LXR (Liver X Receptor) Inhibition as a Root Cause of ME/CFS?

[Jesse2233]

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

 

[Learner1]

Fascinating!

Does he have any suggestions for fixing this problem??

 

[Jesse2233]

@Learner1

Yes, he thinks rapamycin addresses many parts of this chain

 

[Eastman]

This reminded me of the thread by @Bdeep86: Over Activation of Farnesoid X Receptor In the Ilium Driving Liver and Gut Disharmony

Also, this paper, of which I don't have full access:

LXRS and FXR: the yin and yang of cholesterol and fat metabolism.

 

[Alvin2]

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

 

[Jesse2233]

For those interested, here are some natural LXR agonists / activators

 

[mariovitali]

@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 :

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) :

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.

 

[Jesse2233]

Very interesting, thanks for that @@mariovitali

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

 

[mariovitali]

Very interesting, thanks for that @@mariovitali

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

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

Thank you again for this post @Jesse2233

 

[adreno]

Both @mariovitali and @Bdeep86 has talked about the importance of UDCA/TUDCA, but that seems to inihibit LXR. Same goes for schisandra, another herb generally associated with liver health. And activation of LXR causes hepatic lipogenesis.

Ursodeoxycholic acid inhibits liver X receptor α-mediated hepatic lipogenesis via induction of the nuclear corepressor SMILE.

Schisandra polysaccharide inhibits hepatic lipid accumulation by downregulating expression of SREBPs in NAFLD mice

 

[adreno]

Liver X receptor (LXR) activation improves glucose homeostasis in obesity. This improvement, however, is associated with several side effects including hyperlipidemia and hepatic steatosis. Activation of peroxisome proliferator-activated receptor alpha (PPARα), on the other hand, increases fatty acid oxidation, leading to a reduction of hyperlipidemia. The objective of this study was to investigate whether concurrent activation of LXR/PPARα can produce synergistic benefits in treating obesity-associated metabolic disorders. Treatment of high fat diet-induced obese mice with T0901317, an LXR activator, or fenofibrate, the PPARα agonist, or in combination alleviated insulin resistance and improved glucose tolerance. The combined treatment dramatically exacerbated hepatic steatosis.

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

 

[adreno]

On the other hand:

A significant conceptual advance in our understanding of the importance of LXR and PPAR signaling pathways in immunity has come from the realization that these nuclear receptors influence self-tolerance and the development of systemic autoimmune disease. Lipid metabolism has been implicated as an accelerating factor in autoimmunity; however, a strong mechanistic explanation for these findings has remained elusive. Recently, Castrillo and colleagues demonstrated that mice deficient in LXRα and β spontaneously develop lupus-like disease characterized by the presence of circulating autoantibodies, immunoglobulin deposition in tissues and immune cell infiltrates resulting in organ immunopathology, such as glomerulonephritis.

And:

The ability of PPARs and LXRs to integrate metabolic and inflammatory signaling makes them attractive targets for pharmacologic intervention in metabolic and autoimmune diseases. It is worth noting that a review of the literature indicates that pharmacologic activation of PPAR or LXR has protective effects in nearly every inflammatory and autoimmune disease model.

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

 

[Cheesus]

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.

 

[Hip]

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.

 

[mariovitali]

@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.

 

[aquariusgirl]

http://www.ebiomedicine.com/article/S2352-3964(17)30374-2/fulltext

@mariovitali

@Bdeep86

 

[wastwater]

IRF4 is something of interest to me

 

[mariovitali]

@adreno

FYI :

Nuclear receptor transcription factors are ligand-activated proteins that control various biological events from cell growth and development to lipid metabolism, and energy and glucose homeostasis. Nuclear receptors are important drug targets for metabolic diseases. Liver X receptors (LXRs) are nuclear receptor transcription factors that play essential roles in regulation of cholesterol, triglyceride, fatty acid, and glucose homeostasis. LXR-deficient mice have shown the association of LXR-signaling pathway dysfunction with several human pathologies including atherosclerosis, hyperlipidemia, Alzheimer's disease and cancer. Thus, LXRs are promising pharmacological targets for these diseases. Synthetic LXR agonists may lower cholesterol, but increase triglyceride and induce fatty liver. The naturally occurring LXR ligands, with moderate activity, may serve as nutraceuticals for prevention or treatment of the disorders, while minimizing potential side effects. In this review, recent advances in natural LXR modulators are summarized including agonist, antagonist and the modulator of LXR pathway.

https://www.ncbi.nlm.nih.gov/pubmed/24666673

 

[Isaiah 58:11]

@adreno 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.

I had low albumin. (Which the doctor said was fine .) So that is now an alarming number + 1. Has anyone polled the patients here to look for trends like this?

 

[perrier]

@Learner1

Yes, he thinks rapamycin addresses many parts of this chain

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