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

[Valentijn]

@Valentijn

I am really glad you attacked me in this way. I am also really glad that what we all say is documented here.

I've attacked your claims, and your basis for them.

 

[mariovitali]

@Valentijn

You're using exactly the same methodology as Yasko, except you're selling a liver theory instead of a methylation theory.

I am not selling anything and this was unaccounted for....And I wouldn't want to be in your place if the Liver is indeed involved to be honest.

 

[Valentijn]

I am not selling anything and this was unaccounted for....

"Selling" is often used in a non-commercial context, and can include the promotion of beliefs. But since you brought it up:

Things are happening behind the scenes (including filing for a Patent on how this Research took place.)

 

[mariovitali]

@Valentijn

Ahh right, now i get what you mean. So am i trying to sell anything or not?

Yes, this is true and as you can see i was very honest about this, not trying to play any sort of Games, even though i had no obligation to discuss this here.

I also tend to admit my shortcomings and mistakes. You on the other hand, apparently you have no shortcomings and you make no mistakes because you never admitted your mistakes.

I am also well aware that you are not going to, even now. The point for going through all of this dialog with you is to have as many people as possible looking at their Liver and not listening to your unjustified -and may i also add *dangerous*- dismissals that since Liver enzymes are ok, the Liver is ok.

Did you have a look at your Pancreas by the way?

 

[Tunguska]

I think the idea in the opening post is really good. I briefly went through the study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007066/) and one or two of its references. And the LXR signaling failure in macrophages leading to auto-immunity looks sound to me. What's attractive is it's the first idea I read on this forum that gives a concrete idea of what would drive uncontrolled extracellular purinergic signaling from cell leakage/apoptosis that naviaux launches from, from what I recall. I won't get into this since no one cares but it even looks like a senescence-promoting scenario. Obviously there's no proven link to ME/CFS in this but this looks good enough to explain a disease.

However I read nothing that causally involves the liver or genetics. The OP study stands well on its own. I'd stick to that.

 

[adreno]

However I read nothing that causally involves the liver or genetics. The OP study stands well on its own. I'd stick to that.

I can see why people would think that because of the name (liver x receptor), but this receptor is expressed throughout tissues, even in the brain.

 

[mariovitali]

@adreno @Tunguska

The fact that 6 out of 7 ME/CFS + Fibromyalgia patients have some stage of Liver fibrosis deserves a closer look. It also appears that the OMF has never performed such test to CFS patients, let alone Liver biopsy.

We simply shouldn't rule out things so easily in my opinion.

@Jesse2233 I would like to confirm the involvement of JNK Pathway as it was selected algorithmically as being relevant.

Is your Researcher friend working for a University (or something equivalent) or is he/she an independent Researcher?

 

[Jesse2233]

@mariovitali he is an independent researcher. I will ask his thoughts on JNK

 

[Jesse2233]

@mariovitali he believes JNK is involved and a good target for inhibition

 

[mariovitali]

@nandixon i am CCing you about IL-6.

@Jesse2233
Could you please forward the following to your Researcher friend, given this mention about High Cholesterol levels?

I guess a good question would be why IL-6 is found in high levels in the first place.

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.

Take From : https://www.ncbi.nlm.nih.gov/pubmed/21757719

The capacity of macrophages to clear apoptotic cells, through the efferocytosis mechanism, as well as to reduce cellular cholesterol accumulation contributes to prevent plaque progression and instability. By virtue of its capacity to promote cellular cholesterol efflux from phagocyte-macrophages, ABCA1 was reported to reduce atherosclerosis. We demonstrated that lipid loading in human macrophages was accompanied by a strong increase of IL-6 secretion. I

and

Taken together, our results indicate that IL-6 favors the elimination of excess cholesterol in human macrophages and phagocytes by stimulation of ABCA1-mediated cellular free cholesterol efflux and attenuates the macrophage proinflamma- tory phenotype. Thus, high amounts of IL-6 secreted by lipid laden human macrophages may constitute a protective response

<SNIP>

Reciprocally, activation of Toll-like receptors 3 and 4 inhibits the induction of LXR target genes, such as ABCA1, in macrophages and strongly reduces cholesterol efflux

Note also MERTK :

Notably the expression of factors known to facilitate the recognition and uptake of apoptotic cells by macrophages, such as c-mer proto- oncogene-tyrosine kinase (MERTK, Fig. 5C), TG2 (Fig. 5D), and THBS1 (Fig. 5E), were found significantly induced (21, 58, and 100%, respectively) in THP-1 macrophages treated by IL-6 for 24 h, whereas the expression of complement C1q and milk fat globule-epidermal growth factor-8 was not affected (data not shown).

 

[nandixon]

I looked at the idea that the liver X receptor (LXR) might be inhibited in ME/CFS from a number of different angles and this looks good.

The one potential inconsistency I saw is that increasing LXR activity appears to increase PDK4 expression in the heart, intestine and in fat cells. On the other hand, LXR apparently decreases PDK4 in skeletal muscle.

So if LXR also decreases PDK4 in peripheral blood mononuclear cells (PBMCs), which is what Fluge & Mella used, then it may be that LXR is indeed inhibited. (Fluge & Mella found increased mRNA expression of PDK4 in ME/CFS.)

@Jesse2233, can you ask your researcher friend what support/studies they might have for this statement with respect to PBMCs (e.g., T cells, etc)?:

LXR inhibition would eventually cause PDK upregulation...

 

[Jesse2233]

@nandixon
@mariovitali

Will do!

 

[Jesse2233]

Spoke to my friend

@nandixon

Here's a reference that says that LXR activation can either upregulate or downregulate PDK4 depending on the fasting state of the person.

https://www.ncbi.nlm.nih.gov/m/pubmed/21609322/

In a fed state it downregulates. In a fasting state however it upregulates. I'll keep digging.

He is reaching out to metabolism experts to better pin down PDK4

 

[Jesse2233]

@mariovitali

He said he's not sure about IL-6 being important but that LXR suppression activates Nf-kB which is a master regulator of inflammation. And that in turn might increase IL-6.

 

[mariovitali]

Naviaux et al have found Phospholipids abnormalities. I found the following which may be of interest, regarding LXR, Phospholipids and ER Stress :

The fatty acyl composition of phospholipids determines the biophysical character of membranes and impacts the function of membrane proteins. Here we define a nuclear receptor pathway for the dynamic modulation of membrane composition in response to changes in cellular lipid metabolism. Ligand activation of LXR preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids through induction of the remodeling enzyme Lpcat3. Promotion of Lpcat3 activity ameliorates ER stress induced by saturated free fatty acids in vitro or by obesity and hepatic lipid accumulation in vivo.

and

ER stress is observed in livers of obese mice and humans and has been postulated to be a contributor to metabolic disease. We observed modest changes in systemic metabolism in response to short-term alterations in Lpcat3 activity. In particular, adenoviral expression of Lpcat3 in the livers of ob/ob mice lowered blood glucose and insulin levels. However, more chronic models (e.g. transgenics or knockouts) are likely better suited to test the ability of Lpcat3 to affect the development or progression of metabolic disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889491/


A simple search on PR shows many people are in pre-diabetic state or already having diabetes.

 

[Tunguska]

By the way some of the claims in the OP are not well described in the references. Don't know if this is the one he read but it does a better job:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568699/

Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory responses has not been established. Here, we identify a biphasic program of gene expression that drives production of anti-inflammatory fatty acids 12–24h following TLR4 activation and contributes to down-regulation of mRNAs encoding pro-inflammatory mediators. Unexpectedly, rather than requiring LXRs, this late program of anti-inflammatory fatty acid biosynthesis is dependent on SREBP1 and results in the uncoupling of NFκB binding from gene activation. In contrast to previously identified roles of SREBP1 in promoting production of IL1β during the induction phase of inflammation, these studies provide evidence that SREBP1 also contributes to the resolution phase of TLR4-induced gene activation by reprogramming macrophage lipid metabolism.

Also you might as well link the whole selfhacked article
https://selfhacked.com/blog/about-liver-x-receptors-lxr-and-natural-activators/
Both are 2016-17.

 

[Tunguska]

Also this works with the lipid raft vs pathogen idea that JaimeS posted, in obvious way. Cells might be trying to prevent cholesterol efflux in order to maintain them.

 

[mariovitali]

@Tunguska

I believe that @JaimeS posted one more interesting information : NLRP3

http://forums.phoenixrising.me/index.php?threads/activation-of-the-nlrp3-inflammasome-in-lps-induced-mouse-fatigue-and-its-relevance-to-cfs.43995/page-2

I search for NLRP3 within my docs and found the following :

Interleukin-6 Protects Human Macrophages from Cellular Cholesterol Accumulation and Attenuates the

Pro-inflammatory Response

By promoting the cellular efflux of cholesterol, high- density lipoprotein (HDL) opposes this process and reduces inflammation. Increased levels of LDL lead to its entry into and retention in the arterial wall, where it may be modified by various processes such as oxidation and aggregation1. This has two key adverse consequences: first, modified LDL functions as a ligand for macrophage pattern recognition receptors, including Toll-like receptors (TLRs), and can thereby directly trigger pro- inflammatory signalling pathways; and second, modified LDL is engulfed by macrophages, causing cellular cholesterol accumulation, which in turn amplifies TLR signalling1–6. Increased TLR activity leads to augmented production of cytokines and chemokines, amplification of the inflammatory process and, when combined with the uptake or Intracellular formation of cholesterol crystals, may lead to NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome activation7,8.

In particular, accumulating levels of cellular cholesterol lead to the formation of specific sterols that activate the liver X receptor (LXR)–retinoid X receptor (RXR) heterodimeric transcription factors. The LXR–RXR heterodimers have a range of anti- inflammatory activities — including upregulating the expression of ATP-binding cassette transporters (ABC transporters) ABC subfamily A member 1 (ABCA1) and ABCG1, and promoting the efflux of cholesterol from macrophages — and thus may counter the amplification of TLR signalling by cellular cholesterol accumulation

From another paper :

Oligomycin induced expression of genes involved in cholesterol efflux (Abca1, Abcg4, Stard1) and cholesterol biosynthesis (Hmgr, Mvk, Scap, Srepb2) arguing that loss of coordinated regulation of sterol homeostasis is caused by loss of mitochondrial ATP generation[113]. In turn, accumulation of free cholesterol or fatty acids can trigger mitochondrial dysfunction, which could promote in ammation via loss of LXRα-dependent repression of NF-κB (above) and upregulation of cytokine expression, but also by NLRP3 in ammasome-dependent and –independent pathways

The same paper mentions CYP27A1, LXR, MERTK, Oxysterols, STARD1 :

Activation of LXRs is also achieved by phagocytosis of apoptotic cells by macrophages increasing expression of receptor tyrosine kinase (Mertk), amplifying phagocytosis and cell clearance, and reducing production of in inflammatory mediators.
<SNIP>

Mitochondrial oxysterols therefore act as key cell signalling molecules, the levels of which can be moderated by sulfation (SULT2B1b), esterification (ACAT-1) or metabolism to soluble bile acid derivatives

What is also interesting is the mention -in the same paper- of EBI2, a receptor that is activated by Epstein-Barr virus :

Thus, it is clear that the biological impact of oxysterols are not solely restricted to LXR activation[63-67]. For example, oxysterols also serve as endogenous ligands for G-protein coupled receptor 183 (Epstein-Barr virus- induced gene 2, EBI2)

The paper can be found here :

Mitochondrial function and regulation of macrophage sterol metabolism and in inflammatory responses


@JaimeS on this Thread you mentioned the following :

I was looking at cAMP and Ca2+ literally just last night and thinking that cAMP would be an intriguing therapeutic target. Interesting. Maybe I'll dig mine out -- I tried it when I was first ill, as I mentioned, and my system has really altered since then. Worth a second go.

Interestingly, EBI2 is associated with cAMP :

EBI2 regulates B cell positioning within the lymphoid tissue and is crucial for launching appropriate T cell-dependent antibody response [3-6]. In addition to being crucial for launching correct humoral response, EBI2 is also involved in inflammatory responses [3, 4, 7]. EBI2 is activated by oxysterols and signals through the per- tussis toxin (PTx)-sensitive heterotrimeric G proteins of the Gi/o family leading to a decrease in cyclic adenosine mono- phosphate (cAMP) production, calcium mobilization and stimulation of the extracellular-signal-regulated kinase (ERK) pathway

Unfortunately Resveratrol downregulates several SULT enzymes and as discussed in my posts, i believe that ensuring proper Sulfation is of outmost importance to us.

 

[Tunguska]

@mariovitali Well thanks, but I'm not sure I can use that information myself at the present. I wasn't too aware that IL-6 had partial anti-inflammatory properties, but all of that might be muddled by the context which is atherosclerosis and other questions.

 

[Jesse2233]

My friend has identified four LXRβ agonists in his meta research

• demethoxycurcumin
• isolicoflavonol
• licochalcone E
• silydianin

https://www.ncbi.nlm.nih.gov/m/pubmed/28920350/?i=6&from=liver x receptor