Low Toxin Diet Grant Genereux's Theory Of Vitamin A Toxicity

[Mito]

A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder

The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment ...

www.ncbi.nlm.nih.gov

 

[Amazoniac]

- LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene

Spoiler

"We previously observed in cells and tissues that RA concentrations increase with impaired lecithin:retinol acyltransferase (LRAT) function (23, 24)."

"LRAT is a member of the N1pC/P60 multigene family of integral membrane proteins. These proteins perform catalysis at the lipid membrane-water interface and use phospholipids as substrates (39). During LRAT catalysis, a thioacyl enzyme intermediate forms, and the acyl group transfers from its thioester bond to ROL. For this purpose, LRAT displays a specific retinoid-binding domain (26), which first evolved in jawless vertebrates (40). LRAT has been shown to be critically involved in cellular uptake of ROL from serum ROL-binding protein into peripheral tissues (41), storage of retinoids in liver and lung (27), as well as visual chromophore synthesis and recycling (28)."

"LRAT acts downstream in the pathway for retinoid biosynthesis and esterifies retinol (ROL) by transferring an acyl moiety from the sn-1 position of phosphatidylcholine (25, 26)."

"We herein describe a novel function of LRAT in the control of intestinal retinoid biosynthesis from dietary BC. Using knockout mouse models, we observed that LRAT-deficient animals were not able to properly utilize dietary BC for retinoid biosynthesis."

"The intestine-specific homeodomain transcription factor (ISX) controls the activity of the vitamin A-forming enzyme β-carotene oxygenase-1 in intestinal enterocytes in response to increasing concentration of the vitamin A metabolite retinoic acid."

"We demonstrate that Lrat−/− mice displayed higher expression levels of the transcription factor than WT mice. Our analysis indicates that this phenotype is caused by increased RA production from dietary vitamin A precursors in the LRAT-deficient intestine. Enhanced retinoid signaling and increased activity of the transcription factor ISX resulted in a suppression of BCO1 activity that prevented BC conversion to retinoids."

"This assumption was corroborated by the pharmacological studies where treatment with a RAR antagonist restored Bco1 expression in LRAT-deficient enterocytes. Similarly, genetic depletion of the Isx gene restored retinoid biosynthesis in an ISX- and LRAT-deficient double-mutant mouse line. In fact, the DKO mice efficiently converted BC to retinoids and distributed them to extrahepatic tissues. These findings demonstrate that dysregulation of Isx expression and subsequent suppression of Bco1 gene expression constituted the molecular basis for reducing the retinoid biosynthesis from BC in the LRAT-deficient intestine."

"Our findings also demonstrate that Bco1 gene expression is directly controlled through ISX and not through an interaction between RARs and the Bco1 gene promoter as previously proposed by others (14). Thus, we conclude that the catalytic activity of LRAT is required to balance intestinal retinoid concentrations and to ensure that the majority of absorbed BC is converted to RE for bodily distribution."

"We previously reported that gastrointestinal immunity is severely impaired in ISX-deficient mice when subjected to BC feeding (42 [167]). We now observed that the different diets had a profound effect on gastrointestinal immunity and barrier function in LRAT-deficient mice."

"Lrat−/− mice on BC diet displayed highly reduced retinoid stores in mesenteric lymph nodes. In contrast, WT mice were able to maintain their retinoid levels when fed with BC. The biochemical phenotype of LRAT-deficient mice of the BC group was associated with decreased expression of Ccr9, a marker gene for gastrointestinal lymphocytes." "We observed 4-fold higher levels of Ccr9 mRNA in the jejunum of the VAS group when compared with BC and VAD groups (Fig. 4D)."

"It has long been known that vitamin A affects barrier function of the intestine, including goblet cells (34). Therefore, we determined mRNA levels of KLF4, a marker gene of these cells (35). In addition, we measured mRNA levels of the mucin-2 gene. The encoded protein is secreted from goblet cells in order to form a protective luminal mucus layer (36), and its expression is regulated by retinoid signaling (37). The analyses revealed that mRNA levels of Klf4 and mucin-2 were respectively 3-fold and 10-fold lower in mice of the BC and VAD groups when compared with mice of the VAS group (Fig. 4E, F). Thus, BC diet similar to VAD diet was not able to maintain retinoid-dependent processes at the intestinal barrier of LRAT-deficient mice."

"The previous and present findings indicate that RA levels at the intestinal barrier must be tightly controlled to maintain a physiological state. In the intestine, RA has a broad spectrum of effector functions and, under specific conditions, RA can promote an inflammatory environment (43)."

"We also observed that LRAT-deficient mice accumulated intact BC in the liver and lymph nodes. Children receiving vitamin A supplements and consuming BC-rich fruits display a similar carotenemia (45). In a gerbil model, oversupplementation with these micronutrients resulted in reduced Bco1 expression in the intestine and BC accumulation as well (46), indicating that suppression of intestinal BCO1 activity results in BC accumulation in the body. Interestingly, we observed that Cd36 gene expression was elevated in the intestine of BC-supplemented Lrat−/− mice." "This scavenger receptor may provide an alternative route for BC uptake from the diet (31)." "Thus, we propose that CD36 facilitates the uptake of BC in enterocytes under this condition."

"The Ross laboratory showed that LRAT is expressed at high levels in the rodent intestine (47). This mode of expression parallels Bco1 and Scarb1 expression and ensures an efficient retinoid biosynthesis from BC. In contrast to the Scarb1 and Bco1, ISX does not suppress Lrat gene expression in enterocytes (15). The absence of this regulation might be an evolutionary adaptation to diets with high vitamin A content. LRAT transforms ROL into its inert ester form and prevents toxic and teratogenic effects of the nutrient, as we previously showed in a zebrafish model (24)."

"In conclusion, we here reported that the catalytic activity of the LRAT enzyme plays a critical role in the control of retinoid biosynthesis in the mouse intestine. In this process, LRAT dynamically adjusts the concentration of retinoids by sequestering RE for body distribution and storage. This homeostatic mechanism ensures adequate regulation of BCO1 activity and portioning of retinoids in the body to maintain physiological processes such as vision, immunity, and cellular differentiation."

Retinol is esterified in the cells of the intestine and most other tissues via enzymes of the endoplasmic reticulum, which use acyl groups from either phosphatidylcholine (LRAT) or acylated coenzyme A (ARAT). These systems show marked specificities for saturated fatty acids, in particular, palmitic acid; thus, the most abundant product is retinyl palmitate.

 

[tim333]

Retinoic acid competes with calcitriol at VDRs. If you have chronically elevated levels of retinoic acid the body will often raise calcitriol levels to compensate. This depletes stores of D3 as well as K2. Taking D3 and K2 may alleviate some symptoms of Hypervitaminosis A but it definitely won't eliminate them. An elevated level of retinoic acid depletes most or all of the B vitamins, vitamin C, vitamin D, vitamin E and vitamin K2. It also inhibits enzyme function throughout the body, an example is transketolase inhibition which affects thiamine metabolism. It acts as a potent carcinogen in the skin upon exposure to sunlight as well as a potent carcinogen in the lungs upon exposure to smoke. Retinoic acid is a hormone like signalling molecule so excess levels are very toxic via that mechanism as well, this is how it can cause birth defects.

I believe that it's best to avoid all vitamin supplements.

Lowering retinoic acid levels can take many years, I have been following a low vit A diet for 2.5 years and the last time I checked my serum retinol was still high. Symptom flare ups are often a part of vitamin A depletion. I experienced extreme fatigue, drowsiness and other symptoms for many weeks when I first started. I experienced multiple food poisoning like episodes during the first year, vomiting up bile gave immediate relief during these episodes. As bile is the main pathway for excretion liver flushes (which I haven't done during this time) are a possible way to speed up retinoic acid depletion. I also experienced shortness of breath for about a month or so at one point.

It's a real shame that the concept of vitamin A not being a vitamin has got mixed up with Hypervitaminosis A awareness. Vitamin A is a proven vitamin and I've seen no evidence to the contrary.

Everybody has a different level of susceptibility to Hypervitaminosis A. Most of the world still consumes a low vitamin A diet, for example the Mexican median intake is one fifth of the RDA. Vitamin A deficiency was common in the past so it's possible that some of us have a genetic expression that favours the conservation of it.

The low vitamin A diet I follow is in complete alignment with what I wish to eat naturally. I have disliked dairy products, liver and carrots my whole life yet I ignored my instincts and consumed them.

When I began the low vitamin A diet 2.5 years ago I had to spray my face, scalp and chest with hydrogen peroxide twice a week to control seb derm. Within months the seb derm drastically subsided. Over the last 2.5 years what was left of it very gradually subsided. In the last couple of months I have been able to completely stop using hydrogen peroxide to control the seb derm. The seb derm/danduff I have left is very mild. It's the first time since I was a child that I don't have to do anything to control dandruff.

I've previously mentioned many other health benefits that I've experienced since following a low vitamin A diet.

Studies have shown that even young people often suffer from Hypervitaminosis A, it's not uncommon. It's really not that difficult an issue to understand either so it baffles me that there is still so little excitement and so much misunderstanding about it.

Mawson has shown how transient elevated levels of retinoic acid play a large role in symptomatology and mortality from COVID so it's an issue everybody should be getting their heads around.

 

[youngsinatra]

It's been a week of high dose vitamin D3 + K2-7 at 50'000 IU / 1000 mcg per day and I observed much reduced yellow-colored hands and sole of the feet. I feel better in general now.
I'd suspect that improving liver health with choline, glycine, taurine, caffeine, K2 and vitamin E could potentially help with excreting excess vitamin A too.

 

[Quelsatron]

After a fairly decent return to form I ate a bit of liver paté as an experiment, equivalent to like 10 grams of pork liver, and within an hour I had this weird pressure behind my eyes that alters my vision so everything is just less distinct, like it's hard to focus and my eyes are tired, it's hard to explain. Does anyone else recognize visual changes from vitamin A?

 

[maillol]

Look out for palm oil

 

[Dr. B]

Look out for palm oil

View attachment 28152

seems dangerous
whats the serving sizes here mate. like 180,000 RE and 30,000 RE per how much amount of palm oil or shark liver oil?
RE is the same as IU? like 30,000 IU vitamin A?
if its per 100g thats a huge amount of fat
says per 100 B...

 

[maillol]

Yeah I'm not sure what 100 B means and I don't know the conversion from RE to IU but either way it's 15 times higher than carrot which is a lot.

 

[rockarolla]

Yes. Lots of symptoms. I felt like I was degenerating and becoming hypothyroid.

Did you consider upping calories instead? Hypo seems to be a secondary condition to chronic glucose defficiency - happens when you unlock your endotoxin receptors with vitamin-less diet as a consequence of increased glucose consumption by immune cells.

 

[rockarolla]

I don't think vitamin A is a toxin anymore.

Vit A is obv. not a toxin otherwise we would not have receptors for it right in the immune cells very close to vit D receptors for complete machinery. And toxicity could be a result of subclinical septic condition from its antibacterial properties against gut microbiome. This could explain why the majority of population is immune to `toxicity` and negative effects from vit A

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases

Vitamin A metabolite retinoic acid (RA) plays important roles in cell growth, differentiation, organogenesis, and reproduction and a key role in mucosal immune responses. RA promotes dendritic cells to express CD103 and to produce RA, enhances the differentiation of Foxp3⁺ inducible...

www.hindawi.com

 

[Dr. B]

Vit A is obv. not a toxin otherwise we would not have receptors for it right in the immune cells very close to vit D receptors for complete machinery. And toxicity could be a result of subclinical septic condition from its antibacterial properties against gut microbiome. This could explain why the majority of population is immune to `toxicity` and negative effects from vit A

Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases

Vitamin A metabolite retinoic acid (RA) plays important roles in cell growth, differentiation, organogenesis, and reproduction and a key role in mucosal immune responses. RA promotes dendritic cells to express CD103 and to produce RA, enhances the differentiation of Foxp3⁺ inducible...

www.hindawi.com

arent there receptors for everything good or bad. like cannabis, opioids, estrogens etc
most people dont react negatively to vitamin A?

 

[Quelsatron]

After a fairly decent return to form I ate a bit of liver paté as an experiment, equivalent to like 10 grams of pork liver, and within an hour I had this weird pressure behind my eyes that alters my vision so everything is just less distinct, like it's hard to focus and my eyes are tired, it's hard to explain. Does anyone else recognize visual changes from vitamin A?

I have to say, this post was fairly useless and done while being off kilter, but it's interesting to note that I just so happened to get a cold (or undiagnosed covid) saturday. I also got a cold after trying a low A diet for a while, and before that I had been immune to getting any kind of infection for 2 years despite feeling like unmitigated bum. Granted, there's something going around at work, but still, it's interesting.

 

[maillol]

I have to say, this post was fairly useless and done while being off kilter, but it's interesting to note that I just so happened to get a cold (or undiagnosed covid) saturday. I also got a cold after trying a low A diet for a while, and before that I had been immune to getting any kind of infection for 2 years despite feeling like unmitigated bum. Granted, there's something going around at work, but still, it's interesting.

I also had a cold recently since going low A, after years of not catching anything, but feeling terrible.

 

[rockarolla]

arent there receptors for everything good or bad. like cannabis, opioids, estrogens etc
most people dont react negatively to vitamin A?

yes, but that's not my point - for vit A there is a specific receptor inside the immune cells, part of VDR-based immune response

The Retinoid X Receptors and Their Ligands

This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional ...

www.ncbi.nlm.nih.gov

totally depriving yourself of A is like cutting all D and we already have a Marshall "vitamin D greater than 0 is a poison" cult with some followers but as with every cult without much success outside very specific cases like sarcoidosis remission

 

[Dr. B]

yes, but that's not my point - for vit A there is a specific receptor inside the immune cells, part of VDR-based immune response

The Retinoid X Receptors and Their Ligands

This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional ...

www.ncbi.nlm.nih.gov

totally depriving yourself of A is like cutting all D and we already have a Marshall "vitamin D greater than 0 is a poison" cult with some followers but as with every cult without much success outside very specific cases like sarcoidosis remission

why does vitamin D cause sarcoidosis? hows that related

 

[LLight]

yes, but that's not my point - for vit A there is a specific receptor inside the immune cells, part of VDR-based immune response

The Retinoid X Receptors and Their Ligands

This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional ...

www.ncbi.nlm.nih.gov

totally depriving yourself of A is like cutting all D and we already have a Marshall "vitamin D greater than 0 is a poison" cult with some followers but as with every cult without much success outside very specific cases like sarcoidosis remission

I believe the reasoning is that these receptors aren't necessarily specific to vitamin A.

 

[rockarolla]

I believe the reasoning is that these receptors aren't necessarily specific to vitamin A.

activating _retinoid_ receptor with alternative ligand is like activating VDR with curcumin

 

[LLight]

activating _retinoid_ receptor with alternative ligand is like activating VDR with curcumin

I have no real expertise but I believe a receptor is not necessarily named according to the ligand with which it has the greatest affinity. It might be based on the first which is discovered.

 

[rockarolla]

What worries me is experiment with A absence could ultimately lead to the same outcomes as with the cases when people start to actively avoid all sources of vit D(including sun) - basically intolerance. What if A helps to control parts of [chronic] microbiome(could be one of the reasons A is milk-included to protect child with undeveloped/weak immune system) from unchecked overgrow(similar to D) .. this could explain why some could not tolerate A any more after several years on a Grant diet...

Consequences of Vitamin A Deficiency: Immunoglobulin Dysregulation, Squamous Cell Metaplasia, Infectious Disease, and Death - PubMed

Vitamin A is an important regulator of immune protection, but it is often overlooked in studies of infectious disease. Vitamin A binds an array of nuclear receptors (e.g., retinoic acid receptor, peroxisome proliferator-activated receptor, retinoid X receptor) and influences the barrier and...

pubmed.ncbi.nlm.nih.gov

 

[rockarolla]

Impaired blood clearance of bacteria and phagocytic activity in vitamin A-deficient rats - PubMed​

The effect of vitamin A deficiency on the functional integrity of the reticuloendothelial system and the phagocytic capacity of circulating polymorphonuclear leukocytes was evaluated in retinoate-cycled vitamin A-deficient rats under conditions such that secondary dietary imbalances were eliminated. Kinetics of blood clearance of 2 X 10(7) Escherichia coli injected intravenously was depressed within 8 days of the withdrawal of retinoic acid; all animals were profoundly affected by Day 12 of deficiency. In vitro, the phagocytic activity of polymorphonuclear leukocytes was similarly affected; by Day 12 of deficiency, phagocytic capacity in all deficient animals was less than 40% of the appropriate control values (P less than 0.01). Animals rendered vitamin A deficient by this procedure also displayed marked susceptibility to endogenous bacterial infection, as judged from the proportion of deficient rats that spontaneously developed bacteremia during the later stages of deficiency. These data together demonstrate unequivocally that reticuloendothelial and polymorphonuclear leukocytic functions are impaired in vitamin A deficiency in the absence of other dietary imbalances.

Vitamin A modulation toward IL-12, IFNγ production and macrophage activity in malaria disease

https://aip.scitation.org/doi/pdf/10.1063/1.4953523

Giving vitamin A per oral solution can increase innate immunity response and acquired immunity in Swiss strain mice which are infected with Plasmodium berghei. This is indicated by the occurrence of elevated levels of IL-12, IFN-γ and phagocytic index. The optimal dose, which is 6 000 IU, causes significant impact on the declined index parasitaemia. It should also continue to see increased activity of molecular cell and organ damage as a result of high doses of vitamin A.​

Based on the study, oral administration of vitamin A has increased number of IL-12 and IFN-γ levels. Statistically, significant difference of IL-12 and IFN-γ levels can be observed in group 1 with group 3 and group 4. Meanwhile, in group 1 and group 2, there was no significant difference. It shows that vitamin solvent did not affect IL-12 and IFN-γ levels. Observations were conducted to determine vitamin A effect in the mice infected with Plasmodium berghei. Vitamin A only worked in general terms, such as in the mechanism of proliferation and differentiation of immune cells. Even in the low compound of vitamin A in the body, immune system is running optimally [18]. The addition of vitamin A only has little effect. However, various studies indicate that specific vitamin A has a function in the immune response, especially in macrophage activities. Low intake of vitamin A also improves cells ability to proliferate [19]. Based on the research data, IL-12 level in group 3 and group 4 were higher than group 1 and group 2. This shows the possibility of vitamin A to modulate the immune system. Increasing IL-12 number triggered by the activation of macrophages into Dendritic Cell (DC) in an effort to fight against the antigen [20]. Vitamin A in the form of provitamin carotenoids and other compounds are easier to be absorbed. Pro-vitamin A would be absorbed by epitel cell in the intestine and converted into retinaldehyde in the cytoplasm [21]. In the cytoplasm, Retinaldehyde will be changed into retinoic acid that will be bonded to the active site of Retinoids A Receptor (RAR) and Retinoid X Receptor (RXR). Retinoic Acid Complex-RAR/ RXR heterodimer is component to activate cell DNA and also as a transcription trigger of acute phase response proteins such as IL-12 and INF α [22]. The high number of IL-12 will stimulate T cell proliferation becomes Th cell and influence NK and Th1 and Th2 cell to secrete IFN-γ [23]. The results showed that IFN-γ levels also increased high enough, the highest production of it has been found in the mice which given 6 000 IU with vitamin A. IFN-γ which secreted will reactivate macrophages. Activation of macrophages into DC boost phagocytosis activity in term of against the antigen.