Review: 'Through the Shadowlands’ describes Julie Rehmeyer's ME/CFS Odyssey
I should note at the outset that this review is based on an audio version of the galleys and the epilogue from the finished work. Julie Rehmeyer sent me the final version as a PDF, but for some reason my text to voice software (Kurzweil) had issues with it. I understand that it is...
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LXR (Liver X Receptor) Inhibition as a Root Cause of ME/CFS?

Discussion in 'General ME/CFS Discussion' started by Jesse2233, Sep 22, 2017.

  1. Jesse2233

    Jesse2233 Senior Member

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    A researcher friend of mine is in the early stages of a hypothesis that chronic inhibition of LXR leads to symptoms.

    He sent me his notes to get feedback on. Hoping someone here can help him with constructive thoughts and criticisms.

    His notes:
    • Viruses, bacteria, mold, and other stressors trigger immune responses of TLR3/4 (Toll-Like Receptor) on macrophages.

    • Through the IRF-3 (Interferon regulatory) pathway TLR4 suppresses LXR (Liver X Receptor) in the first phase of a normal immune reaction to an infection

      This preserves certain fatty acids for the second phase of the immune reaction called resolution

    • LXR is supposed to be reactivated at around 12-24 hours after infection for resolution. However, there are possible ways this could get inhibited

      LXR works by activating all sorts of genes. One is called SBREP1. High cholesterol levels in the cell is an inhibitor of SBREP1 and can prevent resolution from occurring.

    • If resolution doesn't occur, damaged and dead cells don't get cleared in apoptosis. Apoptotic cells release distress signals (CDR) which call to T cells and cause them to respond to distress signals (they view these apoptotic cells as antigens).

    • This is a major risk and cause of chronic inflammatory and systemic autoimmune illness complete with T cell expansion and activation, TGF-b over-expression, and B-cell autoantibody release. Basically something very much resembling the immune side of ME/CFS.

    • LXR has recently connected metabolism and immunity. So LXR inhibition has metabolic effects. Genes we know are upregulated like PPAR delta appear to be compensatory to the loss of LXR.

    • LXR inhibition would eventually cause PDK upregulation and PDH inhibition. This combined with diminished phagocytosis (the clearance of dead cells) appears to cause the body to go into a sort of survival mode.

    • Without TGF-b, this illness would probably be fatal. Loss of phagocytosis is bad news. Dead cells leak stuff like DNA which can further drive autoimmune processes and cause necrosis. Necrosis would lead to organ damage and failure and death if it weren't for increased TGF-b and IL-10.
    Tagging some people who might know more about LXR and its downstream effects: @Hip, @nandixon, @mariovitali

    Thanks!

    References:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007066/figure/F2/?report=objectonly
    https://i2.wp.com/selfhacked.com/wp-content/uploads/2015/10/liver-x-protien-lxr-statins.jpg?ssl=1
    http://journal.frontiersin.org/article/10.3389/fimmu.2017.00909/full
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/
    https://i0.wp.com/selfhacked.com/wp-content/uploads/2015/10/JCI0627883.f3.jpg?ssl=1
     
    Last edited: Sep 22, 2017
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  2. Learner1

    Learner1 Professional Patient

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    Fascinating!

    Does he have any suggestions for fixing this problem??
     
  3. Jesse2233

    Jesse2233 Senior Member

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    @Learner1

    Yes, he thinks rapamycin addresses many parts of this chain
     
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  4. Eastman

    Eastman Senior Member

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  5. Alvin2

    Alvin2 If humans were rational...

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    I don't have the brain power to read your post but i do know primary biliary cirrhosis can cause symptoms similar to ME/CFS. How does this relate to this theory, i have no idea
     
  6. Jesse2233

    Jesse2233 Senior Member

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    For those interested, here are some natural LXR agonists / activators
    upload_2017-9-22_20-41-12.png
     
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  7. mariovitali

    mariovitali Senior Member

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    @Jesse2233

    Thank you for this post. Some key points (i had to re-post this with correct data) :



    1) The following link you mentioned :

    http://journal.frontiersin.org/article/10.3389/fimmu.2017.00909/full


    Contains mentions on the roles of GAS6, MERTK (among others) in Apoptotic clearance.

    2) For more about LXR, GAS6, MERTK and Apoptosis see here :

    http://forums.phoenixrising.me/inde...s-discussion-thread.53372/page-28#post-895820

    and also here :

    http://forums.phoenixrising.me/inde...s-discussion-thread.53372/page-28#post-896762

    Hopefully, these will be considered from Ron and the OMF.


    3) Now, look at the following table that shows SNPs with less that 5% MAF and their Homozygous/Heterozygous frequencies among 62 people having CFS, Post-Finasteride Syndrome, Post-Accutane Syndrome and Fibromyalgia. This table is sorted out of 182 Gene types.

    Observe how many entries we have on CYP27A1, PPARs, XDH, SERCA :


    SNPs.png

    It is time to expose yet one more node of the Network Analysis graph which shows Xanthine Oxidase (CC @Gondwanaland ) with which XDH Gene is directly associated with (shown in top right corner) :
    network8.png


    In other words, Network Analysis has selected many of the Genes appearing on the MAF Table shown above and actually i used these results to test SERCA, PPARs, CYP27A1 etc to the sample of DNA Data i had. More specifically it selected :

    -SERCA (associated with Calcium transport - more on this coming up)
    -CYP27A1
    -TYRO3 + GGCX (=Vitamin K Related)
    -Xanthine Oxidase (XDH)
    -PPARs
    -LXR (not shown at the table as its MAF is > 5%)

    What i am trying to say is that LXR is one piece of the puzzle but there are more things at play. I will send these results to Ron through @Janet Dafoe (Rose49) so they can outright test these findings.

    However, it is interesting that 3 independent Researchers (to the best of my knowledge it's me, @Bdeep86 and a third one) show a different direction to this Research which is great.
     
  8. Jesse2233

    Jesse2233 Senior Member

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    Very interesting, thanks for that @@mariovitali

    Do you have a grand unifying theory that contextualizes your results?
     
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  9. mariovitali

    mariovitali Senior Member

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    The big picture here is the Liver, i will post more soon about this.

    Thank you again for this post @Jesse2233
     
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  10. adreno

    adreno PR activist

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    mariovitali likes this.
  11. adreno

    adreno PR activist

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    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065641
     
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  12. adreno

    adreno PR activist

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    On the other hand:

    And:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007066/
     
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  13. Cheesus

    Cheesus Senior Member

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    I had idiopathic elevated ALT for a long while. The reference range is 0-40, but I was averaging around 120 and went all the way up to 300 at one point. We were never able to find out the cause.

    It wouldn't surprise me at all if liver dysfunction played a role for some people.
     
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  14. Hip

    Hip Senior Member

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    I have never heard of the liver X receptor before, so without further investigation, I would not know what to make of this research.

    However, I did find this study on LXR knockout mice (mice genetically altered so that they don't have any liver X receptors), which shows what happens in the complete absence of LXR activation. Basically there were some neurodegenerative brain changes in these knockout mice, including neuronal loss and astrocyte proliferation.
     
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  15. mariovitali

    mariovitali Senior Member

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    @adreno

    It appears that LXR activation through pharmacological means leads to steatosis. Natural agonists do not create the problem you mentioned. I am sure i read this somewhere, i will try to find the reference and post it here.

    Regarding UDCA you are right, apparently UDCA/TUDCA should not be used from people with certain SNPs on LXR (?). This is why i think we need a Liver expert on board.

    @Cheesus

    If possible, take a Fibroscan (aka Liver Elastography) test to rule out Liver Fibrosis.

    EDIT : Apart from the fact that 6 out of 7 CFS patients that took a Fibroscan had fibrosis (Stage 2 and Stage 3) what is also alarming is the number of mentions in PR from people having low albumin levels.
     
    Last edited: Sep 23, 2017
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  16. aquariusgirl

    aquariusgirl Senior Member

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  17. wastwater

    wastwater Senior Member

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    IRF4 is something of interest to me
     
  18. mariovitali

    mariovitali Senior Member

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    @adreno

    FYI :


    https://www.ncbi.nlm.nih.gov/pubmed/24666673
     
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  19. Isaiah 58:11

    Isaiah 58:11

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    A Sun-Scorched Land
    :bang-head: I had low albumin. (Which the doctor said was fine :rolleyes:.) So that is now an alarming number + 1. Has anyone polled the patients here to look for trends like this?
     
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  20. perrier

    perrier Senior Member

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    There must be folks here who have taken rapamycin. Or alternatively, has it been tried on CFS patients anywhere? What would the result be?
     

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