Unfolded Protein Response and A Possible Treatment for CFS

[Bdeep86]

@aquariusgirl you are taking mitosynergy currently?

 

[aquariusgirl]

Just stopped for a short holiday after a day or more of unpleasant headaches which I assume is the copper clearing out pockets of fungal/bacterial infections

 

[Flo]

Check this out: I think proper copper & biotin have helped my mitos

http://m.jn.nutrition.org/content/137/1/25.full

This is a 2006 article from Bruce Ames & co which I thought was interesting.

Apart from the importance of biotin to mito function & in a further step heme synthesis, there is a really interesting throwaway line about how copper & biotin work together :

However, as expected from copper's role in complex IV, the recovery of complex IV was more efficient when copper and biotin were both added to the medium (data not shown).

I just made a post on another forum about biotin!
http://forums.phoenixrising.me/index.php?threads/seborrheic-dermatitis.43157/

Taking 10,000mcg totally got rid of my seborrheic dermatitis! I also think it is helping me in other ways as well. I though I had more energy just because I felt better but now I think it might be doing more. A friend helped me look at tow of my genes; BTD and HLCS. I will get the SNPs from him soon!

 

[whodathunkit]

@mariovitali:

So I'm plowing back through this thread again with fresh eyes and a better understanding of some things. Not such a good understanding of others.

Below in bold are the snps I have that are risk factors UPR and ER stress, according to the list you made. I'm currently taking basically everything on your list except Reservratrol, although some things I just started. Based on my snps and what I"m already taking, do you have any other recs?

Worth noting is that a little over a year ago (December 2014) I had a short time where I felt motivated as hell and had incredibly energy due to taking choline and some things that work synergistically with it like ALC and sulbutiamine. And although I had energy I was also kind of wired and wasn't sleeping good. But everything came to a screeching halt when I came down with HELLACIOUS stomach virus where I pooped green water for several days. It didn't feel like it was a bad thing, more like a detox or "clean out". I was physically better after it, although the motivation never came back and I was not "cured". Because of the snps below and previous experience, I am definitely making sure I'm getting enough choline, and am trying to remember to add back in some things I was taking back when I had the motivation (like ALC). But so far I haven't been able to replicate that incredibly energy burst I had back then.

BTW, have you taken a look at the B2: I love you! thread? I've been doing B2 and manganese for several months according to Dog Person's recs, and am finally starting to notice some positive changes. Poops are consistent and of a good color (they had gotten orange or paler in color). Digetstion is better. Etc. Based on what I learned in that thread I think I had a B2 deficiiency from doing Freddd's methylation protocol without enough B2 (folate and B12 require B2 to work), and I also have iron storage problems (too much iron in liver). I think the B2 may be very helpful in getting liver problems straightened out for some of us.

It all fits together somehow. But my poor scrambled pea brain isn't making the leaps fast enough. LOL I mention the B2 thread in case it might give you some info to work with or think about.

Anyway, do you have any additional recs or comments based on my snps?

Thanks again for all your hard work in this thread. I think there's a lot of important stuff here that shouldn't be overlooked. But it takes a while for many of us to get our heads wrapped around it.


ER Stress response


rs13045 (EIF2AK3-PERK) : Risk C (no call)
rs2239815(XBP1) : Risk C, CC**
rs10918270(ATF6) : Risk A, AG**
rs391957 (HSPA5 aka BIP aka GPR78) : Risk C, (no call)


GCH1, associated with lower levels of BH4 (low BH4 => ER Stress)

rs10483639 : ( Risk C), GG
rs3783641 : (Risk A), TT
rs8007267 : (Risk T), CC
rs12147422 : (Risk C), TT
rs3783637 : (Risk T), CC
rs3783641 : (Risk A), TT
rs41298442 : (Risk T), TT**
rs4411417 : (Risk C), TT
rs752688 : (Risk T), CC
rs841 : (Risk A), GG (no call)
rs998259 : (Risk T), CT**
rs7147286 : (Risk A), GG




Choline Metabolism (impaired Choline absorption => impaired TMAO => ER Stress+UPR)

rs3733890 (Risk A), AA**
rs2461823 (Risk C) NAFLD Disease, CT**
Rs7643645 Risk G NAFLD Disease, AG**
rs7946 (Risk T) (PEMT), CT**
rs4244593 (Risk G) (associated with PEMT), GT**
rs2236225 (Risk A) (MTHFD1), AA**
rs9001 (Risk G) (CHDH), TT

 

[Violeta]

@whodathunkit , we had been talking about B2 for a while when someone whose user name started out ppodhjaski (something like that) was here and brought up about FMN and thioredoxin. Yes, B2 is important.

 

[Flo]

@whodathunkit , we had been talking about B2 for a while when someone whose user name started out ppodhjaski (something like that) was here and brought up about FMN and thioredoxin. Yes, B2 is important.

nevermind.

 

[Violeta]

I have a feeling that all the good news regarding coffee and disease might be from its high riboflavin content.
http://nutritiondata.self.com/foods-000109000000000000000.html
35mg in a cup of decaf!

Something seems wrong with that measurement of riboflavin in coffee. This site says .2mg per 8 ounce cup.

 

[mariovitali]

@whodathunkit

I know that this Thread is huge, probably i will have to make a new Thread i guess, since the information presented in the first Page is somewhat outdated.

My regimen looks like this :


08:00 Dibencozide, FMN, Metafolin
10:00 Alpha GPC, Manganese, Biotin, pantothenic Acid
12:00 TUDCA, Selenium P5P, Ubiquinol
16:00 TMG (Betaine)
23:00 Alpha GPC

Not only i have no sides but i also beginning to change as a person...yes i know this sounds crazy but bear with me. It seems to me that my "ups" and "downs" are not there any more. I had these for many years...you know i was mostly getting negatively affected by things happening to my life.

...Not anymore and -believe me- this is not just about Serotonin being low or anything like it. I think this is more profound. My Gums had Periodontitis for years. Now my Gums have a Pink color which i haven't seen for a decade or even more. I do not get any incidences of Sinus pains, conjunctivitis etc.

Regarding the SNP list this has changed quite a bit (i will PM you).

 

[Flo]

Something seems wrong with that measurement of riboflavin in coffee. This site says .2mg per 8 ounce cup.

Oh shoot, sorry. That initial reading was for a 200 calorie serving! And coffee has about zero calories.

Good eye!

 

[Violeta]

Oh shoot, sorry. That initial reading was for a 200 calorie serving! And coffee has about zero calories.

Good eye!

Very unfortunate, I really wanted it to be true!

 

[Bdeep86]

@whodathunkit how do you know that you have iron overload in your liver? I have suggested in talking with @mariovitali that I believe this is what starts this whole awful dysfunction in the liver.

 

[mariovitali]

@Bdeep86

I think that is very critical to find out the direction of the relationship, so which of the following is true in our case? :

High Iron => Liver Disease
Liver Disease => High Iron
Liver Disease <=> High Iron


In an article named "Preventive Strategies in Chronic Liver Disease" i found this :

Patients with chronic liver disease have a tendency to accumulate an excessive amount of iron in their liver parenchyma. Those with alcoholic liver disease, nonalcoholic steatohepatitis or hepatitis C virus infection have a particular tendency toward secondary hemosiderosis.

Patients who have secondary iron overload must be distinguished from those with hereditary hemochromatosis, in which a primary genetic defect leads to an excessive hepatic and total-body iron load. The level of iron loading is much greater in patients with primary hemochromatosis than in those with secondary hemosiderosis.
As many as 30 percent of patients with liver disease have high serum iron levels, and 10 percent have excessive amounts of iron in their liver tissue.30,31 The reason for the iron excess is not known, but postulated mechanisms include the release of iron from injured hepatocytes and their uptake by Kupffer cells, acute-phase reactions associated with chronic inflammatory states, increased uptake of iron through the gastrointestinal tract, and ineffective erythropoiesis with redistribution of iron from sites of utilization to sites of storage. The most likely mechanisms of liver injury from excess iron are increased generation of free radicals and increased peroxidation of lipids, which, in turn, lead to mitochondrial dysfunction, lysosomal fragility and cell death.

Of course i found entries where the contrary is true (=Iron Overloading damaging the Liver)

The same applies for NAFLD (For ferritin levels) :

Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease.
Kowdley KV1, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, Sanyal AJ, Nelson JE; NASH Clinical Research Network.
Author information

Abstract
Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, ≥ 18 years) with biopsy-proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 × upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin-iron saturation, iron stain grade, and decreased platelets (P < 0.01). Histologic features of NAFLD were more severe among patients with SF >1.5 × ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (P < 0.026). On multiple regression analysis, SF >1.5 × ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.62; P = 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06-3.75; P = 0.033).

CONCLUSIONS:
A SF >1.5 × ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis.

 

[Sam7777]

Yea these last two pages just make me that much secure in what lipoic acid and kefir yogurt do. Liver disease is really at the center of a lot of this. I am willing to bet different strains in kefir affect gxr and bile gene expression. Kefir really dampened my brutal histamine sulfur issues. Excess non bioavailable copper is a common issue im chelation forums. Wouldnt surprise me if iron does the same. That is one of the big features of lipoic is that it chelates excess iron and copper particularly the excess free radicals from copper and iron. As for choline I know huperzine helps me enormously. GPC would be good too.

 

[mariovitali]

@Sam7777 @Violeta @Bdeep86 @Flo @whodathunkit @ahmo
@jump44



We are getting very close ...

For a long time, bile acids were considered solely as steroidal detergents and emulsifying agents. But now their roles as regulatory/signaling molecules have been recognized. They are ligands for the orphan nuclear receptors FXR and PXR. Through activating FXR, bile acids regulate many genes in the liver and intestine, which modulate the biosynthesis and metabolism of bile acids and lipoproteins and determine the composition of the intestinal flora and fuana [3, 7, 8, 17, 18]. Recently, δ-aminolevulinate synthase, the rate limiting enzyme of porphyrin-heme synthesis, has also been identified as a gene regulated by FXR, indicating a role of bile acids and their precursors in regulating hepatic heme biosynthesis [19]. The secondary bile acid, lithocholic acid activates PXR [20] and the vitamin D receptor [21, 22]. PXR in turn regulates the expression of CYP3A4, which encodes the major drug and xenobiotic catabolizing P450 isozyme in human liver. The secondary bile acid, ursodeoxycholic acid activates the glucocorticoid receptor and exerts immunomodulatory effects [23–25]. Bile acids also activate several signaling pathways including the c-Jun NH2- terminal kinase (JNK) 1/2 pathway (to feedback inhibit bile acid biosynthesis) [8], the protein kinase B (AKT) pathway (to regulate glucose metabolism) [8, 26], FXR, short heterodimer partner (SHP), liver X receptor (LXR), and the sterol regulatory element- binding protein (SREBP)-1c pathway (to regulate lipid metabolism) [8, 27], the extracellular-signal-regulated kinases (ERK) pathway (to prevent apoptosis) [28, 29], and the epidermal growth factor receptor (to modulate intestinal permeability) [30]. A recently identified G protein-coupled bile acid receptor (TGR5) [31] further expands the function of bile acids and their roles in energy metabolism [32], inflammation [33, 34], and gallbladder contractility [35]. Bile acids also affect cardiac function by regulating vascular tone and myocardial contractility, but the underlying mechanism for this remains largely unknown [36].

Please check the following SNPs :


HSD3B7 (rs9938550) Variant Allele : G
GPBAR1 (rs3731859) Variant Allele : A




Why Choline helps (My Hypothesis)



The role of dietary choline in the beneficial effects of lecithin on the secretion of biliary lipids in rats.
LeBlanc MJ1, Gavino V, Pérea A, Yousef IM, Lévy E, Tuchweber B.
Author information

Abstract
Earlier studies showed that dietary soybean lecithin increases biliary lipid secretion, which mainly comes from the contribution of high density lipoprotein (HDL) and hepatic microsomal pools of phosphatidylcholine and cholesterol. In addition, a lecithin diet enhances bile secretion and prevents bile acid-induced cholestasis. This study evaluated the contribution of choline, a component of lecithin, to the observed effect of lecithin on biliary secretory function. Rats were fed either a control diet (CD), a choline diet (ChD) or a lecithin-enriched diet (LD) for 2 weeks. Results showed that like LD, ChD induced an increase in bile flow and bile acid secretion rate when compared with the control diet. However, unlike LD, ChD did not significantly increase biliary phospholipids and cholesterol output. An increase of hydrophilic bile acids (i.e. ursodeoxycholic and muricholic acids) in bile of rats fed choline could explain why the biliary phospholipid and cholesterol secretion was not increased. During taurocholic acid infusion, both experimental diets increased bile flow and the bile acid secretion rate maximum (BASRm). The cholestasis usually observed after the BASRm is reached was inhibited by ChD and LD. Both diets induced a decrease in plasma cholesterol (total and HDL), however, only LD induced statistically significant changes. Analysis of total cholesterol and phospholipid content of microsomes and canalicular membranes indicated no statistically significant difference between control and experimental groups either under basal conditions or after bile acid infusion. Similarly, the phospholipid classes and fatty acid composition of biliary phosphatidylcholine were not altered by feeding ChD and LD. We conclude that choline contributes to the beneficial effect of a lecithin diet on bile secretion. It is postulated that this effect may be attributed to modulation of HDL and an enhancement of the cholesterol and phospholipid pools destined for biliary secretion.

 

[mariovitali]

I *really* think we need a Cholestasis expert in here : Please check whatever exists in the following chart for any Alleles :

Pay particular attention to : CYP7B1,CYP8B1,CYP7A1, HSD3B7,AKR1D1, AKR1C4, 3βHSD

 

[Violeta]

@mariovitali , I think this is my favorite part in the first article that you linked two posts up.

"Recently, δ-aminolevulinate synthase, the rate limiting enzyme of porphyrin-heme synthesis, has also been identified as a gene regulated by FXR, indicating a role of bile acids and their precursors in regulating hepatic heme biosynthesis [19]"

Very good news if one has porphyria and maybe c pneumoniae, as that seems to enjoy the porphyrin build up.

 

[mariovitali]

OK so here is my Data :

29 rs3808607 CYP7A1 G/T T G 0.4758 58500364 G TT OK
30 rs3824260 CYP7A1 A/G G A 0.4493 58500630 A GG OK
31 rs3732860 CYP8B1 C/T C T 0.3157 42872519 T TT HOMOZYGOUS
32 rs35724 NR1H4 C/G C G 0.3996 100561599 G CG HETEROZYGOUS
33 rs10808739 CYP7B1 A/G G A 0.2175 64727702 A AA HOMOZYGOUS
34 rs72554620 CYP7B1 C,T C T NA 64604752 A GG OK
35 rs7083869 AKR1C4 A/G G A 0.2045 5202331 A GG OK
36 rs3731859 GPBAR1 A/G G A 0.4489 218259498 A AG HETEROZYGOUS
154 rs9938550 HSD3B7 A/G A G 0.4934 30987820 G GG HOMOZYGOUS

By looking at the chart above we see :

1. I am ok for CYP7A1....BUT
2. I am Homozygous to HSD3B7
3. AKR1D1 is not in my chip( probably)
4. I took Finasteride which downregulated AKR1D1 (...)
5. The SNP i have for CYP7B1 is probably non-pathogenic
6. I am heterozygous for NR1H4 = FXR Receptor

So with a faulty HSD3B7, CYP8B1, FXR AND a down-regulated AKR1D1 (From Finasteride) there goes the whole chain down the drain...

Did you see the words CoA, ER, Mitochondria in the chart?

Add to this impaired Fatty Acid Synthesis, impaired Acetylation / phosphorylation, impaired A,D,E,C,K absorption...i will have to generate a whole list of what exists beneath this Pathway but i am sure you get the picture.

 

[Flo]

@mariovitali I think bile acids and choline are way to complex to be the root issue.

I am leaning towards, for the majority of people with ME, excess H2O2 is the problem.

https://en.wikipedia.org/wiki/Peroxisome

 

[aquariusgirl]

http://www.ncbi.nlm.nih.gov/m/pubmed/12163687/

Is this relevant here?

 

[mariovitali]

@Flo

Could you help (if you know of course) finding the rs# for AKR1D1 ? See the positions below :

RESULTS:

Mutations in the SRD5B1 gene were identified in all three children. Patient MS was homozygous for a missense mutation (662 C>T) causing a Pro198Leu amino acid substitution; patient BH was homozygous for a single base deletion (511 delT) causing a frame shift and a premature stop codon in exon 5; and patient RM was homozygous for a missense mutation (385 C>T) causing a Leu106Phe amino acid substitution.
All had liver biopsies showing a giant cell hepatitis; in two, prominent extramedullary haemopoiesis was noted. MS was cured by treatment with chenodeoxycholic acid and cholic acid; BH showed initial improvement but then deteriorated and required liver transplantation; RM had advanced liver disease when treatment was started and also progressed to liver failure.