Jesse2233
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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:
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
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.
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
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