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Inhibition of NAD+ Synthesis by Oncogenic URI Causes Liver Tumorigenesis

http://www.ncbi.nlm.nih.gov/pubmed/25453901
Inhibition of De Novo NAD+ Synthesis by Oncogenic URI Causes Liver Tumorigenesis through DNA Damage

Highlights

    •URI causes NAD+ depletion-dependent DNA damage leading to HCC development
    •Restoring NAD+ pools in vivo protects from DNA damage and HCC
    •URI inhibits AhR/ER transcriptional activity-mediated de novo NAD+ synthesis
    •URI-mediated de novo NAD+ synthesis inhibition may occur in human HCC

Summary

Molecular mechanisms responsible for hepatocellular carcinoma (HCC) remain largely unknown. Using genetically engineered mouse models, we show that hepatocyte-specific expression of unconventional prefoldin RPB5 interactor (URI) leads to a multistep process of HCC development, whereas its genetic reduction in hepatocytes protects against diethylnitrosamine (DEN)-induced HCC. URI inhibits aryl hydrocarbon (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes implicated in L-tryptophan/kynurenine/nicotinamide adenine dinucleotide (NAD+) metabolism, thereby causing DNA damage at early stages of tumorigenesis. Restoring NAD+ pools with nicotinamide riboside (NR) prevents DNA damage and tumor formation. Consistently, URI expression in human HCC is associated with poor survival and correlates negatively with L-tryptophan catabolism pathway. Our results suggest that boosting NAD+ can be prophylactic or therapeutic in HCC.

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Avatar universal
The mutation introduction will directly correlate with the time of exposure.
I don't know of measurements in humans on etv. But etv can be incorporated into the growing dna chain and upon the next replication round will effect a permanent base change in this position.

But the 3d structure of etv makes the add on of the next nucleotide very unlikely, there was a paper that analyzed the reaction on an in Silicon structure of the gamma polymerase adding entecavir. It concluded  that due to steric restrictions the mutation producing next nucleotide add on is very unlikely, considering it a "pseudo obligate chain terminator ". Thus the incidence is most likely very low. Nevertheless, the carcinogenic potential of entecavir, well known, is probably the result of this mutation introduction.
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Avatar universal
The consequence of these mutations , once introduced, is that they render a portion of the  mitochondrial genome useless to produce functional proteins.
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Avatar universal
Nr is indeed a metabolic precursor to nad+, placing it where it is needed for the critical effect, which is in the cell nucleus. Several enzymes participate in the various transformations from nicotinic acid aka niacin to the final product nicotinamidadenindinucleotide. Nr is an intermediate in this pathway, very bioavailable.
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Avatar universal
Quite impressive effects, if the nicotine mideast ribosome was truly behind those.

To measure energy levels in real life, it would be difficult to quantitative ATP levels in tissues, as it is done in the animal studies.

Measuring NAD levels in peripheral blood would not give meaningful correlations.

But the best method to assess global mitochondrial function is to measure maximum oxygen consumption. You work out on a bike or treadmill to maximum voluntary capacity in the sports physiology lab, while wearing a mask that quantitates oxygen extraction by your body.


It has been shown eg that in HIV patients after starting antivirals  the max O2 was decreased, indicating reduction in mitochondrial mass.
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Avatar universal
Lol the "nicotine mideast ribosome" was created by the computer out of nicotinamide riboside...
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Avatar universal
Will taf slow down mitochondrial toxicity over tdf and etv
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Avatar universal
Certainly in the kidneys, where tenofovir from TDF massively accumulates.

the exposure of other tissues and resulting TAF uptake there is not clear at this time.
While the total dose is 90% less, TAF enters all organs with greater ease.
Thus it is a compromise between a much smaller total amount but a better uptake, for example in the muscle tissue.
Lymphocytes eg have up to 10 times more tenofovir diphosphate upon TAF dosing, making TAF so particularly valuable for HIV.
The TAF dose for HIV is only 10mg vs 25mg for HBV.

In the phase II trial with TAF for HBV, 8mg was exactly as effective in vl suppression than 25mg.
But the 25mg dose was chosen to have a good safety margin against resistance development. But the price is of course a larger non liver  body exposure.

I have described the finer details of the pharmakokinetic difference between VIREAD ...TDF..and TAF in a previous post.
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Avatar universal
"It has been shown eg that in HIV patients after starting antivirals the max O2 was decreased, indicating reduction in mitochondrial mass."
is it reversable after stopping antivirals of course in hbv context ?
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1 Comments
Also how about bone density loss on antivirals ? Is it reversable after stopping it ?
Avatar universal
After stopping antivirals, mitochondrial mass will grow back to regular size. The blockage in the gamma pylymerase is removed, mitochondrial DNA CAN be synthesized at full speed again. With entecavir there is the potential for permanent mitochondrial mutations, that will propagate indefinitely, but nobody knows the magnitude of this problem. Tenofovir makes no mutations, it is an obligate chain terminator.

I think bone loss should slowly revert back to normal, once kidney function is normalized.
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2 Comments
thanks for explanation, that "potential for permament mitochondrial mutations on etv" depends on the time of curation or is just random ? Any cases of this or it's just the theory ?
what are the consequences of those mutations ?
Avatar universal

what do you think about nicotinamide-riboside as a measure to prevent aging diseases and nucs sides effects on mitochondria and tumors

i am trying this type of vit b3 supplement since few days and it really changes metabolism and energy (in a bad manner too i had to up thyroid hormones dose for my mild hypothyroidism)
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Avatar universal
i find nicotinamide riboside quite fascinating. In the famous mouse paper by David Sinclair, where they were able to reverse age dependent ATP loss in the mitochondria, they used nicotinamin mononucleotid, but the riboside form will convert to that and then to NAD+ relatively easy.
If it can work against tumorigenesis and mitochondrial depletion in nucs treated humans is of course just good speculation, but not unlikely considering that the protein misfolding response by chaperons requires a large amount of  ATP energy.
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Avatar universal
improvement continues, now i know i ll get rid of glasses completely, just using reading glasses to read now, this was my condition 8 years ago minimum, started NR jan 14 2016

now i found this interesting study:
http://www.ncbi.nlm.nih.gov/pubmed/26660162

The SIRT1 inhibitor, nicotinamide, inhibits hepatitis B virus replication in vitro and in vivo.
Li WY1, Ren JH1, Tao NN1, Ran LK1, Chen X1, Zhou HZ1, Liu B1, Li XS1, Huang AL1, Chen J2.
Author information
Abstract
We previously reported that SIRT1, an NAD+-dependent deacetylase belonging to the class III histone deacetylases, enhances hepatitis virus B (HBV) replication by targeting the transcription factor AP-1. However, the potential antiviral effects of nicotinamide, a SIRT1 inhibitor, have not yet been explored. In this study, we show that nicotinamide exhibits potent anti-HBV activity with little cytotoxicity. Nicotinamide suppressed both HBV DNA replicative intermediates and 3.5-kb mRNA expression. Moreover, nicotinamide treatment also suppressed core protein expression and the secretion of the hepatitis B surface antigen (HBsAg) and the hepatitis B e antigen (HBeAg) in HBV-expressing cell models. Importantly, nicotinamide treatment suppressed serum HBV DNA, HBsAg and HBeAg levels and liver HBV DNA in HBV-transgenic mice. Furthermore, using a dual-luciferase reporter assay, it was found that nicotinamide exhibited a marked inhibitory effect on the HBV core, SpI, SpII and X promoters, accompanied by decreased expression of the transcription factors AP-1, C/EBPα and PPARα. Therefore, nicotinamide suppresses HBV replication in vitro and in vivo by diminishing HBV promoter activity. This study highlights the potential application of nicotinamide in HBV therapy.
PMID: 26660162 [PubMed - as supplied by publisher]
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Avatar universal
i dotn think we can expect much from nicotinamide but i ll keep NR as antiage of course

is hbv transgenic mouse close to in vivo humans for this case?too bad no doses are mentions here
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now i can read newspaper without glasses with a lot of sunlight and some effort, i guess by 6 months of NR i will be able to read it without effort and normal light

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http://www.google.com/patents/CN104784178A?cl=en

maybe some ideas about doses with some possible (although improbable) effect
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If there is any contraindication to use nad+ together with interferon ?
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how can we order this? Whats the dose?
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Avatar universal
we don t know if it has any effect yet, probably none but  nicotinamide is very cheap vit b3, high doses slow release can make high alt, better fast release.

check ast-alt if you try it, it is a very strong antibacterial and anti tbc too, it increases neutrophils potency according to latest research

i guess doses are 3g but i dont know, not mentioned, 3g is also borderline to make higher alt, it is rare but it can happen and in case of high alt best stop it
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2 Comments
What is he riboside part? Is nicotinamide-riboside (NR) different from the form of b3 nicotinamide?  
Is it correct to say that NR is the building blocks for NAD? And if so is one more beneficial than the other?
Avatar universal
No clear answer, nr is more expensive so they will not tell you if they re the same
Study for hcc is on nr, antiage is on nr too, so we cannot say nicotinamide has the same effect

Some researcher said nicotinamide is then transformed to nr in our body, dont remember if the liver makes it, but i havent seen a study on these pathways
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Avatar universal
I see no reason why ifn could not be used together with nicotinamide riboside.

I use 300 mg twice a day btw, a relatively high dose. Objective effects are hard to report.
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1 Comments
studyforhope: Stef mentioned something about ALT increase, but my ALT on peginf is now 120 IU so not very high.
Any specific reason why you take it ? Or it's just because of it's anti-aging features ?
Avatar universal
i started that to see if i can recover the vision loss i had after peg (blurred vision) and by few days of 300mg daily:
i dont need glasses to see far but i need it only for reading close
sleep is getting regular, i get asleep at 22pm instead of 2am
wake up fresh and sleep less 8hrs vs 10hrs
very very sharp mind

how can we see mitochondrial depletion effects in real life?faster aging?loss of energy?or only by lower levels of nad+ in blood?

thanks
Helpful - 0
Avatar universal
i am on 500mg spread during the day because some got response only on this dose so even if 300mg worked for me i want to be sure i get max effect for eyes view.nad+increase 50% whatever the dose but doses over 300mg sustain levels for longer

as regards nicotinamide effect on hbv: is it the same taking nicotinamide or nicotinamide riboside?
Helpful - 0
Avatar universal
https://drive.google.com/file/d/0B8E77QizhkLQOWZON3pyalBJN2M/view?usp=sharing

here s the full study but too complicated for me to understand doses used

Materials and methods
Drugs and antibodies
Nicotinamide was purchased from Sigma-Aldrich (Sigma-
Aldrich, Missouri, USA). Nicotinamide was prepared in a
1 M phosphate-buffered saline (PBS) solution and stored at
-20 °
Nicotinamide was diluted in 500mcg/l PBS
and injected through the caudal vein once daily for 5 days
in each group at a specified dose (0mcg/g, 10mcg/g, 100mcg/g,200mcg/g body weight). Twenty-four hours after the last
injection, the mice were euthanized to collect serum and liver samples
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Avatar universal
anyway i guess we should go with safe highest dose which is around 3g and check that ast/alt don t change
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