Hypothesis: Anhydroretinol causes intracellular hypercalcemia leading to downstream alterations of metabolic function and, in excess, apoptosis.

The importance of ALDH7A1 competition in anhydroretinol formation

ALDH7A1 is an enzyme that moonlights throughout the cell and goes where it is needed based on cellular metabolism.  In oxygen deprivation it becomes a regulator of cellular energy homeostasis.  This enzyme also is tied up in lipid peroxidation detox, histamine metabolism, and betaine production in the setting of a low betaine diet (Gluten free diets are a huge cause of burden on ALDH7A1). Betaine is the cofactor for BHMT that runs methionine salvage pathways in the liver, kidneys, and small parts of the brain (this is found in a model of MS) while under conditions of low 5-methylfolate production or B12 deficiency or during a high nitric oxide state which inhibits the enzyme methionine synthase. 

If ALDH7A1 is not doing lysine metabolism this results in an increase in P6C and inactivation of P5P (vitamin B6). This can lead to insufficiency of B6 and the body will have to choose where to use it.  One problem with low B6 levels is that this leads to poor denovo NAD production. NAD is a cofactor needed for ADH that is required to deal with the tiny bit of alcohol produced during digestion (3 grams – about 1/2 shot glass) and also the alcohol being made from gut dysbiosis (alcohol producers such as candida, aspergillus, s. boulardii. s cerevisiae, e.coli, clostridia).  

This increase in alcohol increases the conditions needed to make anhydroretinol (see blog post and anhydroretinol pathway). 

If you can minimize lipid peroxidation, the need to make betaine, or consume enough betaine, and limit histamine needing ALDH7A1, then this will allow normal lysine metabolism and normal de novo NAD metabolism and then we are no longer reluctant alcoholics. 

This requires focusing on each person’s ability to deal with oxidative stress as well as their methylation pathway.  The innate immune system plays a role as well because activated macrophages cause increased iNOS expression which results in increased nitric oxide formation and inhibition of methionine synthase.  Thus, chronic bacterial infections will trigger a major downstream effect resulting in a risk factor for making anhydroretinol. 

Anhydroretinol obliterates f-actin which is a cytoskeletal protein. This scaffold controls the calcium exporter PMCA that is found in all cells as a housekeeper to regulate calcium. Actin is found in the G-Actin state or the F-actin state or an in-between state called an oligomer.  
When it’s an oligomer it turns on calcium export to bring the cells back to a normal intracellular calcium level, so it doesn’t go through apoptosis. When it grows into F-actin, PMCA is turned off and calcium accumulates. It cycles back and forth between the long F-actin chains and oligomers, but being destroyed down to G-Actin by anhydroretinol would in theory cause loss of PMCA function.  If anhydroretinol stays around too long, then apoptosis occurs due to loss of cytoskeleton and hypercalcemia.

If cellular levels of anhydroretinol are not to the point of causing apoptosis, the resulting excess calcium in cells will cause overactivation of calmodulin. Calmodulin is what causes the Stra6 pore to prefer to stay open, but instead of doing a normal influx and efflux, when calcium is high it lets retinol leave the cell and doesn’t let retinol in cells as much. This also occurs in the setting of magnesium deficiency because calmodulin overactivation is controlled by an EF-hand on calmodulin that requires magnesium. If calmodulin is overactivated, this causes low retinol uptake and thus cellular retinoic acid deficiency, but high serum vitamin A levels due to efflux back onto RBP4 which we classically see as vitamin A toxicity. What I have found is that vitamin A toxicity is actually both a toxicity and deficiency at the same time. 

The provision of “fresh” retinol in a cell from postprandial chylomicrons could save the day because it has been shown to stabilize F-actin in a model where anhydroretinol destroys it.  Dietary retinol could work as long as alcohol is dealt with properly in the gut, and the person does not make anhydroretinol in their gut.  Anhydroretinol can be made into rehydroretinol when cellular alcohol levels are low, but it is only about 7% of the activity of the original retinol molecule, and so whether or not it also can act to stabilize F-actin is questionable.

One more interesting aspect of F-actin is that it is the scaffold for KEAP1 which regulates NFR2 activation. If F-actin is destroyed by anhydroretinol, this causes alteration in KEAP1 scaffolding and this could lead to dysregulation of NRF2. I’m finding that mostly it leads to overactivation of NRF2 which causes hyperkeratosis as NRF2 not only turns on genes for dealing with oxidative stress, but also turns on keratin producing genes. I believe this is the cause of hyperkeratosis. My vitamin A toxic client experience shows they are all struggling from hyperkeratosis and keratosis pilaris.  

How do we keep anhydroretinol in control? We control alcohol levels.

What factors deal with alcohol.
1. NAD (The biggest concern is de novo production via kynurenine pathway or maximize recycling of cytosolic NAD via avoidance of high oxalate diet if needed.)
2. SULT (acts as a backup buffer) (SULT1A1 in human intestines)
3. Vitamin E (can help restore NAD recycling and prevent lipid peroxidation)

4. CYP2E1 (although this is the last resort because it causes oxidative stress)

What can lower #1 NAD?
1. Functional B6 deficiency from ALDH7A1 competition leads to low NAD production
2. Cytosolic recycling of NAD is inhibited by oxalate inhibition of LDH
3. Pyroluria
4. High alcohol intake

5. Gut dysbiosis 

What can lower #2 SULT?
1. SUOX issues (Moco, B2, B6)
2. Arsenic, chlorate, and perchlorate inhibit PAPS synthase
3. Salicylates inhibiting SULT
4. Quercetin inhibiting SULT
5. Excess H202 causing sulfite radicals instead of sulfate to produce which causes lower levels of PAPS

What can cause issues with #3 vitamin E?
1.  Low E diet due to eliminating too many foods
2.  Excess oxidative stress causing increasing vitamin E needs

What can cause issues with #4 CYP2E1?

Inhibitors (which could be good due to CYP2E1 causes more oxidative stress, but if #1-3 is down, CYP2E1 may be the only way to deal with alcohol in the liver).  Inhibitors of CYP2E1 include – quercetin, cannabidiol, niacin, niacinamide, menadione 

Calcium excess in cells has side effects (here are just some of them):

1. Seizures

2. Mast cell activation

3. Decreased aromatase activity leading to low estrogen and slow PEMT needed to make PC for making CDP-Choline for plasmalogens (leads to membrane instability)

4. Hypotonia, muscle weakness, constipation

5. POTS due to vascular endothelial dysfunction. 

Retinoic acid deficiency in the gut due to making anhydroretinol instead of correctly metabolizing retinol to retinaldehyde and to retinoic acid causes alteration in the innate immune response in gut associated lymphoid tissue.  I won’t go on and on about that, but here is an article on the role of retinoic acid in the immune system. Vitamin A and immune regulation: Role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance – PMC (nih.gov)

Other sources.

Sci-Hub | Regulation of the Plasma Membrane Calcium ATPases by the actin cytoskeleton. Biochemical and Biophysical Research Communications | 10.1016/j.bbrc.2017.11.151

F-actin as a functional target for retro-retinoids: A potential role in anhydroretinol-triggered cell death | Journal of Cell Science | The Company of Biologists

680.tif (rupress.org)

Physiologically Relevant Free Ca2+ Ion Concentrations Regulate STRA6-Calmodulin Complex Formation via the BP2 Region of STRA6 – ScienceDirect

Sci-Hub | | 10.1016/s0021-9258(18)56486-3

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