Saturated Fatty Acids,including Lauric Acid Activates TLR4

paymanz

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Some studies showing coconut oil has anti stress effects,but this one surprised me!

Fatty Acids Modulate Toll-like Receptor 4 Activation through Regulation of Receptor Dimerization and Recruitment into Lipid Rafts in a Reactive Oxygen Species-dependent Manner


The saturated fatty acids acylated on Lipid A of lipopolysaccharide (LPS) or bacterial lipoproteins play critical roles in ligand recognition and receptor activation for Toll-like Receptor 4 (TLR4) and TLR2. The results from our previous studies demonstrated that saturated and polyunsaturated fatty acids reciprocally modulate the activation of TLR4. However, the underlying mechanism has not been understood. Here, we report for the first time that the saturated fatty acid lauric acid induced dimerization and recruitment of TLR4 into lipid rafts, however, dimerization was not observed in non-lipid raft fractions. Similarly, LPS and lauric acid enhanced the association of TLR4 with MD-2 and downstream adaptor molecules, TRIF and MyD88, into lipid rafts leading to the activation of downstream signaling pathways and target gene expression. However, docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, inhibited LPS- or lauric acid-induced dimerization and recruitment of TLR4 into lipid raft fractions. Together, these results demonstrate that lauric acid and DHA reciprocally modulate TLR4 activation by regulation of the dimerization and recruitment of TLR4 into lipid rafts. In addition, we showed that TLR4 recruitment to lipid rafts and dimerization were coupled events mediated at least in part by NADPH oxidase-dependent reactive oxygen species generation. These results provide a new insight in understanding the mechanism by which fatty acids differentially modulate TLR4-mediated signaling pathway and consequent inflammatory responses which are implicated in the development and progression of many chronic diseases.

Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways

Toll-like receptor 4 (TLR4) and TLR2 were shown to be activated by saturated fatty acids (SFAs) but inhibited by docosahexaenoic acid (DHA). However, one report suggested that SFA-induced TLR activation in cell culture systems is due to contaminants in BSA used for solubilizing fatty acids. This report raised doubt about proinflammatory effects of SFAs. Our studies herein demonstrate that sodium palmitate (C16:0) or laurate (C12:0) without BSA solubilization induced phosphorylation of inhibitor of nuclear factor-κB α, c-Jun N-terminal kinase (JNK), p44/42 mitogen-activated-kinase (ERK), and nuclear factor-κB subunit p65, and TLR target gene expression in THP1 monocytes or RAW264.7 macrophages, respectively, when cultured in low FBS (0.25%) medium. C12:0 induced NFκB activation through TLR2 dimerized with TLR1 or TLR6, and through TLR4. Because BSA was not used in these experiments, contaminants in BSA have no relevance. Unlike in suspension cells (THP-1), BSA-solubilized C16:0 instead of sodium C16:0 is required to induce TLR target gene expression in adherent cells (RAW264.7). C16:0-BSA transactivated TLR2 dimerized with TLR1 or TLR6 and through TLR4 as seen with C12:0. These results and additional studies with the LPS sequester polymixin B and in MyD88−/− macrophages indicated that SFA-induced activation of TLR2 or TLR4 is a fatty acid-specific effect, but not due to contaminants in BSA or fatty acid preparations.
 

richofden

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I´ve learned from Atom Bergstrom that coconut oil should only be consumed in the morning (00.30 - 12.00). I think that it can be highly allergic otherwise, at least for some people. But dang, have I found out how beneficial lauric acid is to me. Hope to cure my craizy inflamed gut soon after reintroducing LA.
 

dukesbobby777

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I´ve learned from Atom Bergstrom that coconut oil should only be consumed in the morning (00.30 - 12.00). I think that it can be highly allergic otherwise, at least for some people. But dang, have I found out how beneficial lauric acid is to me. Hope to cure my craizy inflamed gut soon after reintroducing LA.
Why would it be allergenic during certain times I wonder? Tbh, one teaspoon of coconut oil upon wakening should be of benefit because it will compete with PUFA based FFAs that (most likely) will be circulating this thing in the morning (after your overnight fast). A tsp of CO and a couple of glasses of juice can reduce the morning (fasted) stress state before you embark on breakfast.

If your breakfast is fat based you can add vitamin E to enhance this effect. And additionally adding policosanol to enhance the effect further.
 

richofden

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Why would it be allergenic during certain times I wonder? Tbh, one teaspoon of coconut oil upon wakening should be of benefit because it will compete with PUFA based FFAs that (most likely) will be circulating this thing in the morning (after your overnight fast). A tsp of CO and a couple of glasses of juice can reduce the morning (fasted) stress state before you embark on breakfast.

If your breakfast is fat based you can add vitamin E to enhance this effect. And additionally adding policosanol to enhance the effect further.
I´m not totally into it, but according to Atom the body is optimized if sync´ed with the sun, and since coconut oil comes from trees, then morning hours, or growth zone 1 as he calls it, is the best time to use and eat it. He´s approach to these issues is a lot of time accompagnied with a "yes no maybe" when it comes to experimenting.

Nice to know in regards to reducing the morning stress. I´ve heard Peat mention that coconut oil by itself can be harsh on the intestines, will juice be enough to encounter this? And regarding the Vitamin E, doesn´t coconut oil itself contain Vitamin E? Or is this simply not enough?
 

dukesbobby777

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I´m not totally into it, but according to Atom the body is optimized if sync´ed with the sun, and since coconut oil comes from trees, then morning hours, or growth zone 1 as he calls it, is the best time to use and eat it. He´s approach to these issues is a lot of time accompagnied with a "yes no maybe" when it comes to experimenting.

Nice to know in regards to reducing the morning stress. I´ve heard Peat mention that coconut oil by itself can be harsh on the intestines, will juice be enough to encounter this? And regarding the Vitamin E, doesn´t coconut oil itself contain Vitamin E? Or is this simply not enough?

Well I (and many others) don’t have this allergic reaction to coconut oil. I notice no I’ll effects from it.

Coconut flour, on the other hand, is definitely allergenic for me. Very strong endotoxin response and intestine irritation.

It probably contains very little vitamin E (if it does). I’ve never heard of it containing E.
 

haidut

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Saturated fats do NOT activate TLR4. Some of prior studies were done in a way that other agents in the cell medium (e.g. bovine serum albumin) where the fats were dissolved activated TLR4 and that was blamed on the saturated fats. As far as in-vivo studies, it was once again endotoxin/LPS that is to blame and the prior studies were quick to blame the fats instead.
"...Based on previous evidence, it was thought that Toll-like receptor 4 (TLR4) sensed fatty acids to induce inflammation and metabolic dysfunction in obesity. Now, Graeme Lancaster, Mark Febbraio and colleagues have shed new light on this hypothesis, showing that TLR4 is not a receptor for palmitate, a long-chain saturated fatty acid, in vivo. “From the mid-to-late 2000s, numerous in vitro and in vivo studies confirmed a major role for TLR4 in lipid-induced inflammation, with the idea being that saturated fatty acids were ligands for TLR4,” explains Lancaster. “However, there are several lines of evidence that argue against saturated fatty acids being direct agonists of TLR4 and that is why we began to explore this area a number of years ago.”
In the present study, Lancaster, Febbraio and colleagues used a number of different approaches to investigate whether palmitate, which has been used previously by investigators to induce cellular inflammation, was an agonist of TLR4. The authors first assessed whether TLR4 undergoes dimerization and endocytosis in the presence of palmitate. They then used a computational technique called molecular dynamics simulations to assess whether palmitate acted in a similar manner to lipopolysaccharide, which is the canonical TLR4 agonist.
The authors report that they were unable to find any evidence that palmitate is a ligand of TLR4. “While our study might appear to fly in the face of over a decade’s worth of previous work, it doesn’t,” adds Febbraio. “We propose that certain signals, for example, obesity-induced increases in circulating concentrations of lipopolysaccharide or perhaps endogenous TLR4 ligands emanating from obese adipose tissue, activate adipose tissue-resident macrophages, stimulating them to adopt the classically-activated, or M1, phenotype.” This TLR4-dependent reprogramming of macrophage metabolism renders the adipose tissue-resident macrophages particularly sensitive to subsequent stimulation with long-chain saturated fatty acids, which induce further inflammatory signalling.

@paymanz @Sucrates @richofden @dukesbobby777
 
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