Palmitic Acid (palmitate) Is A Fatty Acid Oxidation Inhibitor More Powerful Than Mildronate

Discussion in 'Scientific Studies' started by haidut, Jun 15, 2017.

  1. haidut

    haidut Member

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    Peat wrote in one of his articles that palmitic acid is one of the most protective substances for metabolism due to its activation of the enzyme PDH, which is the primary factor of proper glucose oxidation.
    Mitochondria and mortality
    "...Thyroid hormone, palmitic acid, and light activate a crucial respiratory enzyme, suppressing the formation of lactic acid. Palmitic acid occurs in coconut oit, and is formed naturally in animal tissues. Unsaturated oils have the opposite effect."

    "...Since lactic acid is produced by the breakdown of glucose, a high level of lactate in the blood means that a large amount of sugar is being consumed; in response, the body mobilizes free fatty acids as an additional source of energy. An increase of free fatty acids suppresses the oxidation of glucose. (This is called the Randle effect, glucose-fatty acid cycle, substrate-competition cycle, etc.) Women, with higher estrogen and growth hormone, usually have more free fatty acids than men, and during exercise oxidize a higher proportion of fatty acids than men do. This fatty acid exposure "decreases glucose tolerance," and undoubtedly explains women's higher incidence of diabetes. While most fatty acids inhibit the oxidation of glucose without immediately inhibiting glycolysis, palmitic acid is unusual, in its inhibition of glycolysis and lactate production without inhibitng oxidation. I assume that this largely has to do with its important function in cardiolipin and cytochrome oxidase."

    "...Fewer mitochondrial problems will be considered to be inherited, as we develop an integral view of the ways in which mitochondrial physiology is disrupted. Palmitic acid, which is a major component of the cardiolipin which regulates the main respiratory enzyme, becomes displaced by polyunsaturated fats as aging progresses. Copper tends to be lost from this same enzyme system, and the state of the water is altered as the energetic processes change."

    "...Therapeutically, even powerful toxins that block the glycolytic enzymes can improve functions in a variety of organic disturbances "associated with" (caused by) excessive production of lactic acid. Unfortunately, the toxin that has become standard treatment for lactic acidosis—dichloroacetic acid—is a carcinogen, and eventually produces liver damage and acidosis. But several nontoxic therapies can do the same things: Palmitate (formed from sugar under the influence of thyroid hormone, and found in coconut oil), vitamin Bl, biotin, lipoic acid, carbon dioxide, thyroid, naloxone, acetazolamide, for example. Progesterone, by blocking estrogen's disruptive effects on the mitochondria, ranks along with thyroid and a diet free of polyunsaturate fats, for importance in mitochondrial maintenance."

    Aspirin, brain, and cancer
    "...The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and this change corresponds to the life-long decline of the person's metabolic rate. In old age, a person's life expectancy strongly depends on the amount of oxygen that can be used. When the mitochondria can't use oxygen vigorously, cells must depend on inefficient glycolysis for their energy."

    Aging Eyes, Infant Eyes, and Excitable Tissues
    "...Cytochrome oxidase is one of the enzymes damaged by stress and by blue light, and activated or restored by red light, thyroid, and progesterone. It's a copper enzyme, so it's likely to be damaged by excess iron. It is most active when it is associated with a mitochondrial lipid, cardiolipin, that contains saturated palmitic acid; the substitution of polyunsaturated fats lowers its activity. Mitochonrial function in general is poisoned by the unsaturated fats, especially arachidonic acid and DHA."


    Glycolysis Inhibited by Palmitate – Functional Performance Systems (FPS)


    A few people on the forum and over email have challenged that view repeatedly, claiming that palmitate is bad for health and that it cases insulin resistance and potentially diabetes. The studies below show that palmitate is in fact a fatty acid oxidation inhibitor and acts similarly to drugs like Mildronate / Meldonium, and actually improves glucose oxidation (as Peat said). The mechanism of action is increase in levels of Malonyl-CoA, which inhibits the activity of the enzyme CPT, and as such lowers fatty acid oxidation. Drugs that inhibit CPT are all the rage right now for treating diabetes, CVD, and especially cancer but unfortunately the existing drugs like Etomoxir, Oxfenicine, and Perhexiline have severe toxicities and will cause more damage than good.
    Fatty acid oxidation inhibitors - Wikipedia

    In addition, I posted some other threads showing that palmitate is capable of strongly inhibiting liver cancer progression and doubling oxidative metabolism.
    Palmitic Acid (palmitate) Strongly Increases Oxidative Metabolism
    Palmitic Acid (palmitate) Dramatically Inhibits Liver Cancer Progression

    This is why having access to a dietary, safe CPT inhibitor (like palmitate) is such a valuable option. The effects in the study were seen with concentrations achievable by doses of about 3g in humans. Also, as can be seen from the attached screenshot, palmitate inhibited fatty acid oxidation by up to 90%! This level of inhibition is something neither CPT inhibitors (above) nor drugs like Mildronate are known to be capable of. Unfortunately, in order to observe these effects prolonged exposure to palmitate (up to 20h) was needed. Given that palmitic acid is usually rapidly metabolized and won't stay intact anywhere close to 20h, a palmitate ester like methyl palmitate (which is resistant to metaboilsm and has much longer half life) may be able to achieve these effects at much lower doses. But even regular palmitate ingested several times a day should still exert some inhibition on fatty acid oxidation and thus improve glucose metabolism, with all of the associated health benefits.

    Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. - PubMed - NCBI
    "...Palmitate oxidation rates were measured in cells that had been pre-incubated for 4 or 20 h in media that contained either oleate:BSA or palmitate:BSA (Table 1). After 4 h pre-incubation in palmitate containing medium the cells oxidize exogenous [1-14C]-palmitate at a comparable rate to control, oleate-treated, cells. However, when the cells were pre-incubated in palmitate:BSA for 20 h, the [1-14C]-palmitate oxidation rate was significantly decreased when compared to oleate:BSA pre-incubation (Table 1). Oxidation of exogenous [1-14C]-oleate was also significantly impaired in cells pre-incubated for 20 h in palmitate-containing media. However, glucose oxidation in cells treated with palmitate for 20 h showed a small but significant increase over control cells at this time (Table 1). No difference in glucose oxidation rates was observed at 4 h. Therefore, for sustained alterations in fatty acid oxidation in cardiac myocytes, prolonged exposure to palmitate is required."

    "...Intracellular malonyl CoA levels regulate the activity of CPT-1 and this interaction comprises the rate-limiting step in fatty acid oxidation. We observed an inverse relationship between fatty acid oxidation and intracellular malonyl CoA levels, with the malonyl-CoA levels, in cells incubated in palmitate:BSA for 20 h, being significantly higher than the levels measured in oleate:BSA incubated cells (Table 1). Similarly we also observed a significant increase in malonyl-CoA in palmitate:BSA treated cells incubated for 20 h over cells incubated in the same media for 4 h (Table 1)."

    "...The mechanism by which palmitate induces programmed cell death is unknown. However, inhibition of fatty acid oxidation may occur either by a palmitate-specific enhancement of malonyl-CoA levels as we observed, or by a decrease in cellular free carnitine concentrations."


    Fatty acid-induced apoptosis in neonatal cardiomyocytes: redox signaling. - PubMed - NCBI
    "...After 4 h of incubation in palmitate, no significant changes in the rates of b-oxidation or malonyl-CoA-inhibitable CPT-I activity occurred. Likewise, the myocytes demonstrated no significant accumulation of ceramide over the levels measured in the presence of oleate alone (Fig. 2). In contrast, by 20 h, both CPT-I and b- oxidation were significantly depressed in the myocytes incubated with palmitate. These myocytes demonstrated low rates of oxidation when either [14C]palmitate or [14C]oleate was subsequently provided as energy substrates (18). Consistent with the lowered rates of fatty acid degradation, both triglyceride (18) and ceramide became prominent products of palmitate metabolism (Fig. 2)."
     

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  2. paymanz

    paymanz Member

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    Very Nice,thank you!
     
  3. 2thecloudsabove

    2thecloudsabove Member

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    Problem is theres no food in nature that has isolated palmitate acid. Whole coconut oil have more fatty acids that will increase blood fatty acids.
     
  4. Mito

    Mito Member

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    Similar to niacinamide with a different mechanism of action?
     
  5. hiconscience

    hiconscience Member

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    doesn't meat contain palmitic acid?
     
  6. Regina

    Regina Member

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    Woot! Defibron!:partydance
     
  7. OP
    haidut

    haidut Member

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  8. OP
    haidut

    haidut Member

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    It does, if it is fresh. Peat said it also contains a lot of glycogen, which degrades with time.
     
  9. Terma

    Terma Member

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    Couldn't there be some cell-type-specific implications from the fact they're cardiac myocites? I could subscribe to this from the view that palmitic acid acts more structural than fat-oxidative (with implications for weight issues) but that's mighty specific cell type, no?
     
  10. RMJ

    RMJ Member

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    "palmitate inhibited fatty acid oxidation by up to 90%" thats pretty heavy

    doesn't the heart use mostly fat as fuel?

    would palmitate be bad for the heart?
     
  11. Kyle M

    Kyle M Member

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    On the one hand, this doesn't make sense. Why would fatty acids inhibit fatty acid oxidation? On the other hand, this makes sense. Palmitate is the primary fatty acid produced in de novo lipogenesis, so perhaps the body is set up to sense high levels of that as a sign to oxidize more glucose and not oxidize fat because it's being produced?
     
  12. OP
    haidut

    haidut Member

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    That's what I thought as well, but apparently palmitate acts the same way in liver too. I will post the study later today. So, it does seem to be a genuine FAO inhibitor in tissues other than the heart as well.
     
  13. OP
    haidut

    haidut Member

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    Yep, it seems to be a negative feedback mechanism because fat and glucose compete for oxidation. Palmitate also seems to be a FAO in liver as well, so the effect seems preserved in other tissues as well.
     
  14. OP
    haidut

    haidut Member

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    Inhibiting FAO is good for the heart, this is the very reason Mildronate was designed. Muscles oxidize mostly fat at rest and under exertion they try to switch over to glucose but since glucose oxidation is inhibited by fats this process does not work well in sick/hypo people. This is the reason why people with diabetes for example fatigue so easily under exertion.
     
  15. Wagner83

    Wagner83 Member

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  16. OP
    haidut

    haidut Member

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  17. paymanz

    paymanz Member

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    Maybe in low doses it is beneficial(by replacing cardiolipin fatty acid composition for example?) , but if you take most of your calories from it then you have to use it as fuel.obviously!



    And anyway you make these fats from carbs, even without energy surplus! I guess.


    So probably you only need small amounts of dietary fats for better digestion!
    At least for generally healthy person it is like that.
     
  18. OP
    haidut

    haidut Member

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  19. dfspcc20

    dfspcc20 Member

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    Wasn't palmitic acid discovered from palm oil? I thought that's where the "palm" part of the word came from.
    Likewise, stearic acid was discovered from beef fat, hence the "stear (or steer)" part.
    I could be completely misinformed on that.
     
  20. OP
    haidut

    haidut Member

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    I think stearic comes from the Greek word for butter-fat. Hence the condition steato-hepatosis. The palm oil was probably named after the tree and palmitic acid and was available/named long before palmitic acid was isolated and analyzed.
     
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