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No Relationship Between Dietary Linoleic Acid Intake And Tissue Arachidonic Acid Content

Discussion in 'Scientific Studies' started by lampofred, Apr 10, 2017.

  1. lampofred

    lampofred Member

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    Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review

    Numerous studies showed that there is no relationship between dietary linoelic acid intake (which the primary PUFA we consume) and tissue arachidonic acid content (the highly unsaturated PUFA from which the harmful prostaglandins are derived from). Several studies actually found an inverse correlation between dietary linoleic acid intake and tissue arachidonic acid content....

    Furthermore, one study found that in just 7 days of consuming .50 grams of AA from eggs/white meat (which have about .08 grams of AA each, which means around 6 eggs daily), tissue AA content increased by 52%.

    So these studies show that eating eggs and lean meat while avoiding other sources of PUFA actually massively increases tissue PUFA content. Damn.

    EDIT: Reading closely, however, what DID help consistently was a low-fat diet. So instead of avoiding PUFA, it might be best to avoid all fat in general and up the carb-intake.
     
  2. Liubo

    Liubo Member

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    This can happen in the short term because the enzyme that turns linoleic acid into arachidonic acid becomes much more active when the body gets low on linoleic acid. Aspirin has been shown to partly block this enzyme, while iron overload causes the enzyme to work harder.
     
  3. Such_Saturation

    Such_Saturation Member

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    That's messed up yo
     
  4. ecstatichamster

    ecstatichamster Member

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    Ray says these pufas get stored. They are very toxic. So no surprise thst the body efficiently removed them from blood plasma.
     
  5. Mufasa

    Mufasa Member

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    Tagging at @haidut because he seemed to have studied PUFA metabolism a lot.
     
  6. haidut

    haidut Member

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    Arachidonic acid is synthesized as needed. I would not take a single measure of tissue levels as a reliable metric. In cases where tissue injury is present, probably a lot of arachidonic acid will be synthesized on-demand. Also, given that arachidonic acid can only be synthesized from linoleic acid I am not buying the argument that controlling linoleic acid intake has no effect on arachidonic acid levels. In metabolic wards where food intake can be tightly controlled it has been shown that restricting linoleic acid and achieving EFA deficiency quickly depletes arachidonic acid and lowers most inflammatory biomarkers. So, PUFA restriction does have an effect, which observational studies probably cannot measure due to poor depletion status in the general population and on-demand synthesis of arachidonic acid which single measurements may miss.
     
  7. Daft

    Daft Member

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    I just want to say I've researched the AA amounts in many different foods, using nutritiondata.com, I believe its 20:4 undifferentiated chain fatty acid(only info given, tho it seperates into o3 and o6 forms, I assume o6 form is the bad one), and have found some interesting things. 1 egg has .080g or 80mg, salmon and fatty fish are stunningly high, sardines about 300mg/100g, salmon 300-500mg if wild or farmed. For meats, Beef is often lowest, followed by pork, chicken fat is highest.

    I've suspected connections between AA intakes and various problems I've had, but at other times when theyve resolved, AA no longer exacerbates. Also originally suspected a connection based on negative effects of using DUCK FAT as a fat, probably highly concentrated in AA!! eugh...

    Its supected in chronic/auto immune inflammatory conditions AA metabolism acts differently and reducing its intake is helpful, such as an apparent common tip to avoid eggs in arthritis, whereas in normal people(without chronic inf disorder) this AA metabolism isnt messed up (unfortunately cant remember study I read this)

    For example:
    Pork, fresh, enhanced, loin, tenderloin, separable lean only, cooked, roasted Nutrition Facts & Calories
    Lean pork has 50mg of 20.4 fatty acid if you expand the fatty acids section. Bacon has 150mg for example. Fatty chicken is usually 130mg. Fatty beef usually remains below 75mg! Dairy has 0mg!

    Another thing I've read is a vegetarian diet can cause Crohns/IBD to go into remission and stay that way, and suspected AA may be part of why. Learnt from a Nutritionfacts.org video
     
  8. Travis

    Travis Member

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    I just read that curcumin—a cyclooxygenase down-regulator—reverses Crohn's to a great extent.

    Perhaps arachidonic acid is made on demand, and most of it turns straight into eicosanoids? Maybe the sum enzymatic rates of cyclooxygenase I, cyclooxygenase II, and lipoxygenase are greater than the linoleic acid elongase and desaturase enzymes?

    Perhaps more informative would have been a measure of all products? and the correlation between linoleic acid intake vs eicosanoid concentration?
     
  9. Daft

    Daft Member

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    Are you asking me? Or about the OP study?

    Also randomly I recall something related to the enzymes, I read somewhere a historically vegetarian Indian ethnicity has recently begun eating meat in the past decade or so and as a result they are developing abnormal rates of inflammatory diseases, I think their enzyme for converting AA to metabolites is suspected to be genetically upregulated.
     
  10. Mufasa

    Mufasa Member

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    What doy you mean with synthesized as needed? Do you think we need AA and his derived PGs for injuries?
     
  11. haidut

    haidut Member

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    Yes, small amounts are necessary for male fertility and things like uterine contractions and initial immune response. It is the chronic inflammation that is the problem, as excess arachidonic acid will readily metabolize into excess prostaglandins and other inflammatory mediators, whether you need them or not.
     
  12. Travis

    Travis Member

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    I think the point is that the linoleic acid ⟶ arachidonic acid ⟶ eicosanoid rate is probably so fast in the inflammatory state that simply measuring arachidonic acid says little about true eicosanoid potential—it can be seen as an intermediate form, an ephemeral molecular species. A better metric might simply be measuring linoleic acid directly. You could examine the Vmax rates of each enzyme, as well as the total synthesis rate, to get an good idea about this.

    But check-out this chart:
    prostaglandin.png reprinted without permission from Godley [1].

    The odds ratio for prostate cancer vs linoleic acid is quite high—higher than any other lipid measured, and higher than anything I've ever seen (androgens, growth hormone, dairy consumption, and prolactin not excluded.) Unfortunately, they did not measure arachidonic acid but they measured three other lipids. (I don't think that α-linolenic acid is a significant precursor for any of the eicosanoids, but I could be wrong. But judging by it's structure, you might think that it could be a precursor to eicosapentaenoic acid—perhaps created through the very same elongase and desaturase enzymes as arachidonic acid from linoleate.*)

    The first one on the list, eicosapentaenoic acid, is similar to arachidonic acid (a.k.a. eicosatetraenoic acid; one less double-bond) and is a precursor to some eicosanoids—but of a different type: the leukotrienes. This is what pharmacologist Juan J. Moreno has to say about that:

    'The beneficial effects of fish oil on inflammation have been attributed to the content of eicosapentaenoic (EPA)/docosahexaenoic acid. EPA is also a substrate for arachidonic acid (AA) cascade enzymes, but it induces the production of alternative eicosanoids such as 3-series prostanoids and 5-series leukotrienes, which are considered to be less proinflammatory than AA metabolites. However, the molecular basis of this action is poorly understood.' ―Moreno
    You can read about how the leukotriene subclass of eicosanoids differs from the arachidonic acid-derived prostaglandins, in vitro, in his study—with a free full-text link below [2].

    Judging by the graph above↑, you would get the impression that eicosapentaenoic acid is less carcinogenic that linoleic acid: the precursor for eicosatetraenoic acid (a.k.a. arachidonic acid)—at least to the prostate. It might also appear from the chart above↑ that linoleic acid could perhaps be a better indicator of prostaglandin production that the ephemeral intermediate arachidonic acid.

    You would think that arachidonic acid concentrations would correlate with prostate cancer risk, but perhaps not as much as linoleic acid. It's probably true that the body will simply store more linoleic acid, and a good biochemist would probably measure both types. If arachidonic acid is released to make prostaglandins, the total conversion (linoleic acid ⟶ arachidonic acid ⟶ eicosanoid) must stop without a store of linoleic acid on standby.

    [1] Godley, Paul A., et al. "Biomarkers of essential fatty acid consumption and risk of prostatic carcinoma." Cancer Epidemiology and Prevention Biomarkers 5.11 (1996): 889-895.
    [2] Moreno, Juan J. "Differential effects of arachidonic and eicosapentaenoic acid-derived eicosanoids on polymorphonuclear transmigration across endothelial cell cultures." Journal of Pharmacology and Experimental Therapeutics 331.3 (2009): 1111-1117.
    [*] Edit: This does appear to be the case. Alpha-linolenic acid has been shown to be converted into eicospentaenoic acid in vivo by using ¹³C-radiolabled α-linolenic acid and determined by chromatography–MS. [3].
    [3] Burdge, Graham C., and Stephen A. Wootton. "Conversion of α-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women." British Journal of Nutrition 88.4 (2002): 411-420.
     
  13. haidut

    haidut Member

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    Thanks.
    Peat said a few times, and I have seen it in studies, that it is the direct signalling effects of linoleic and linolenic acids that is actually a bigger issues long term than the inflammatory cascade through arachidonic acid. Linoleic and linoleinic acids have "membrane" destabilizing properties that arachidonic acid does not (to my knowledge), so they make the cell more vulnerable to all kinds of stress mediators and toxins. They also make the cell very hydrophilic, which is probably the most dangerous systemic effect of these acids. In effect, linoleic acid is the fatty acid equivalent of estradiol and in animal studies produces the same growth effects on female reproductive organs as estradiol, even when it is not converted to arachidonic acid.
     
  14. Travis

    Travis Member

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    Chen, Wei, Timothy R. Pawelek, and Richard J. Kulmacz. "Hydroperoxide dependence and cooperative cyclooxygenase kinetics in prostaglandin H synthase-1 and-2." Journal of Biological Chemistry 274.29 (1999): 20301-20306.

    "Measurement of PGHS-1 Cyclooxygenase Kinetics—PGHS-1 cyclooxygenase kinetics were determined for reactions with 0.5–20 mM arachidonate using both radioisotope and oxygen electrode measurements (Fig. 1)."

    To give an idea for how fast arachidonic acid becomes prostaglandin G₂, and then prostaglandin H₂, this is a good article to check-out.
    "The cyclooxygenase activity of prostaglandin H synthase (PGHS)¹ catalyzes the oxygenation of arachidonic acid to PGG₂, a key control step in the biosynthesis of all prostanoids (1)."

    I'm getting the impression that prostaglandin H synthase is an enzyme complex composed of two enzymes, a peroxidase and a cyclooxygenase. The peroxidase adds H₂O₂ to arachidonic acid forming prostaglandin G₂ which is then quickly isomerized to prostaglandin H₂ by nearby cyclooxygenase. Kinetic rates for both component enzymes had previously been reported, but what is more useful is the rate of the entire process: the conversion of arachidonic acid into the stable and bioactive prostaglandin H₂.
    "The values of the fixed parameters were: Vmax(POX), 165 s⁻¹ ; Km(PGG), 2.5 mM; Vmax(COX), 15 s⁻¹ ; Km(AA), 3 mM; and Kp, 21 nM (for PGHS-1) or 2.3 nM (for PGHS-2). These values are based on experimental observations (6, 12, 17). The Vmax values were scaled to give comparable activities for PGHS-1 and -2, based on the reported cyclooxygenase activities of the recombinant human isoforms (6). The initial conditions were: E, 10 nM; AA, 0.4–100 mM, and PGG₂ (or equivalent hydroperoxide), 1 nM."

    It's apparent that cyclooxygenase is the limiting enzyme—peroxidase having a Vmax eleven times greater. Here is a graph of how quickly cyclooxidase converts arachidonic acid into prostaglandin H₂.

    AA.png [Figure 1] click to embiggen
    The line represents the rate (∂S/∂t) in μM per second, which tapers-off over time as the test tube's concentration of arachidonic acid lowers (the more consumed). It's easy to see how the free arachidonic acid concentration couldn't become very large in the cell.

    The maximum velocity is roughly the
    Vmax of cyclooxygenase, since the peroxidase is 11 times quicker. This is equal to 15 μmol/s, and the graph in Figure 2 indicates ~10 μmol/s averaged over the first second. This is for one unit.
    "The cyclooxygenase specific activities ranged from 80–100 units/mg protein for PGHS-1..."

    The total conversion rate for one milligram protein would then be ~1 mol/mg·s, and one mole of arachidonic acid is of course 6.022 × 10²³ individual molecules.

    Obviously the arachidonic acid which is stored as phospholipids would be safe, but you'd expect any free AA to be rapidly converted to prostaglandin H₂ at a rate of nearly one mole per milligram protein per second. So you might not even expect much variation of arachidonic acid in normal tissue; what you would expect is exactly what is found: High linoleic acid concentrations in some people, primarily in the adipose tissue. This is associated with cancer and would be expected to produce an increased steady-state stream of free arachidonic acid converted nearly simulateneously to prostaglandin H₂ which binds the PPARγ nuclear receptor—inducing transcription of mRNA encoding proteins such as fatty acid synthesase whose function is to store energy at the expense of metabolism. It should be no surprise that PPARγ is involved in hibernation and diabetes.

    The review article of this thread's title lists all of the studies the author had found on this. He has a nice table, but I think it would be better with one more column: Tissue Measured. The inconsistent results—some studies showing changes, some not—could possibly be attributed to this one fact alone, as not all membranes may be enriched to the same extent. There may be evolutionary reasons to have phospholipid-bound arachidonic acid high in certain membranes, in certain locations, and low in others. And one might think the cells turnover rate could, in part, determine the extent in which it's enriched by dietary lipids.
     
  15. Travis

    Travis Member

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    Good point. It's easy to get to focused on prostaglandins and forget about the inherent effects of linoleic acid, a bioactive molecule in its own right. It has the right shape to displace estrogen from sex steroid binding protein, and it has even been shown to be the fatty acid most capable of displacing tryptophan from serum albumin (I'm serious, and I'll find the study if anyone asks to see it.) Free tryptophan incrases brain serotonin, and brain serotonin stimulates the production of growth hormone. Linoleic acid is the most problematic fatty acid for a number of reasons despite having only two double bonds.
     
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