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

[Isaiah 58:11]

@perrier Yes, it has: http://forums.phoenixrising.me/inde...mune-helps-5-me-cfs-patients-in-dallas.50550/

 

[adreno]

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

Sounds good in theory. But is it true? Morin is a flavonoid. If that can alleviate steatosis, surely it is possible a natural compound with the opposite effect can do harm.

Our data reveal that morin is a dual antagonist of LXRα and LXRβ and suggest that morin may alleviate hepatic steatosis and other associated metabolic disorders via the suppression of LXR signalling and, therefore, shows promise as a novel therapy or nutraceutical for nonalcoholic fatty liver disease.

https://www.ncbi.nlm.nih.gov/pubmed/28646531

 

[mariovitali]

@Isaiah 58:11

From Wikipedia :

Albumin is synthesized in the liver, and low serum albumin may be indicative of liver failure or diseases such as cirrhosis or chronic hepatitis. Hypoalbuminemia can also present as part of the nephrotic syndrome, in which protein is lost in the urine due to kidney damage. Low albumin levels can be an indicator of chronic malnutrition or protein losing enteropathy.

I believe that we have some kind of Chronic Hepatitis / Inflammation of Liver that perpetuates a vicious cycle.

@adreno

The truth is that i don't know. Perhaps the trick is to activate LXR through other means (=Oxysterols? / PPARs ?) and not directly.

I am taking Bee Pollen for the last 10 days, 3000 mg per day before food. I would have felt something is not right by now but then again this is me, maybe this will not be the case for others.

Someone with knowledge in Liver/Bile Acid/Cholesterol metabolism should be looking at this hypothesis.

 

[Learner1]

I believe that we have some kind of Chronic Hepatitis / Inflammation of Liver that perpetuates a vicious cycle

An infectious disease specialist looked at my labs (high serum ferritin, AST, ALT) and pronounced that I had hepatitis... not A, B, or C, but something unspecified.

My naturopath thinks one or more of my infections (c. pneumoniae, EBV, etc.) has set up shop in my liver.

A gastro/liver specialist said "that's ridiculous, no one has infections like that in their liver," and told me to stop taking supplements as they were causing liver inflammation and to get a colonoscopy.

Working the infectious angle and treating hemachromatosis has improved my labs to almost normal. And infections do tend to end up in the liver - just a few examples:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2932915/

https://www.hindawi.com/journals/av/2012/987471/

https://www.researchgate.net/public..._a_case_of_Chlamydophila_pneumoniae_infection

https://www.researchgate.net/public...epatitis_Iritis_and_Atypical_Erythema_Nodosum

http://hhv-6foundation.org/category/liver-disease

http://www.pathologyoutlines.com/topic/liverCMV.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628021/

The liver filters things from our blood and processes them using various chemicals. If its working hard at this, it can have a hard time keeping up and biochemical reserves can be depleted, causing a cascade of other biochemical problems which cause symptoms all over the body.

It would seem that a systems approach of removing whatever is bothering the liver, be it an infection or a toxin, and replenishing the chemicals to right imbalances and restore damaged tissue would be a successful approach.

Adding a new point intervention without tackling it with a systemic approach could produce unwanted consequences.

 

[aquariusgirl]

@Learner1

You have hemochromatosis???

Iron is a virulence factor for bugs...that would explain a lot wouldn't it?

 

[mariovitali]

@Learner1

Secondary Hemochromatosis
Secondary hemochromatosis usually is the result of another disease or condition that causes iron overload. Examples of such diseases and conditions include:

• Certain types of anemia, such as thalassemias and sideroblastic anemia
• Atransferrinemia and aceruloplasminemia—both are rare, inherited diseases
• Chronic liver diseases, such as chronic hepatitis C infection, alcoholic liver disease, or nonalcoholic steatohepatitis

 

[Tunguska]

Lots could be said here regarding the macrophages. But anyway, endogenous ligand for LXR is more or less squalene:
https://www.ncbi.nlm.nih.gov/pubmed/28492976
(but dosage needed may be high)

 

[Tammy]

My naturopath thinks one or more of my infections (c. pneumoniae, EBV, etc.) has set up shop in my liver.

A gastro/liver specialist said "that's ridiculous, no one has infections like that in their liver," and told me to stop taking supplements as they were causing liver inflammation and to get a colonoscopy.

Working the infectious angle and treating hemachromatosis has improved my labs to almost normal. And infections do tend to end up in the liver - just a few examples:

When my daughter got MONO her liver enzymes shot through the roof due to liver inflammation. The EBV had attacked her liver. Her Dr. told me not to even think about giving her any Tylenol........not even 1 pill. I agree that infections can set up shop in the liver.

 

[Tammy]

The liver filters things from our blood and processes them using various chemicals. If its working hard at this, it can have a hard time keeping up and biochemical reserves can be depleted, causing a cascade of other biochemical problems which cause symptoms all over the body.

One example is methylation problems.

 

[Learner1]

@Learner1

Secondary Hemochromatosis
Secondary hemochromatosis usually is the result of another disease or condition that causes iron overload. Examples of such diseases and conditions include:

• Certain types of anemia, such as thalassemias and sideroblastic anemia
• Atransferrinemia and aceruloplasminemia—both are rare, inherited diseases
• Chronic liver diseases, such as chronic hepatitis C infection, alcoholic liver disease, or nonalcoholic steatohepatitis

Thanks @mariovitali - good point. I actually have primary or hereditary hemachromatosis, which had been missed as it was milder due to being heterozygous for the 2 main HFE variants and not homozygous for the one.

My CFS doc encouraged me to do phlebotomies to get rid of the excess as excess iron can make infections worse:

http://www.sciencedirect.com/science/article/pii/S1201971207000811

https://www.ncbi.nlm.nih.gov/pubmed/11422085

 

[mariovitali]

@Learner1

I see. Please also be aware that high Iron can damage the Liver (due to Oxidative Stress).

So we could also make the hypothesis here that if Hemochromatosis has been left untreated for some time, it affected your Liver function (?)

Have you ever had a Fibroscan by any chance?

 

[Learner1]

@Learner1

I see. Please also be aware that high Iron can damage the Liver (due to Oxidative Stress).

So we could also make the hypothesis here that if Hemochromatosis has been left untreated for some time, it affected your Liver function (?)

Have you ever had a Fibroscan by any chance?

Yes, well that was why we investigated so thoroughly. Too much iron is indeed a bad thing. Your concern is warranted.

My serum ferritin was sky high for a year and I've been on a full liver support protocol. My doctors did a CT scan and checked several cancer markers but we stopped short of biopsy/Fibroscan. If it hadn't gone down, I'd be considering it.

Serum ferritin is an acute phase reactant. Lots of things can cause it to be high... toxicity, infections, hemochromatosis, etc. Its useful to have an iron study (TIBC, UIBC, serum iron and iron saturation) as well as testing AST, ALT, GGT, glutathione, and various infectious causes.

In my case, it was a multi-headed problem.
In general, supporting all the metabolic pathways that help the body get rid of toxins and trash is important, especially when our bodies aren't functioning at their best. Milk thistle, artichoke, curcumin, methylation nutrients, NAC and glutathione are all helpful.

 

[Jesse2233]

@mariovitali besides rapamycin, what are your thoughts on using TUDCA or coffee enemas to support the liver and LXR activation?

 

[mariovitali]

@mariovitali besides rapamycin, what are your thoughts on using TUDCA or coffee enemas to support the liver and LXR activation?

@adreno discussed that TUDCA/UDCA is an antagonist of LXR. I used it and it helped me possibly because i do not have problems in FXR. As it appears however, i do have a lot of issues in PPARs. There are people i know that TUDCA has helped them to recover. One particular case in Finland, although not recovered, said to me that TUDCA has helped his ADHD problems tremendously.

About Coffee enemas i do not know if they may help.

Since Autophagy appears to be a big piece of the puzzle of CFS/ME, Rapamycin may work. But things get tricky because if we accept the Hypothesis that the Liver is the main problem, we know that putting burden to the Liver with Medications may not be a good idea.

Some questions that i would like to ask all people that benefited from Rapamycin are the following :

a) Their age
b) How long they've been having CFS/ME
c) The severity of their disease
d) If they have had minor symptoms even before they got CFS/ME

I will have to stress once again that we have to support multiple pathways. There are some more issues i am working on at the moment and i will post them here on PR, CCing Janet Dafoe in hope that they will be considered from Ron.

From what i see so far, Beneficial supplements appear to be Magnesium, Biotin and Thiamine. Regarding Thiamine's potential role particularly, i had no idea about.

As an example, regarding Thiamine Deficiency (TD) :

Taken from :

Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy

We have also shown that TD activates double-stranded RNA-activated protein kinase (PKR) which is also believed to play an important role in ER stress [97, 98]. These findings suggest that ER stress may underlie TD-induced damage to the CNS. To date, the mechanisms underlying TD-induced ER stress is unclear. It has been well documented that oxidative stress and disruption of calcium homeostasis can cause ER stress [99, 100].

Note the mentions about ER Stress and disruption of Calcium homeostasis

These results suggest that autophagy is neuroprotective in response to TD-induced neurodegeneration in the CNS. There are several potential mechanisms for TD-induced autophagy. For example, TD is shown to affect mechanistic target of rapamycin (mTOR) and AMP- activated protein kinase (AMPK) pathways which are crit- ical regulators of autophagy [73]. Additionally, TD may activate autophagy through the induction of oxidative stress and/or ER stress because both oxidative stress and ER stress are known to stimulate autophagy

and finally a Thread called "Significant Improvement Story : Focus on Thiamine deficiency" :

http://forums.phoenixrising.me/inde...ent-story-focus-on-thiamine-deficiency.24059/

I do not believe that we all have Thiamine issues of course. I hypothesise that we have a combination of issues that affect Autophagy, Bile Acid homeostasis, ER Stress, Sulfation Phase (and some others ).

 

[aquariusgirl]

DR Constantini on B1


http://www.google.com/patents/WO2012147003A1?cl=en
atigue associated with these diseases.

SUMMARY OF THE INVENTION

The present invention is based on the discovery that chronic fatigue associated with multiple sclerosis, chronic hepatitis C, multinodular goiter, celiac disease, Parkinson's disease, cerebrovascular disease, ulcerative colitis, thyroidites, Basedow's disease, fibromyalgia, psoriasis and psoriatic arthritis, rheumatoid arthritis, can be cured by administering high doses of vitamin B1 (thiamine).

While not wishing to bound the present invention to a specific mechanism, on the basis of the studies reported herein, it can be hypothesized that chronic fatigue, and other disorders associated thereto, such as, e.g., sleep disturbances, depression, anxiety, cognitive impairment, muscle pain, cardiac arrhytmias, cold intolerance, in all of the above-listed pathologies, be due to a dysfunction of active transport of vitamin B1 from blood to mitochondria, or to a structural alteration of the enzymes which have as coenzyme the vitamin B1 and are fundamental for the oxidative metabolism of glucose. It can be hypothesized that the possible dysfunction of active transport of vitamin B1 from blood to mitochondria might lie at the level of high-affinity thiamine carriers, or at the level of the cytoskeleton .

In fact, patients suffering from the above-listed diseases have a normal absorption of vitamin B1 in the small intestine, normal levels of thiamine and thiamine pyrophosphate in blood (i.e., lack of vitamin B1 is not of nutritional origin) and thiamine deficiency in the cells. This entails the onset of all the aforesaid symptomatology, which is the clinical expression of an average deficiency of intracellular vitamin B1. This situation can be corrected by administering high oral or parenteral doses of vitamin B1. In fact, at normal thiamine concentrations in blood , the former is introduced in cells only through a highly specific carrier, carrying the vitamin into the cytoskeleton and then arriving to the mitochondria, where it binds to the enzymatic structures present in these organelles, which are fundamental for oxidative metabolism of glucose.

 

[kurt]

Fascinating. But we don't generally have all of the LXR related problems, do we? Atherosclerosis, diabetes, inflammation, and Alzheimer's disease. Well, inflammation for sure, but many possible causes of that. For those who have 23andMe results, might be interesting to check for the LXR bad genes.

1. RS1405655 (LXR)
2. RS17373080 (LXR)
3. RS2279238 (LXR)
4. RS2695121 (LXR)

 

[wastwater]

I have elevated liver ALT at 70 and always thought it was due to processing increased toxins like cytokines interferons and what not
I consider it another collateral damage organ like the thyroid Without antibodies

 

[ScottTriGuy]

Fascinating. But we don't generally have all of the LXR related problems, do we? Atherosclerosis, diabetes, inflammation, and Alzheimer's disease. Well, inflammation for sure, but many possible causes of that.

For those who have 23andMe results, might be interesting to check for the LXR bad genes.

1. RS1405655 (LXR) - TT
2. RS17373080 (LXR) - CC
3. RS2279238 (LXR) - CC
4. RS2695121 (LXR) - TT

I've added my 23andMe in bold - some increase risk for tuberculosis, others decrease risk - a couple do increase risk for Alzheimer's - but I have little / no knowledge of interpreting their interplay.

 

[mariovitali]

@kurt ,

CC : @ScottTriGuy

If you look at the Network Analysis that was generated there is a combination of issues at play, not just the LXR Receptor, including CYP27A1, XDH, CYP7B1, PPARA, PPARG (and more coming up).


I looked at the rs numbers you posted and on the DNA Samples i have (62 people with CFS, Post-Finasteride, Post-Accutane Syndrome) the most interesting appears to be rs2695121 having a MAF of 22%.

Out of 62 people :

48.28% are Heterozygous
15.52% are Homozygous
36.20% have no mutation.

 

[Valentijn]

I looked at the rs numbers you posted and on the DNA Samples i have (62 people with CFS, Post-Finasteride, Post-Accutane Syndrome) the most interesting appears to be rs2695121 having a MAF of 22%.

MAF of 22% is very high. And it's twice as high in those with European ancestry, at 44.4%. Expected genotype frequency is therefore 49% heterozygous and 19% homozygous. Your sample looks pretty average.