haidut

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Yet another study that points the finger straight at fat as a key factor in one of the most common causes of inpatient hospital mortality - sepsis. Sepsis is currently considered to be a condition of infectious (bacterial) etiology, driven by endotoxin. However, in light of the new findings it may be more appropriate to consider sepsis a metabolic/energetic disease. Despite all the "advances" in modern medicine, sepsis remains a condition with mortality in the 30%+ range. Over the last several years a number of studies were published indicating a simple combination of thiamine, vitamin C (and sometimes cortisol) is remarkably effective in decreasing mortality from sepsis. However, the mechanism of action of this approach remains unknown.

Well, as the study below demonstrates, overactivation of the enzyme fatty acid synthase (FAS) likely plays a major role in the sepsis pathology. While the study does not mention it, overactive FAS means reduced glucose oxidation as a result of the Randle cycle. This may explain the benefit of thiamine in the thiamine+Vit C+cortisol combo, as thiamine activates the enzyme and improves glucose oxidation. When the scientists administered a FAS inhibitor (C75), the mortality rate in septic animals dramatically decreased. There are several inhibitors of FAS approved by the FDA for other conditions but they all (including C75) have toxic side effects. The least risky of these is probably orlistat and it is available OTC in the US, but even that chemical can cause severe side effects. One of the lesser known effects of aspirin is inhibition of FAS, and as such it may be able to achieve the same benefit without much of the side effects. Combining it with thiamine and niacinamide may further improve the effectiveness against sepsis by improving glucose oxidation and reducing lipolysis respectively.

Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation
Researchers step closer to raising sepsis survival rate dramatically - Korea Biomedical Review

"...Sepsis is a disease that infects the body with bacterial infections and damages major organs. Around 30 million people develop sepsis a year, and 30 percent of sepsis patients die within a month. Pharmaceutical firms have developed numerous treatments, but the uncertain cause of sepsis and complex disease progressions have made it difficult to achieve meaningful results. Neutrophils kill bacteria but an excessive release of cytokines, which quickly remove bacteria and damage the body, should be avoided. Thus, it is difficult to find the right balance. Despite the eradication of bacteria, the patient could still die, which was the stumbling block in sepsis treatment. The leading cause of sepsis is endotoxin, a toxin in bacteria. The researchers investigated why endotoxins release large amounts of cytokines from leukocytes and damage the body. The researchers found that “MYD88 (myeloid differentiation primary response protein) palmitoylation” induced by bacterial endotoxins was important. MYD88 is an inflammation-mediated protein in white blood cells. Palmitoylation is a process in which a lipid is bound to a protein, and the activity of the protein is modified. The research team administered fatty acid synthase (FASN) inhibitor, which produces palmitic acid, a material for palmitoylation, to mice with sepsis. The result showed that mice treated with FASN inhibitor significantly improved survival rate with fewer abdominal infections."
 

Luann

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This is interesting! Humans can only synthesize sat and mono-unsaturated fats except for Mead's acid and the fat involved in sebum, whatever that one's called. So inhibiting the sat and mono fats in favor of glucose oxidation is what protects the mice from sepsis. Am I reading this right?
 

haidut

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This is interesting! Humans can only synthesize sat and mono-unsaturated fats except for Mead's acid and the fat involved in sebum, whatever that one's called. So inhibiting the sat and mono fats in favor of glucose oxidation is what protects the mice from sepsis. Am I reading this right?

Yes, and it also helps to keep in mind that upregulated FAS is a hallmark of cancer as well as diabetes, AD, Parkinson, etc. Estrogen is a potent inducer of FAS.
Anyways, in general, anything that upregulates FAS is likely detrimental.
 

bdawg

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Yes, and it also helps to keep in mind that upregulated FAS is a hallmark of cancer as well as diabetes, AD, Parkinson, etc. Estrogen is a potent inducer of FAS.
Anyways, in general, anything that upregulates FAS is likely detrimental.

Haidut, ive asked about this before. Where does that leave us in Peat world in regards to sat-fats such as dairy and mono such as Coconut oil if they discourage glucose utilisation

Separately its glucose 'oxidation' a damaging process to cells or is it largely regulated
 

haidut

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Haidut, ive asked about this before. Where does that leave us in Peat world in regards to sat-fats such as dairy and mono such as Coconut oil if they discourage glucose utilisation

Separately its glucose 'oxidation' a damaging process to cells or is it largely regulated

Coconut oil does not contain monounsaturated fats. It is still mostly SFA, but it is medium chain types which can get into the mitochondria without the need for special transport (like long-chain fats do) and as such get oxidized more like sugar.
The FAS is overexpressed in cancer because cancer needs fat to survive. FAS is a minor pathway of fat provision, dietary fat is a bigger one. Also, palmitic acid improves the oxidation of glucose by activating PDH and I think saturated fats have a negative feedback mechanism with FAS. So, if any fat is to be had, it's best to be of medium chain length and the long chain fats still have benefits.
Palmitic Acid (palmitate) Strongly Increases Oxidative Metabolism
Palmitic Acid (palmitate) Is A Fatty Acid Oxidation Inhibitor More Powerful Than Mildronate
 
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