Vitamin A metabolism and Circadian Rhythm.

This post is a work in progress! I actually hope to have a research lab that I know who is very interested in sleep disorders to help me out here.

What if sleep disorders are just impaired vitamin A metabolism?I constantly hear this from clients and patients, “When I eat “x” I can’t sleep.”

🤔

Zoey’s no sleep foods include: chocolate, beans, and french fries. These are all high oxalate foods. Oxalate is a potent inhibitor of LDH which lowers NAD recycling. Low NAD will prevent vitamin A metabolism to retinoic acid which is the “active” form of vitamin A in the body.

Luckily, Zoey never had plantain flour after noon. By the way, plantain flour is not low oxalate and this is what led to her current vitamin A toxicity issues. You can read the short story here, or for the long version you can head to

I am now convinced that we are cycling between retinol/retinal and retinoic acid throughout the day in various organs. I think that people who stay in a high retinol/retinal state have a risk of vitamin A toxicity.

If people have low NAD habits, they will have a high risk of toxicity, but even without toxicity, low NAD habits can lead to physiological low levels of retinoic acid in various organs.

I think we who are NAD compromised must compartmentalize. People with mitochondrial disorders definitely compartmentalize. They can’t have healthy skin AND sleep. They can’t have a normal immune system AND sleep. Then, when NAD is really low they can’t have any of these because there is no more retinoic acid to compartmentalize with.

Well, retinoic acid is a ligand for Retinoic Acid Related Orphan Receptors that code for many proteins that have various functions in the body including making circadian rhythm proteins. In a low NAD state we aren’t making retinoic acid in sufficient amounts. I see this with my own daughter and also with my clients. They have all the signs of vitamin A deficiency, but are actually vitamin A sufficient and many have hypervitaminosis A due to being in a low NAD state too long.

Circadian Rhythm Proteins!!! Zoey’s mouse model of MBD5 makes very low amounts of these. If you add in a functional vitamin A deficiency, retinoic acid deficiency, then….BAM…no sleep.

What if InZomnia (my nickname for Zoey’s sleep habits when they are disrupted) is actually poor retinoic acid production? I think it is.

How to win back sleep! The Solution?

  • First, if you aren’t vitamin A toxic, I would avoid high oxalate foods after 2PM daily.
  • If you are vitamin A toxic, you could still avoid high oxalate foods after 2PM daily, but be aware that you must fix your detox pathways before you start to mobilize more retinol/retinal to retinoic acid. Going low oxalate before you are able to detox high amounts of retinoic acid could be problematic. Read here for more information on this.
  • Getting 30 minutes of morning sunlight every morning without sunglasses to set the clock for triggering melatonin release. Melatonin isn’t the only circadian rhythm protein, but it is a big one. Avoid melatonin supplements. This impair vitamin A by lowering NAD+ and also using up NAD plus in metabolism. You can read more about that here.
  • Alternatively you can purchase a therapy light. I have a Verilux Happy Light that we use in our home.
  • Avoid blue light two hours before bed. You can buy glasses with blue blockers, or put your device in nighttime mode to decrease blue light.
  • Make your room COLD. It makes us want to stay under the covers. I’m sure it helps in other ways, but I haven’t researched this yet. Feel free to comment if you know more about this.
  • Establish a soothing bedtime routine. Perhaps a bath, a non-electronic book, and prayer, to get you in the sleepy mood you need to be in.

EGGS for sleep????

Eggs will help with sleep because a metabolite of cholesterol can be a ligand for ROR. Eggs are a good source of cholesterol. However, they also do contain vitamin A…that’s a whole controversy in the vitamin A detox world. The benefits of eggs, in my opinion, outweigh the risk. Eggs are a good source of phosphatidyl choline which is needed for the very last phase of liver detoxification when drug metabolites (and vitamin A metabolites) are excreted into bile for removal from the body. At the same time that bile salt is excreted, phosphatidyl choline also leaves the liver cells. Hypervitaminosis A places a huge burden on phosphatidyl choline needs and over medication can do this as well. We can add to that the need to metabolize environmental toxins, and it is easy to see that phosphatidyl choline is an under-rated nutrient.

Also, statins would be bad here because they lower cholesterol production. No amount of coenzyme Q10 restoration is going to replace the metabolites of cholesterol that are needed as ROR ligands. These effects could go beyond just sleep proteins as you can see in this article.

So…that’s about it. Good night, sleep tight, don’t let the NAD bugs bite!

This is not written to diagnose or treat a condition, but only for informative purposes. Please consult your doctor before stopping or starting medications or supplements, and before making dietary or lifestyle changes based on the information provided. –  Meredith Arthur, MS, RD, LD 

Oxalate is a Potent Inhibitor of LDH resulting in decrease NAD recycling and impaired vitamin A metabolism

OXALATE from plants or made from VITAMIN C or GLYCINE or Miralax (PEG) in the body can impair Vitamin A metabolism

Oxalate is a component of plants that is impossible for the body to completely break down. It is a poison.  We absorb it at variable rates, but some of us make it in our bodies from vitamin C and glycine.  Excess vitamin C becomes oxalate through direct breakdown and without enzymes. Usually this occurs in vitamin C over 2000 mg, but it can happen at lower doses as well. Never take vitamin C to “bowel tolerance” as this is likely actually death of the intestinal cells due to oxalate poisoning.  Glycine is metabolized to oxalate in a B6 and thiamine deficient state, but when there is adequate B6 and Thiamine, it does not become oxalate.

When oxalate is high it impairs an enzyme called Lactate Dehydrogenase (LDH).  We have to make some lactate to keep energy metabolism going. When the body is producing lactate, it also produces NAD+ which is what drives vitamin A (retinol and retinal) metabolism forward. What I found through a deep dive into literature is that Oxalate doesn’t directly inhibit alcohol dehydrogenase or retinol dehydrogenase or aldehyde dehydrogenase which was what I was searching for.  Oxalate actually impairs lactate dehydrogenase (LDH) which lower NAD+ levels.  I hypothesize that oxalate takes away the “energy” needed to drive those reactions forward by impairing LDH. 

LDH is actually the last enzyme involved in the formation of oxalates. I believe that oxalate being able to have a feedback inhibition on LDH is a safety mechanism built into our human biology, but that it backfires and wreaks metabolic havoc on vitamin A metabolism and also energy metabolism.

Oxalate impairs LDH activity via NAD dependent pathway

https://pubmed.ncbi.nlm.nih.gov/14646967/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC473141/

https://www.sciencedirect.com/science/article/abs/pii/0009898168903768?via%3Dihub= 

Oxalate Pathogenic In Autism (Perhaps this is the connection! If oxalate impairs LDH, resulting in low NAD, then retinal levels increase. These complex with ethanolamine causing A2E and microglial activation resulting in neurological decline. Read this post for more information.)

https://pubmed.ncbi.nlm.nih.gov/21911305/


Lactate and pyruvate act as redox buffer to balance NADH/NAD

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983055/

Jenny Jones, PhD, pointed the article below out to me as supporting evidence for the connection between need for normal LDH reaction to restore NAD levels. She is the oracle to my batman!

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869616/

The article bleow is an excellent article! This gives the big picture of NAD production, recycling, and salvage pathways. Amazing! LDH, which is inhibited by oxalate, plays a pivotal role in NAD recycling.

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

https://www.nature.com/articles/s41392-020-00311-7

Solutions:

1. Low oxalate diet 

2. Avoid excess  vitamin C in excess (variable per person, but most kids don’t need more than 500 mg per day)

3. Ensure adequate levels of B6 and thiamine  (Seizure meds tend to deplete B6 – ask doctor about 50 mg of P5P, active form of B6) – ask doctor before starting supplements – CAUTION!!! I believe that supplementation of any form of B6 in a low NAD state will cause B6 toxicity. Read this post for that hypothesis.

4. Avoid glycine supplements and also collagen powders as these are high in glycine

5. Avoid Miralax or any PEG product (macrogol is another name for PEG) – see below

MIRALAX can become OXALATE and also can tie up alcohol dehydrogenase and dehydrogenase that are needed for Vitamin A metabolism

Approximately 3.7% of PEG based laxatives are absorbed. This can be metabolized by the body to glyoxylate and then to oxalate especially in a B6, Thiamine, or Niacin deficient state. This will impair LDH, subsequently lower NAD, and thus impair vitamin A metabolism, but also overall metabolism.  In addition the first two steps of PEG metabolism involve alcohol dehydrogenase and aldehyde dehydrogenase. They are enzymes used in vitamin A metabolism. So Miralax may tie up these enzymes for an unknown period of time. This would be an interesting study in a rat lab.

So many people with Autism take PEG (Miralax). PEG can also cause gut dysbiosis (see below for info on bacterial steal of NAD+) Perhaps many have A2E complexes of the essential ether lipid ethanolamine due to increasing retinal levels (this is a hypothesis). 

PEG with weights greater than 4000 aren’t absorbed (1960 studies), but somewhere along the way a manufacturer changed it out for PEG 3500, probably due to cost, and the researchers felt absorbing 200 ml out of 5400 ml was no big deal.

I propose that 3.7% absorbed of the PEG laxative are causing a big deal. And the unabsorbed product is causing gut dysbiosis.

Ever notice that the label says not for use in children? Also to not use more than a week?

Studies…

https://onlinelibrary.wiley.com/…/3527600035.bpol9012

https://www.gastrojournal.org/…/S0016-5085(17…/fulltext

Solution:

1. Ask your doctor if you can stop Miralax

2. Ask your doctor for alternatives such as magnesium, senna, glycerin suppositories, etc.

This is not written to diagnose or treat a condition, but only for informative purposes. Please consult your doctor before stopping or starting medications or supplements, and before making dietary or lifestyle changes based on the information provided. –  Meredith Arthur, MS, RD, LD