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Saturated Fat (palmitate) Does NOT Activate TLR4

Discussion in 'Scientific Studies' started by haidut, Sep 12, 2018.

  1. haidut

    haidut Member

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    We must have had hundreds of discussions on this topic on the forum. Some forum users strongly believe that saturated fat (SFA) increases inflammation by binding to and activating the endotoxin (LPS) receptor TLR4. Among all SFA, palmitate is the one most commonly blamed and has been "implicated" in many of the purportedly negative effects of SFA such as obesity, CVD, inflammation, dementia, cancer, etc.
    This new study decided to put the idea to the test and...to rest. The scientists looked at whether SFA is able to act as agonist on TLR4. Palmitate was found unable to activate TLR4. While the study only directly tested palmitate, the authors think that other SFA acids are even less likely to act as TLR4 agonists, so the results should apply to all SFA. They cite another study confirming myristic acid is also unable to activate TLR4.
    In order to save the popular hypothesis that SFA are bad for health, the authors propose that the negative effects reported in other studies must be due to SFA somehow uniquely changing the microbiome that then leads to TLR4 activation. However, the vast majority of HFD studies claiming to test a high saturated fat diet used either lard or a mixture of SFA and PUFA. Lard is mostly MUFA, then PUFA, and then SFA. So, most of these studies really tested the effects of a high PUFA/MUFA (mixed with some SFA) diet on gut health and inflammation.
    A much simpler conclusion would be that bacterial overgrowth leads to endotoxemia and this leads to disease. SFA are probably the least likely culprits but a diet high-fat diet with mostly SFA would still be less preferable to low-far, high-sucrose diet that does not lead to increased endotoxin levels.
    Well, at least the cat is out of the bag and SFA can no longer be directly blamed for the inflammation, obesity and disease a HFD is known to induce. FDA is apparently taking notice and is about to reverse its standing on dietary SFA just as it did with cholesterol last year.

    https://www.cell.com/cell-metabolism/abstract/S1550-4131(18)30192-X
    "...Herein, using a number of independent experimental approaches, we provide evidence that the lcSFA palmitate is not an agonist for TLR4. This finding challenges one of the central paradigms by which lcSFAs are believed to induce inflammation."

    "...Moreover, we observed that palmitate was unable to induce the dimerization and endocytosis of TLR4, events that are absolutely fundamental to the activation of TLR4 signaling. Finally, inhibition of TLR4/MD-2 activation using LPS-Rs or TAK242, both of which prevent LPS-Ec-induced JNK activation, had no effect on palmitate-induced JNK activation. Collectively, these data provide compelling evidence that lcSFAs are not TLR4 agonists."

    https://medicalxpress.com/news/2018-09-rethinking-inflammatory-receptor-obesity.html
    "...Peter Bond's team, from the A*STAR Bioinformatics Institute, has been studying TLR4 for a long time, looking at how the receptor interacts with a lipid molecule found on the surface of bacteria, called a lipopolysaccharide, and how this can lead to sepsis; a potentially deadly immune over-reaction to infection. It was believed that dietary fatty acids could also bind to TLR4, and that this was the mechanism underlying the increased inflammation associated with high-fat diets and metabolic disease. However, Bond was skeptical of this. "It made no sense to me that this receptor would be activated by such dietary fatty acids, because they look very different from bacterial lipids," he says. He was also puzzled as to why such a major component of our diets would trigger this potentially dangerous inflammatory reaction. He and colleagues hypothesized that TLR4 didn't interact with fatty acids directly, but instead indirectly influenced fat-induced inflammation. To prove this they first had to demonstrate that fatty acids couldn't bind and activate TLR4. They did this by modelling the possible ways that fatty acids—in particular, palmitate—might bind to the receptor and activate it. The team found that no model allowed palmitate to bind to TLR4 in a stable fashion."

    "...Meanwhile, collaborators Graeme Lancaster from the Baker Heart and Diabetes Institute, Mark Febbraio from the Garvan Institute, and colleagues in Australia were conducting wet laboratory experiments to explore possible interactions between palmitate and TLR4. As with the computer simulations, they found that palmitate was unable to activate TLR4. Subsequent research by the team confirmed the idea that TLR4 influenced fat-induced inflammation indirectly."

    "...The team's theory is that a diet high in fats could change the bacterial populations in the gut, and that this would expose TLR4 to more bacterial components, such as lipopolysaccharides, which in turn could make cells overly sensitive to fatty acids in obese adipose tissue. "The exposure of TLR4 to bacterial components is priming the cells to alter their metabolism and be activated in other ways by these fatty acids," Bond says. "The bacteria themselves are over-activating the immune system and making it more sensitive to fats."
     
  2. Kartoffel

    Kartoffel Member

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    @haidut What's your opinion on the studies showing saturated fat (coconut oil) to increase postprandial endotoxin levels in the blood while PUFA lower them? I don't know of any long-term studies comparing different fats, but these single meal studies are often used to demonstrate that SFA=endotoxemia.

    [​IMG]


    Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia
    Postprandial serum endotoxin in healthy humans is modulated by dietary fat in a randomized, controlled, cross-over study
     
  3. OP
    haidut

    haidut Member

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    The pig study fed corn-soybean dough while the human one fed oatmeal. Both meals are expected to raise endotoxin due to the resistant starch in them. The pig study had good fat design - i.e. the group that got coconut oil had a fatty acid composition of 89% SFA, 2% PUFA and 1% MUFA. However, something in that study does not add up. Unless I am missing something, none of the fat groups have the percentages add up to 100%. In the case of SFA, the total is 89 + 1 + 2 = 92% fat, but where is the remaining 8% fat?? The other groups have even bigger gaps. Do you know what is going on?
    That issue being put aside, the pig study does seem to show that SFA combined with corn-soybean starch raised endotoxin more than the other fat groups. Not sure why, but I would like to see this study repeated without starch - just sucrose (or sugar from fruit), protein and fat.
    The human study is an example of the mixed-bag fat presented as SFA. If you look at Table 2 in the human study you will see that the high SFA meal had 35% fat but only 15% was SFA. This means the other 20% is either MUFA or PUFA, so not really a real high SFA in the sense of it being mostly/only SFA.
    So, as a summary - results of first study seem legit but something does not add up in the described diet comsposition, while the second study is not really a true high (as in "mostly" or "only") SFA diet.
     
  4. Pointless

    Pointless Member

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    What is the best dietary source of lcSFA? Butter?
     
  5. OP
    haidut

    haidut Member

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    That, as well as chocolate, beef tallow, sheep fat, lanolin, etc.
     
  6. Kartoffel

    Kartoffel Member

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    My first guess was that coconut oil's antibacterial properties might be responsible. Coconut oil kills gram negative bacteria, and this in turn might lead to increased endotoxin that gets absorbed into the blood stream. I actually found a long-term study with mice while looking through the references of the Mani et al. study. It shows that milk fat and palm oil resulted in significantly lower endotoxemia than rapeseed or sunflower oil. Interwstingly, the palmoil group displayed the highest level of inflammation in the form of plasma IL-6, and also had the highest concentration of LBP, the protein that "presents" endotoxin to TLR4 and CD14. Consequently, TLR4 was highest in WAT in the palmoil group compared to all the others.
    One possible explanation might be that palm oil increased Escherichia coli bacteria compared to the other fats, so there might actually be something to the hypothesis that saturated fats somehow change the microbiome. They often use palm oil in their high-saturated fat models.

    https://www.physiology.org/doi/pdf/10.1152/ajpendo.00314.2011


    upload_2018-9-13_1-57-47.png

    upload_2018-9-13_2-9-33.png
     
  7. Mito

    Mito Member

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  8. jb116

    jb116 Member

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    It's true something like coconut oil mobilize endotoxin into the blood stream, but the most important part is being left out here: that the coconut oil also neutralizes the endotoxin, rendering it uneffective.
     
  9. OP
    haidut

    haidut Member

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    Thanks, that is actually a great find. All the studies I had seen so far showed that SFA and specifically things like monolaurin and caprylic acid being effective only against Gram positive bacteria. Being effective against both types is a rare property among natural substances. Add to that the anti-fungal effects and it is clear why peat is so fond of MCT like coconut oil.
    Btw, in that study you posted, only the MF diet had acceptable level of PUFA and it was still about 7% omega-6. The palm oil had almost 13% omega-6, so not surprised it raised IL-6, even though the S and R groups should also have boosted IL-6.
     
  10. OP
    haidut

    haidut Member

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    Very true, but unfortunately I know of no studies that actually look at whether the endotoxin was neutralized or not by the consumed fat. If you know of any studies please post.
    Here is something (which you have probably seen already) that is relevant to your comment.
    Coconut Oil "completely Abolished Responses To Endotoxin"
     
  11. jb116

    jb116 Member

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    I've asked Peat to send the references but I haven't heard back yet. Will definitely post if I get them. I do remember him talking about this aspect of endotoxin and coconut oil on kmud. Funny though, that study you posted gets us half way there. I think the main error in a lot of the studies is that they tally up endotoxin activity in the intestine and ignore blood effects. PUFA for example don't necessarily increase mobility but they also mimic and amplify the effect of endotoxin. Most importantly, PUFA cause leaky gut. Peat has always stressed endotoxin in the blood, leaking through intestine, as the main problem. So stopping the perspective at the intestine is short sighted. After mobilization there should be measurements of effects, for example NO on the body.
     
  12. CLASH

    CLASH Member

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    Protective effects of medium-chain triglycerides on the liver and gut in rats administered endotoxin. - PubMed - NCBI
    “All rats given corn oil died after LPS administration; however, this mortality was prevented by MCT in a dose-dependent manner. Rats given corn oil showed liver injury after LPS administration. In contrast, MCT prevented this pathologic change nearly completely.“


    Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats. - PubMed - NCBI
    “The liquid diets were based on a modified Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long-chain saturated fatty acids) or medium-chain triglycerides (MCT, exclusively medium-chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanol-induced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression, and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and zonula occludens-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent.”



    Effect of Bile Acids on the Intestinal Absorption of Endotoxin in Rats
    The study is scanned so I can’t copy and paste. Essentially bile acids prevent endotoxic absorption and degrade the endotoxin that is absorbed. Heres the abstract:
    “The absorption of tritium-labeled Escherichia coli O89 Westphal-type endotoxin from the peritoneal cavity of rats was diminished by bile by 23% and by sodium deoxycholate by 47%, respectively. Practically, there is no endotoxin absorption from the intestinal tract of normal rats. The bile duct of rats was chronically cannulated for experimental purposes. A significant amount of perorally administered endotoxin absorbed from the intestinal canal into the blood in the rats treated thus. Absorption was demonstrated by the lethal effect of endotoxin on rats previously hypersensitized by lead acetate, and by the radioactivities found in the blood samples. The intestinal absorption of endotoxin in rats, rendered bile-deficient, may be prevented by sodium deoxycholate. Supported by their experimental findings, we emphasize the important role of bile acids in the defense mechanism of the macroorganism against bacterial endotoxins.”


    Kupffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin. - PubMed - NCBI
    Rates of alcohol elimination were around 3.5 mmol/kg/hr in control rats. After 4 weeks of ethanol treatment with or without antibiotics, elimination rates were not changed. Translocation of horseradish peroxidase was increased about 3-fold in gut segments by treatment with ethanol. This increase was not altered by treatment with antibiotics. Moreover, portal vein endotoxin levels were increased from nearly undetectable levels to 80 pg/ml in plasma of rats treated with ethanol. As expected, this increase was prevented (<20 pg/ml) by antibiotics. In isolated Kupffer cells from rats treated with ethanol for 4 weeks, CD14, LPS-induced intracellular Ca2+, and TNF-alpha all were increased. These phenomena were blocked by antibiotics.


    ——————————————————————

    I think the triggering of TLR4 by SAFA is due to the lipid raft formation with endotoxin. So it is the endotoxin in the SAFA that triggers.
    It seems that long chain saturated fatty acids do increase endotoxin absorption however I would bet that the interaction of the lipid component of lipopolysaccharide with the fatty acid actually serves to detoxify the endotoxin from the the intestinal lumen and the body overall. Perhaps it may actually be beneficial to remove endotoxin from the small intestinal lumen to keep it functioning optimally as long as the endotoxin is neutralized, I think LC SFA do this (I’ll have to look for some studies).

    The long chain fatty acids also stimulate bile release which has been shown to breakdown LPS and inhibit its absoprtion, see the above study. Bile acids also help to sterilize the small intestine as much as possible and the fatty acids themselves are often bacteriostatic if not bacteriocidal. The LC SFA also increase hepatic detoxification enzymes of endotoxin, protecting the liver from endotoxin (see the study above).

    We also know that LC SFA protect against PUFA by saturaing tissues and certain fatty acids such as stearic acid displace arachidonic acid from the membrane. We also know that saturated fatty acids dont convert into inflammatory mediators.

    As for MCT we see that it doesnt potentiate the infammatory cascade and protects the body from intravenous LPS by increasing intestinal integrity and inhibiting endotoxin absorption and/or neutralizing it if it’s absorbed.

    I put the ethanol study to show that the vast majority of damage is from decreased intestinal integrity and leakage of endotoxin from the lumen of the intestine, not actually the alcohol itself. The study discusses alcohol as actually having an effect on kuppfer cells that is somewhat paradoxical. The endotoxin leakage removes that paradox pretty clearly. It isnt the alcohol that damages the liver so much as it is the endotoxin leaking from the intestine (alcohol causes a leaky gut). If you combine the idea that alcohol causes a leaky gut, thus allowing endotoxin to hit the bloodstream with the study showing corn oil consumption killing the rats administered endotoxin via IV, you have a pretty clear picture. Endotoxin is the spark to the metabolic derangement and PUFA is the combustible material. This combined with the other evidence showing the protective effects of saturated fatty acids seems to point towards either a high saturated fatty acid diet if that suits you or a low fat diet with whatever fats there are in the diet being mostly saturated). Because of all the benefits of SAFA acids for bile stimulation, endotoxin detoxification, intestinal health and liver protection I would say that going too low may actually be detrimental in the long run. Personally my digestion, libido, mood, stress tolerance and focus all suffer on low fat diets so I have a bias towards more fats.
     
  13. rei

    rei Member

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    Very short-term and especially single-dose studies are worthless. When you significantly change your diet there is a mandatory "adjustment period" and especially MCT oils are expected to cause a reaction due to the effective antiseptic and antifungal properties. The diet should be kept stable for a few days before taking the measurements, otherwise "endotoxin load" might only be evidence for drastically improving GI flora.
     
  14. OP
    haidut

    haidut Member

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    Thanks, great links.
    Btw, where did you see that LC-SFA increase endotoxin absorption? I do not see that mentioned anywhere and in fact in the study with cocoa butter, it actually reduced liver endotoxin levels while MCT did not.
    "...CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1)."
     
  15. Reaper242xx

    Reaper242xx Member

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    I never did like the fact they considered lard a saturated fatty acid. Lard only becomes completely solid if you put it in the refrigerator. It develops a cloudy, thick liquid consistency if you leave it out at room temperature. Butter, coconut oil, and beef/lamb fats don't do this. Btw, this was lard I picked up on a farm that pasture fed their pigs. The standard soy fed pigs probably produce lard that's not all that different from soybean oil.
     
  16. paymanz

    paymanz Member

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    if you look at tittle of study and also full paper they still say its inflammatory but not through tlr4 receptor.it activates jnk.

    too much fat is not good in ray view anyway.
     
  17. OP
    haidut

    haidut Member

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    Yes, but they contrast the effect of endotoxin/LPS with palmitate on JNK/inflammation. The endotoxin/LPS immediately activated JNK and increased NF-kB, while palmitate only activated JNK, and it activated JNK only after 4 hours of exposure. Without increase in NF-kB, activation of JNK is not even known to contribute to inflammation. Also, exposure to palmitate for 4 hour is unlikely unless the person is in ketosis most of the time.
    "...As expected, treatment with LPS induced rapid JNK and MKK4/7 phosphorylation as well as the phosphorylation of p65 and the degradation of IkBa, indicative of canonical NF-kB activation (Figures 2A–2D). In contrast to the effects of LPS, palmitate-induced JNK and MKK4/7 phosphorylation occurred only after 4 hr of treatment (Figures 2E and 2F), and we observed no evidence of NF-kB activation over the course of the experiment (Figures 2G and 2H)."

    But I agree that too much fat is probably not good, even if it is fully saturated. Optimal health seems to require somewhere around 15% of fat as calories, more than 20% and less than 10% are associated with various pathologies, both acute and chronic.
     
  18. CLASH

    CLASH Member

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    @haidut
    The cocoa butter normalized hepatic endotoxin levels yes, but not by blocking absorption, by upregulating detoxification:

    "...CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1).”

    Also cocoa butter was unable to normalize serum endotoxin level meanwhile MCT was:

    “Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB.”

    I dont think this shows that Cocoa butter increases endotoxin absorption per say, as the ethanol induced gut permeability is what is causing the leakage of endotoxin into the blood stream but these two pieces together are showing that the cocoa butter may be binding the endotoxin in chylomicrons and shielding the body from endotoxins effect as well as facilitating detoxification in the case of the ethanol induced permeability. The MCT seems to be directly reestablishing the gut barrier directly so the mechanism is different for that yet still beneficial.

    Its not these direct studies that I was refering to, to show LC SAFA increasing endotoxin absorption, I was coming from the point of view that was already well established via the lipid raft proviced by chylomicrons with SAFA. These studies where more of an acceptance of that fact and then an explanation as to why thats actually not a bad thing about LC SAFA. The combination of MCT and LC SAFA seems to me to be a pretty strong endotoxin protection system. I think this is why people do well on low carb high fat. The fat re-energizes and protects the liver/ damaged small intestine, while the avoidance of starches/grains etc. Prevents fermentation by pathogenic bacteria. At this point I dont think CICO every made anyone obese or even grossly overweight, I think inflammation and hormones have.

    On a seperate note, what pathologies are associated with fat over 20% and less than 10%?
     
  19. raypeatclips

    raypeatclips Member

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    Peat has said up to 50% of the diet could be fat if it is something like hydrogenated coconut oil, and has otherwise suggested a 33/33/33 macro diet a few times.

    Why would Peat suggest a 33/33/33 diet if 33 percent of saturated fat was so damaging, do you think?
     
  20. OP
    haidut

    haidut Member

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    I think he makes a distinction of diet for healthy people and optimal diet for improving health. The 33% fat is probably OK for somebody with good metabolism, as it represents a lot of calories. The 10%-15% fat would be for someone struggling with health issues and trying to improve their health. He also said in that interview mentioning the 33% that "the optimal ratio of macronutrients is not currently known" and then added "it is probably about equal percentage in calories". I have found that for me optimal fat ratio depends on season. In the winter I do better on higher fat, especially eaten later in the day while in the spring/summer I do better on higher carbs and protein.
     
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