance to see several long term keto folks (one for over 16 years) and several I have seen for several years who have become cancer free and many who never had cancer just live the keto way and have never developed cancer in that period.

Of course what is 4, 6, 8 months to a rat--given that they only live to be 2 years old I think--and only those on 8 months of deep keto with these fake fats had tumor growth--would mean based on the average human lifespan now of 80 I believe, that people would have had to have been in the deep ketogenic diet for over 30 years--deep means deeper than nutritional ketosis so over 3.8.

I have not heard of such persons yet other than the aboriginals and the natives (like the Native Americans) who used to eat on the keto all their lives in some regions and lived to be of old age and cancer free... but we don't know their ketosis levels... I think inbreeding also matters. There are many factors--also factor #1 is that what they feed rats as rat chow is rat cereal and that is not their normal diet. So we take a bunch of diabetic rats to start with, and with special mutations with inbreeding, and what do we get? Confused data.

That's my 2 cents worth...