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

[Jesse2233]

Good news! My friend is talking to Ron Davis on Friday about LXR

 

[Jesse2233]

Dr Davis has reviewed my friend's theory and is sharing it with the Stanford team, he's also looking into possible connections with rapamycin

 

[anni66]

One example is methylation problems.

This is an interesting thread for me. My daughter has had skin reaction problems following chickenpox ( when under 5) and glandular fever /mono when 14. I never linked the skin problems/ allergies to liver function - our NHS was useless for this when she was small, treated it as eczema that she would grow out of, prescribed multiple hydrocortisone creams and we eventually saw a naturopath who determined an intolerance for bleached food. Cut this out for a while and the skin issues receded ( eat too much bleached flour/sugar and it comes back).

Naturopath also advised that things would kick off again at puberty with headaches/ dizziness and skin - as my daughter got glandular fever and ME it's a bit academic, but the glandular fever has increased the intolerance/ sensitivity, and the migraines and dizziness have been issues.

I didn't realise that food is bleached with benzoates, and that the problems we have had with coloured pills ( certain E numbers) is salicylates - all of these implicate liver not being able to process compounds properly. Problems with sulfonation would also I think affect methylation?

We also have symptoms of hypothyroid, though tests are in UK range - but I am now thinking that this could be due to hormonal synthesis in liver also not working properly? I imagine at puberty there is a huge increase in liver function required for this.
We had a very disappointing appointment with an endocrinologist, who had no notes, took no history, and was ready to dish out thyroxine like sweeties. She will get some testing, but appointment and details still to come through.

My current problem is that she has tested positive for H Pylori and I have concerns re the NHS treatment protocol for this - she's currently functioning at around 25-30%, mostly bedbound. I've looked at toxaprevent, which would be a more targeted treatment, but don't know the implications for liver. Resolving H Pylori could greatly affect fatigue and brain fog which preclude doing anything much.

Can anyone suggest testing/processes which may be of some use? My scientific knowledge is improving, but serious lack of sleep recently have impacted any logical thought processes!

 

[mariovitali]

@anni66 please consider taking a Fibroscan test

 

[anni66]

@anni66 please consider taking a Fibroscan test

Thanks @mariovitali Can you advise what is this please?

 

[mariovitali]

Fibroscan is an alternative to Liver Biopsy. Note that even if Liver enzymes are normal, you may have advanced Liver Disease.

You can ask your GP although having lived in the UK i am quite certain that a GP will only approve a Fibroscan in case of elevated Liver Enzymes only.

Here is more info :

http://www.fibroscan.com/en/products

 

[Seven7]

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?

I had low albumin. Never took those drugs

 

[anni66]

Fibroscan is an alternative to Liver Biopsy. Note that even if Liver enzymes are normal, you may have advanced Liver Disease.

You can ask your GP although having lived in the UK i am quite certain that a GP will only approve a Fibroscan in case of elevated Liver Enzymes only.

Here is more info :

http://www.fibroscan.com/en/products

Many thanks for this - we have a GP appointment next week so I will find more info to back up request.

 

[mariovitali]

@anni66

No problem. I also suggest you test for Transketolase, Albumin, Zinc, Copper, Ceruloplasmin and Total Bile Acids..i know these are difficult to get but i am writing them in any case.


@Inester7

How did you get ME/CFS?

 

[anni66]

@anni66

No problem. I also suggest you test for Transketolase, Albumin, Zinc, Copper, Ceruloplasmin and Total Bile Acids..i know these are difficult to get but i am writing them in any case.


@Inester7

How did you get ME/CFS?

Thanks, i will try

 

[mariovitali]

Here is a small update and a paper that i wanted to share with you.

One of the findings by Researchers for ME/CFS is Mitochondrial Dysfunction. I wanted therefore to explore furhter potential causes/associations for this finding.

This is a snapshot from one of the Tools i am using :

Basically the tool identifies as relevant the Mitochondria (which we would surely expect) and also MTOR pathway.

What is also interesting is the entry PGC1. Regarding PGC-1 we read :

• The protein encoded by this gene is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with PPARgamma, which permits the interaction of this protein with multiple transcription factors. This protein can interact with, and regulate the activities of, cAMP response element binding protein (CREB) and nuclear respiratory factors (NRFs). It provides a direct link between external physiological stimuli and the regulation of mitochondrial biogenesis, and is a major factor that regulates muscle fiber type determination. This protein may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity. [provided by RefSeq, Jul 2008]

More importantly, we also read :


"In the liver, activation of LXR led to the suppression of the gluconeogenic program including down-regulation of peroxisome proliferator-activated receptor coactivator-1(PGC-1), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase expression. "


Interestingly, Network Analysis has captured this association between LXR and Gluconeogenesis (see LXR and Glucose-6-Phosphatase below):

So we may hypothesise that LXR and Gluconeogenesis may be somehow associated with Mitochondrial Dysfunction.

 

[anni66]

From memory ( and lack of sleep may factor in), if there is an inability to produce sufficient ATP via glycolysis, the body will switch to fat burning ( perhaps upregulating liver?) before switching to amino acids as a last resort. The amino acid used as fuel would suggest that the fat/ liver option is not sufficient/ impaired. I had thought that this might be due to SULT snps and sulfation problems, but perhaps thete is another mechanism

 

[mariovitali]

@anni66

There are a lot of other things at play and your mention about sulfation is spot on. ME/CFS exposes our vulnerabilities if that makes sense to you. This is because key Liver functions are being downregulated and then the perfect storm sets in.

We must keep in mind that people get ME/CFS by different ways. I am really happy that some people begin to consider that their problems may have started by certain medications.

If you look at the output of Feature Selection shown in my previous message you can an entry mrp2.

MRP2 is Multi-Drug resistance associated protein 2.

Some interesting excerpts from : https://www.ncbi.nlm.nih.gov/pubmed/18626887

Medications can directly inhibit mtDNA transcription of ETC complexes, damage through other mechanisms ETC components, and inhibit enzymes required for any of the steps of glycolysis and b-oxidation. Indirectly, medications may damage mitochondrial via the production of free radicals, by decreasing endogenous antioxidants such as glutathione and by depleting the body of nutrients required for the creation or proper function of mitochondrial enzymes or ETC complexes. Damage to mitochondria may explain the side effects of many medication

and

Ox-phos is the major cellular energy-producing pathway. Energy, in the form of ATP, is produced in the mitochondria through a series of reactions in which electrons liberated from the reducing substrates nicotine adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH) are delivered to O2 via a chain of respiratory proton (H+) pumps [8

and

Compounding the problem, once a mitochondrion is damaged, mitochondrial function can be further compromised by increasing the cellular requirements for energy repair proc- esses [9]. Mitochondrial dysfunction can result in a feed- forward process, whereby mitochondrial damage causes additional damage

So what do we do about it? Assuming that Hepatitis B is a viral infection which affects Liver function :


Please read the following excerpts below from this paper : https://www.nature.com/articles/nri.2016.62

“liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients.The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury."


In the same paper we read mentions of Autophagy, Unfolded Protein Response (UPR) and how these topics are relevant to a Hepatitis B virus infection:

"During autophagy ER integrity is restored to maintain the viral replication. Therefore, autophagy promotes the hepatocyte survival[67] and in turn helps to maintain the viral persistence which is serious risk factors for liver cancer[68]. Taken together these observations support the idea that HBV proteins harbor oncogenic effects, mediated by the induction of ROS and ER stress factors.Thus, it is pertinent to control the liver injury caused by induced ROS and ER stress by effective antioxidants and ER stress relief strategies"

 

[wastwater]

If interferon regulatory factor was missing or silenced isn’t that a lot like a switch that would be left on or open permanently ie no regulation giving high interferon endlessly and the side effects of that,driven along by just having EBV in latency

 

[aquariusgirl]

http://www.sciencedirect.com/science/article/pii/S0960076016301029

 

[aquariusgirl]

https://www.ncbi.nlm.nih.gov/m/pubmed/2830204/

Does this mean you can’t absorb forms of Vit D if your bile salts are messed up?

 

[mariovitali]

http://www.sciencedirect.com/science/article/pii/S0960076016301029

This is a good find @Violeta Thanks !

 

[aquariusgirl]

http://www.sciencedirect.com/science/article/pii/001650859190407C

Iron excretion thru bile acids when the liver is loaded with iron