Hyperlipid by Petro Dobromylskyj
26 January 2020You need to get calories from somewhere, should it be from carbohydrate or fat?
Dr Malcolm Kendrik has a very interesting post over on his blog relating to coronary artery calcium scoring. I think it is fair to say that he is not in favour of the test.
My ears pricked up (metaphorically) when he mentioned myositis ossificans, about which he comments "This does not end well".
I have spent some time in the past thinking about pathological arterial calcification, as applied to the aorta of of patients with familial hypercholesterolaemia. Bear in mind that the dietary advice for patients with FH is about the worst you could possibly imagine and, of course, has no evidence base. My thoughts and assorted links are in an old blog post here. At the time I had never heard of Sci-hub so was unable to access this rather neat diagram of the mechanism of action of insulin, Pi and pyrophosphate:
Back to pathological soft tissue calcification. Clearly the obvious question about myositis ossificans has to be to ask whether it is in part driven by hyperinsulinaemia/hyperglycaemia or both.
As far as I am aware this is not a question which had been asked. It is simply genetic and that's it.
However, a similar question has already been answered in relationship to a serious generalised soft tissue mineralisation condition described as "calcinosis and scleroderma", back in a publication from 1932 (apologies to the person who tweeted the link, I didn't note their name to acknowledge. And twitter is ephemeral). That is too long ago to be listed on Pubmed so if you would like to read it you can go and ask Elsevier how much they would like to charge you for a peek in to the past or you can go to that awful place that none of use ever use to download any paper for free.
CALCINOSIS AND SCLERODERMA: TREATMENT OF A CASE BY USE OF THE KETOGENIC DIET
"Calcinosis and scleroderm" looks to be one of a family of soft tissue calcification diseases. The case report from 1932 describes the complete remission of this extremely unpleasant condition in a child following a period of time on ketogenic diet of the type used at the start of the last century, before dieticians were invented/summoned from Hades.
Did the ketogenic diet resolve this child's pathological calcification by suppressing insulin levels, glucose levels or both? Does it work by lowering alkaline phosphatase production by cells in/around inflammatory lesions? Or by some other mechanism?
Would it do the same for pathological arterial calcification? Given a tool like the ketogenic diet, perhaps there is some logic to CAC testing?
Unless you feel that tissue calcification is an appropriate part of healing until it gets to scleroderma levels...
I quite enjoyed Barja's review
The Cell Ageing Regulatory System (CARS)
but found this section a little uncomfortable:
Hmmmmmm. Plant based, healthy fruit and vegetables, bad animal fats. Not my sort of outlook really.
In another of his publications here
Highly resistant macromolecular components and low rate of
generation of endogenous damage: Two key traits of longevity
there is this comment
"It was also found that 6–7 weeks of dietary restriction are enough to decrease MitROS production and 8-oxodG in mtDNA and nDNA in rat liver (Gredilla et al., 2001a )".
Gredialla et al (incl Barja) 2001a is
Effect of short-term caloric restriction on H2O2 production and oxidative DNA damage in rat liver mitochondria and location of the free radical source
Here they found, by eyeball, an approximately 50% reduction of in 8-oxodG in mitochondrial DNA after those six weeks of quite severe caloric restriction:
Now let's compare this with the degree of damage reduction (this time using the term 8-OHdG as the marker rather than oxo-8dG, which appears to be the same thing).
Here's the change in mtDNA damage marker in brain mitochondria using F3666, one of the worst ketogenic diets around:
Just by eyeball I make the drop in mtDNA damage out to be greater than 50% by two days and something like 75% by three weeks. On ad-lib food consumption. No hunger.
Considering that F3666 does not extend longevity in mice (it doesn't shorten lifespan either, despite causing liver damage and it does actually improve health during ageing in rodents) this does, for me, slightly knock some of Barjas core ideas.
Sad but true.
Better post this one while I have a few minutes. I picked it up while looking for refs for Gustavo Barja's epic The Cell Ageing Regulatory System (CARS) in which longevity is tied to the Double Bond Index of the mitochondrial inner membrane (Thanks Bob!). BTW it is possible to modify the DBI but, with current data, it looks like you cannot alter the saturated or MUFA percentages, it is replacing omega 3s with omega 6s which mimics the mitochondria of long lived mammals!
Anyway, here is the cocoa butter paper:
Differential effects of saturated versus unsaturated dietary fatty acids on weight gain and myocellular lipid profiles in mice
Here are the diet compositions:
The line in red is the total percent of calories from linoleic acid in each diet. Here are the body weight changes:
The bottom two lines are the low fat high carbohydrate diet which happens to come in at just 1% linoleic acid and the cocoa butter diet which comes in at 1.4% of calories as linoleic acid. The high palmitic acid gives the most weight gain as it delivers 4.5% of calories as PUFA. Olive oil is a close second, also with 4.5% linoleic acid. The oddity is the safflower oil diet which is very high in PUFA but only gives intermediate obesity. Quite what is going on here is difficult to say but you have to wonder at what level of omega 6 PUFA that "next level up" signalling (lipid peroxide based) kicks in. No data on that, just a guess/excuse from the Protons perspective. There are a number of other studies showing this phenomenon of limited weight gain with safflower oil.
Still, stearic acid as cocoa butter is still looking pretty good. All of the high fat diets were based around different fat sources placed in to the D1245 background so are equally high in sucrose and starch too, comparable amounts across all of the higher fat diets.
A couple of things came up in emails recently. First is that I never mention that I had a chat with Ally Houston on the Paleocanteen podcast. It was fun. I think I sound like me. It's here
Second is that karl asked if there was a general formula for working out the F:N ratio for assorted fatty acids.
Edit: cavenewt pointed out that for people unfamiliar with the FADH2:NADH ratio concept there is a reasonable introduction at Protons: FADH2:NADH ratios and MUFA. PubMed-ing Dave Speijer and CoQ makes good reading too. End edit.
There wasn't but given a few minutes and some algebra it works out like this for even-numbered, fully saturated fatty acids of carbon skeleton length n:
F/N = (n-1)/(2n-1)
So stearate (C18) is 0.486
Palmitate (C16) is 0.484
Caprylate (C8) is 0.467
For MUFA/PUFA you just subtract one FADH2 per double bond (db). This doesn't affect the NADH term.
F/N = (n-1-db)/(2n-1)
Oleate (db = 1) is 0.457
Oleate is the MUFA of stearate. Saturated fats allow us to resist insulin, MUFA allow insulin to act.
Linoleic acid, also C18 but with two double bonds, gives 0.429
This is lower than stearate or oleate. The switch for ROS generation occurs between roughly 0.486 (high physiological ROS) and 0.457 (low physiological ROS). LA is lower than oleic acid.
Glucose has an F/N ratio, from memory, of 0.2 so LA is the "glucose-like" of the common fatty acids, in Mike Eades' terminology, and so will fail to generate fatty acid appropriate ROS. Which will allow continued insulin action when it should be resisted. That will make you fat, and the loss of calories in to adipocytes will make you hungry. The exact opposite of stearic acid...
Happy New Year all.
This paper came up in comments to the last post:
Dietary Stearic Acid Leads to a Reduction of Visceral Adipose Tissue in Athymic Nude Mice
I think we can say that, at least in athymic nude mice (which do not seem to be derived from the C57Bl/6 strain), omega 6 PUFA do not cause obesity when compared to either a low fat or high stearic acid synthetic diet (ie the low fat arm is equally synthetic, not more "food-like" ie not chow). At least when you look at total body weights:
So omega 6 PUFA appear to get a free pass here. The actual composition of the diets is in Table 1 of this previous paper and all four contain generous amounts of starch and equal amounts of sucrose:
Dietary Stearate Reduces Human Breast Cancer Metastasis Burden in Athymic Nude Mice
However if you dexa scan the mice you find that the low fat, corn oil and safflower oil groups all have reduced lean mass (probably muscle) and increased visceral fat mass compared to the stearate group. A picture is worth a thousand words so here are some postmortem images with the size of the inguinal fat pads outline by the authors of the paper (no need for me to doodle on this one!). Fig 3:
I really like these images.
Now, cavenewt questioned the relevance of weight/fat alterations from stearate compared to other potential health effects, particularly its affect on cancer metabolism.
The third paper from this same group is
Prevention of carcinogenesis and inhibition of breast cancer tumor burden by dietary stearate
I've been through all three papers and searched on "insulin". The group appears to have no concept that insulin has anything to do with adipocyte size or cancer progression.
A slight handicap when it comes to insight.
In the stearate-visceral fat paper there is a single measurement made of plasma insulin/glucose. Insulin does not vary between diet groups but glucose is significantly lower in the stearate group. I have been unable to work out if the measures were fasting or fed, or even what time of day the samples were taken (ie when the mice were killed). I think that with glucose values in to 200-250mg/dl range these were probably "fed" glucose and insulin levels. The paper does not give us the measured insulin levels, merely that there was no statistically significant difference between groups. But insulin levels come with such huge standard deviations that getting a p value below 0.05 with small group sizes is not going to happen. A ns result does not automatically mean that there were no differences.
Of course a single insulin measurement at one terminal time point tells us nothing about the long term 24h exposure to insulin of the mice, of their adipocytes or of their cancer cells.
So we have to, once again, look at the significance of the changes in fat distribution to attempt to gain insight in to overall insulin exposure. I spent quite some time looking at visceral fat and its significance early last year in this post:
On phosphorylation of AKT in real, live humans. They're just like mice!
and on how stearate might avoid systemic hyperinsulinaemia here:
Dairy and diabetes
Visceral fat is a surrogate for chronic hyperinsulinaemia, particularly fasting hyperinsulinaemia. While I consider non-inflamed visceral fat to be completely benign, or even beneficial for controlling the hunger of fasting, the insulin which maintains that visceral lipid storage is not benign. Chronically elevated insulin (or, more accurately, insulin signalling) should drive both visceral fat storage and xenograft tumour growth in the mice. Probably in humans too.
Happy Solstice and assorted mid-Winter celebrations. If you live in the northern hemisphere that is. Not that I envy those with a Solstice-on-the-beach-without-wooly-hats-and-gloves situation!