Okay, time to look at this study
Monocyte Chemoattractant Protein-1 (MCP-1)
Macrophage inflammatory protein-1 (MIP-1)
F4/80 is a gene for the surface marker of macrophages
and good old TNFα and Il6 get thrown around too.
We can ignore the anti-inflammatory gene expression Ym1 and Ym2.
This is what they found for pro-inflammatory gene mRNA relative expression, linoleic acid is tall hatched bars. It's a log scale:
So we can say LA is pro-inflammatory in this model. No one in obesity research wants to find that the cardiological darling and cholesterol lowering PUFA are pro-inflammatory. I told you they were rank amateurs. Anyway, they developed another model, in-vivo this time, which got the correct results.
They fed the mice the diets I mentioned in the last post for four weeks then looked at pro-inflammatory gene expression in both white adipose tissue and liver tissue immediately after euthanasia.
This was much more satisfactory. In both tissues the high PUFA diet was not inflammatory, with a trend towards it being anti-inflammatory in adipose tissue:
Adipose, from Fig 2:
and liver from Fig 3:
However, there is another snippet of information also available in Fig 3. The activity of myeloperoxidase system tells us slightly more than the relative mRNA for inflammatory genes do in the bulk of the figures. Myeloperoxidase tells us whether the WAT cells in Fig2 are actually using the pro inflammatory genes to produce inflammation. This is what they found. The chart is split in two because the HF (high fat diet, something like D12492) was so activating it was an order of magnitude higher than all of the others, so needed it's own scale:
I think we have to be very, very careful about what we mean by "inflammation". In fact I might just take a brief pause here and explain what I think "inflammation" means, before running through what is happening in this study. That may need some cellular physiology rather than mitochondrial physiology.
Here's my conundrum:
CVD is an "inflammatory" condition, sic.
The most potent anti-inflammatory agents available to modern medicine are the corticosteroids.
Corticosteroids make CVD much, much worse.
Somebody, somewhere, has an odd idea about what "inflammation" might be.
With apologies for the hiatus.
Peter
14 comments:
Hm, LA is tricky, very confusing. When not oxidized, almost nothing happens. When burned, excessive insulin sensitivity appears (I think by supplying NAD+ via DECR), this elevates fat storage and after a while it elevates H2O2 and LA is auto-oxidized. This triggers protective measures like peroxisomes or pseudohypoxia on. And here researcher's missing the point. The final product of peroxisomal beta oxidation is protective systemic acetate. Nobody measures flow of acetate. We are totally blind. If in the fat mixture is some other trigger of peroxisomal protection, then acetate is produced from the start. This way omega-3 alpha linolenic acid works but not other longer omega-3.
Rodents are sensitive to level of oxidation of LA. Their gut don't suppress products like 9-ONA, that's why they react on LA immediately. Humans have gut protection, products like 9-ONA are not absorbed. LA have to be oxidized in the tissue. That I see as the main difference between rodent vs human papers.
And the missing elefant in the room is flow of acetate, it can involve intestinal and hepatic sources. Main function is suppresion of de-novo lipogenesys and supply of cytosolic acetyl-CoA, de-facto restart of the cell metabolism. That's my explanation of variabilities in LA research. Unless researcher's start measure peroxisomal activity, dicarboxylate and acetate flow, we stay blind.
Jaromir
Inflammation is very poorly and variously defined (hand waving?) - the shift in the CVD mantra is now slowly away from frantic hand-waving about LDL to hand-waving about inflammation - which they pretend to measure in no end of ways.
My take is inflammation is actually a range of responses to injury or infection. Mostly a really good thing that stops infections and starts tissue repair processes. These processes are utterly complex and not reducible to some blood test. Also, some people equate inflammation to ROS levels - (ROS actually appear to be a genetically ancient signal that helps control a cell - true systemic anti-oxides appear to do harm by screwing up this homeostasis signal. )
(Higher levels of ROS found in cancers appear to damage mDNA - which begs the arrow of causation question - is caner caused by mutations or does do the mutations cause cancer? )
The term 'inflammation' seems to be used as a tool to push the supplement of the week or to support weak disease narratives.
,.,.
Another inconvenient fact that those parroting the ungrounded CVD narratives have to deal with is something I found in a deep deep dive into oxLDL (sometimes oxoxLDL - and oxLp(a) etc). There is an intervention that lowers oxLDL - but no one gets to sell a new pill - simply reduce dietary PUFA. Statins may actually increase oxLDL.
Another way to think about oxLDL is it that the oxidation has damaged the fatty acid that LDL transports - or it can be seen as damaged LDL.
My take is that CVD is primarily a thrombotic disease - plaque appears to be blood clots that are paved over with new intima. What is key is it is not about lipids - rather that oxLDL and friends increase clotting - Remember that LP(a) where the (a) is a genetic relative of firbrogen. "The LPA gene that codes for apo(a) evolved from plasminogen in Old World monkeys: high homology between apo(a) and plasminogen" So these clots are full of fibrin and amyloid proteins - mis-folded.
CVD is a thrombotic disease probably only related to lipoprotiens via the clotting factors they transport.
https://www.sciencedirect.com/science/article/abs/pii/S0049384814003685
https://www.sciencedirect.com/science/article/abs/pii/S0939475320300971
Anyway - I was able to lower my oxLDL levels to the bottom 5-percentile of the population by avoiding PUFAs in the diet.
@ mct4health
PUFAs want to oxidize - the double carbon bonds are not as stable as what we see in SFAs. The question is how long before they do oxidize?
@karl
They surely oxidize, but our intestines are different from rodents. And if they are oxidized even more, they can be beneficial, like AzA.
A lipid peroxidation product 9-oxononanoic acid induces phospholipase A2 activity and thromboxane A2 production in human blood
https://doi.org/10.3164%2Fjcbn.12-110
The Induction of Lipid Peroxidation in Rat Liver by Oral Intake of 9-Oxononanoic Acid Contained in Autoxidized Linoleic Acid
https://doi.org/10.1080/00021369.1985.10867151
Intestinal and Hepatic Uptake of Dietary Peroxidized Lipids and Their Decomposition Products, and Their Subsequent Effects on Apolipoprotein A1 and Paraoxonase1
https://pubmed.ncbi.nlm.nih.gov/34439506/
Protective effects of azelaic acid against high-fat diet-induced oxidative stress in liver, kidney and heart of C57BL/6J mice
https://pubmed.ncbi.nlm.nih.gov/23361364/
Some papers from my blog....
Jaromir
https://www.statnews.com/2024/03/19/intermittent-fasting-study-heart-risk/
Fatty liver? No worries! Just take beby aspirin!
"In small study, baby aspirin cuts fat buildup in liver disease patients." https://www.statnews.com/2024/03/19/baby-aspirin-liver-disease-masld/
It's paywalled, and I didn't bother to search for the study paper.
@mct4health
Looked at your links - this one:
https://pubmed.ncbi.nlm.nih.gov/23361364/ => better link =>
https://sci-hub.se/10.1007/s11010-013-1566-1
I was not able to find the actual diet data-sheets - realize that listing things like carbohydrate can be misleading (is it sucrose or cornstarch? Same in both diets? (they often pump sucrose in the HFD ) and fat (which is often NOT animal fat, but plant oils - often hydrogenated).
The question is if consuming these plant-oils would do more harm via modulation of clotting factors (UP) - vs the claimed secondary metabolite.
After years of reading papers on the health claims of supplements etc - I think the state of the art is dismal - most of them are poorly controlled studies - often funded by the people selling the supplement.
My alternative is to trust of evolution, which means we are likely well evolved to eat fish/meat as hunter gathers - exposed to times of fasting and not very far along with evolving to eat farmed products. I don't think these ancestors had access to bottles of various oils.
I tried lots of life-style-hacks along the way. (artificial sugars for for example that I now believe are harmful (spikes insulin)). Many life-style-hacks interventions will turn out to have unintended consequences - similar to other novel foods. The heuristic(rule of thumb) I use now is to no buy any foods that have an ingredient list (likely to have additives - no all additives get listed - some additives are unprescribed antibiotics paraded as preservatives) and to eat only foods my great grandmother would know - back when T2D was exceedingly rare.
@altavvista
I generally suspect anything from the AHA is likely garbage. Chinese paper - not published. Recall study - lots of contrary papers.
https://www.abstractsonline.com/pp8/#!/20343/presentation/379
Also, when people go on crash diets - which might be confused with intermittent fasting - they CAN damage their hearts. No one is going to do a good study as there is no patentable pill to sell.
@cavenewt
Papers that change the names of terms are suspect - NAFLD becomes MASLD (tiresome)..
Anyway - here is a better link:
https://www.medpagetoday.com/gastroenterology/generalhepatology/109281
Interesting - my father was a subject of the original 'doctors study' for low dose aspirin. (It was not a good study - the experimental group not only got ASA - but also magnesium.)
Of course NAFLD is not the only out come of having T2D(AKA insulin tolerance). Much better to quit eating the wrong foods. Foods with ingredient labels are not really human foods - tend to be addictive.
Karl Pufa start to oxidise as soon as you heat them up in metal cookware and the lipoperoxides produced generate a catastrophic cascade of lipoperoxidation when consumed. Perhaps this is another dusastrous aspect of modern foods and food preparation. In terms of ancestral foodstuffs, bulk quantities of oil cooking in a pot over the hearth probably wasn't on anyone's menu.
Now it may be that uncooked seeds and raw mongongo nuts are not quite as harmful as the contemporary hard baked equivalents?
sorry for OT, but very interesting: https://www.nytimes.com/2024/03/21/obituaries/yvonne-barr-overlooked.html
The flaneur has spoken.
https://twitter.com/nntaleb/status/1770463325878440264
Sample too small, confounders too big.
@altavista... It's even less serious than that. There's a pretty good discussion by Bret Weinstein and Heather Heying at https://rumble.com/v4kf5t9-the-217th-evolutionary-lens-with-bret-weinstein-and-heather-heying.html, (01:44:40) Intermittent fasting and early death. Better, also listen to the prior segment about another talk at the same AHA conference, (01:33:20) Sunbathing and heart disease.
The best word for both of these "scientific talks" would be "silly".
@karl
I don't suspect AzA not be beneficial, it is used I think often in dermatology.
It fits to my picture of how dicarboxylic acids control fasting metabolism. Omega oxidation and peroxisomal metabolism, not insulin, likely controls level of FFA in fasting state. And here omega-3/omega-6 C18 fats take place, PPARa/PPARg. Surprisingly AzA could be protective the same way as ALA, by elevating formation of acetate.
It's interesting, that DNL and GNG elevates and suppresses together. Acetate can suppress both. It reminds me computer restart. Understanding fasting I see as the key, I'm trying to delve into.
Jaromir
Malcolm Kendrick has a nice post — and quip — on inflammation:
"Whenever I see anyone stating that inflammation is a cause of anything I simply change the word inflammation to the word ‘healing,’ to see how sensible it then sounds."
@cavenewt
Induction of omega-oxidation of monocarboxylic acids in rats by acetylsalicylic acid
https://pubmed.ncbi.nlm.nih.gov/1752948/
@karl said: (Higher levels of ROS found in cancers appear to damage mDNA - which begs the arrow of causation question - is caner caused by mutations or does do the mutations cause cancer?)
I think you said the same thing twice (mutations → cancer ?) — but I think I know what you're saying.
In my (biased) opinion the vast multitude of somatic mutations and genomic instability observed in tumor cells arise as downstream effects of mitochondrial issues and the disease (tumor progression) itself. One can certainly inherit or acquire genetic mutations that make them more susceptible to the disease (i.e., risk factors), but they are neither necessary nor sufficent to cause cancers.
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