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

[LLight]

Do they do that incidentally or by design? My understanding is they are always undesirable and are a major cause of arteriosclerosis.

I'm not really knowledgeable about this topic . Maybe the confusion might be due to the fact that oxysterols are a class of compounds which may have different impacts on the body (in addition to the potential activation of the LXR).

My "claims" were based on these publications:

4β-Hydroxycholesterol Signals From the Liver to Regulate Peripheral Cholesterol Transporters

"Like many other oxysterols, 4β-hydroxycholesterol (4βHC) is a ligand for liver X receptors (LXRs), the major regulators of lipid metabolism (Janowski et al., 1996; Lee and Tontonoz, 2015). Both LXRα (NR1H3) and LXRβ (NR1H2) are activated by 4βHC to a similar degree in vitro (Nury et al., 2013), but the role of 4βHC in the regulation of LXR targets is yet to be explored. LXRα is expressed in the liver, intestine, kidney, adipose tissue, adrenals, and macrophages, while LXRβ is expressed ubiquitously (Lee and Tontonoz, 2015). The activation of LXR leads to upregulation of lipogenesis in the liver and induction of cholesterol efflux transporters such as ATP-binding cassette transporters A1 (ABCA1), ABCG1, and ABCG5/8, as well as repression of LDL receptor-mediated lipoprotein uptake in the liver and macrophages via inducible degrader of the LDL receptor (IDOL) (Lee and Tontonoz, 2015). The activation of LXR is generally considered to reduce atherosclerosis, while the induction of hepatic lipogenesis may lead to hepatosteatosis (Lee and Tontonoz, 2015)."
​

Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

" Furthermore, in the liver, LXR promotes cholesterol conversion to bile acids by cytochrome P450 7A1 (CYP7A1)."
​

The Liver X-receptor Alpha Controls Hepatic Expression of the Human Bile Acid-Glucuronidating UGT1A3 Enzyme in Human Cells and Transgenic Mice - PubMed

"Glucuronidation, an important bile acid detoxification pathway, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT1A3 is considered the major human enzyme for the hepatic C24-glucuronidation of the primary chenodeoxycholic (CDCA) and secondary lithocholic (LCA) bile acids. We identify UGT1A3 as a positively regulated target gene of the oxysterol-activated nuclear receptor liver X-receptor alpha (LXRalpha)."​

 

[tim333]

I'm not really knowledgeable about this topic . Maybe the confusion might be due to the fact that oxysterols are a class of compounds which may have different impacts on the body (in addition to the potential activation of the LXR).

My "claims" were based on these publications:

4β-Hydroxycholesterol Signals From the Liver to Regulate Peripheral Cholesterol Transporters

"Like many other oxysterols, 4β-hydroxycholesterol (4βHC) is a ligand for liver X receptors (LXRs), the major regulators of lipid metabolism (Janowski et al., 1996; Lee and Tontonoz, 2015). Both LXRα (NR1H3) and LXRβ (NR1H2) are activated by 4βHC to a similar degree in vitro (Nury et al., 2013), but the role of 4βHC in the regulation of LXR targets is yet to be explored. LXRα is expressed in the liver, intestine, kidney, adipose tissue, adrenals, and macrophages, while LXRβ is expressed ubiquitously (Lee and Tontonoz, 2015). The activation of LXR leads to upregulation of lipogenesis in the liver and induction of cholesterol efflux transporters such as ATP-binding cassette transporters A1 (ABCA1), ABCG1, and ABCG5/8, as well as repression of LDL receptor-mediated lipoprotein uptake in the liver and macrophages via inducible degrader of the LDL receptor (IDOL) (Lee and Tontonoz, 2015). The activation of LXR is generally considered to reduce atherosclerosis, while the induction of hepatic lipogenesis may lead to hepatosteatosis (Lee and Tontonoz, 2015)."
​

Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

" Furthermore, in the liver, LXR promotes cholesterol conversion to bile acids by cytochrome P450 7A1 (CYP7A1)."
​

The Liver X-receptor Alpha Controls Hepatic Expression of the Human Bile Acid-Glucuronidating UGT1A3 Enzyme in Human Cells and Transgenic Mice - PubMed

"Glucuronidation, an important bile acid detoxification pathway, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT1A3 is considered the major human enzyme for the hepatic C24-glucuronidation of the primary chenodeoxycholic (CDCA) and secondary lithocholic (LCA) bile acids. We identify UGT1A3 as a positively regulated target gene of the oxysterol-activated nuclear receptor liver X-receptor alpha (LXRalpha)."​

Interesting. I'm not very knowledgeable about this area either. Perhaps this oxysterol is produced by the body rather than through free radicals?

 

[tim333]

With all this talk of oxysterols I just wanted to make clear I eat a lot of meat, chicken and fish. Beans just help to reduce my meat intake slightly. I don't prioritize lowering oxysterol intake over everything else I know about good nutrition.

 

[LLight]

Perhaps this oxysterol is produced by the body rather than through free radicals?

Indeed, I believe it is thought that the CYP3A4 enzyme could have a role in the transformation of cholesterol in 4beta-hydroxycholesterol.

 

[Amazoniac]

There's now an obsession with supporting the enzymatic pathways required in poisonoids metabolism, but it's the same question as before: isn't it suspicious that you'd have enough reagents to process a large dose of ethanol at once with ease, but struggle to utilize a few milligrams of poisonol?

It's like showing a diagram of venom D metabolism needing magnesium in multiple steps and accepting that it's because of this that the mineral is limiting; that the limitation will be in acting upon it rather than elsewhere that's also dependent on magnesium, venom D could stop working for sensing that it's not productive to be metabolized at the time and it will look like the blockade is in its activation. For someone obtaining 0.05 mg of venom D, a consumption of 300 mg of magnesium in a day would make the dose seem nothing in comparison, even if one venom D molecule uses up various of magnesium.

It may be argued that once the enzymes are covering basal functions, nutrition will only return to them after other needs that compete for resources are met. It must be that the body regulates these pathways accounting for the cascade of reactions that they (are going to) trigger, not just the immediate availability of nutrition. Processing of ethanol would be an emergency and prioritized, but it was possible to do it. Disconsidering these aspects leads to silly notions such as believing in being capable of manipulating how the enzymes are going to behave simply by withholding or not specific nutrients, as if getting more nutrition would result in overwhelming the detoxification of poisons.

The attention has to be on the overall impact that they have as signalling molecules (amounts are low relative to their broad effect) instead of obsessing with 'dehydrogenases', as mentioned in the interview. This shifts the perspective from feeding enzymes to nourishing the body and figuring out why they're behaving in such way (instead of blaming on toxins or intractable malnutrition). It would leave time to question 'dehydrogenating what?' if there are no changes in this regard from poisonal to poisonoic acid. Apparently, it's because the molecule is oxidized with water participating:

C20H28O (poisonal) + NAD+ + H2O → C20H28O2 (poisonoic acid) + NADH + H+​

 

[Amazoniac]

The simplified formulas are tricky, it actually seems that OH− is incorporated from water and NAD+ will accept a hydrogen from poisonal.

Isolating the interactive group:

• C19H27-CHO (poisonal)
  
• C19H27-COOH (poisonoic acid)
• C19H27-COO− (poisonoate)

C19H27-CHO (poisonal) + NAD+ + H2O → C19H27-COOH (poisonoic acid) + NADH + H+​

- Anti-Peat - Grant Genereux's Theory Of Vitamin A Toxicity

- Redox regulation by reversible protein S-thiolation in Gram-positive bacteria

Spoiler

"Catalytic mechanism of NAD+-dependent aldehyde dehydrogenases. NAD+ binds tightly to the enzymes active site, resulting in a conformational change and activation of the catalytic Cys thiol. (1) Nucleophilic attack on the carbonyl carbon of the aldehyde substrate leads to the formation of a covalently bound tetrahedral thiohemiacetal intermediate. (2) Hydride transfer from the tetrahedral thiohemiacetal intermediate to NAD+ generates a thioester intermediate. (3) Deacylation of the thioester intermediate by nucleophilic attack of a water molecule produces a second tetrahedral intermediate. (4) The acid product and NADH are released from the enzymes active site and a new NAD+ molecule binds. This figure is adapted from [94]."

⬑ [94] Crystallographic evidence for active-site dynamics in the hydrolytic aldehydedehydrogenases. Implications for the deacylation step of the catalyzed reaction

Spoiler

- Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

Spoiler

 

[YourUniverse]

I havent read the whole thread, I have about 1,000 posts left to read (...) but the snippets I skimmed made me wonder something. If there is a similar sentiment posted previously, I apologize for bumping the thread.

Vitamin A is essential for growth, steroid hormone production, immunity, bone health, and etc. But it is necessary for it to be balanced with other things.

Vitamin A is fat soluble, excesses are stored in body fat. Excessive vitamin A can slow metabolism.

I do believe getting adequate vitamin A is important, but less talked about is vitamin A metabolism - I'm sure its possible that a person can have plenty of vitamin A in their system but are lacking the co-factors needed to utilize it fully.

I theorize that fatter or more hypothyroid people, especially those "eating healthy", have too much vitamin A in their fat stores, and not enough co-factors for its metabolism. Conversely, thinner people struggling to gain weight (another form of hypothyroidism) would do better adding additional sources of vitamin A. Truly healthy people would thrive on the standard RP diet advice - and having their eggs, butter, milk, liver, carrot (carotene), orange juice (carotene), maybe sweet potato (carotene), shellfish, etc.

The implication for heavier people might be to chill with the vitamin A, and replace fats with coconut oil. Nathan Hatch wrote that coconut oil can deplete vitamin A, but I dont think the claim was referenced and I dont understand how that could be true.

Another implication would be for heavier people to drastically increase their B12, to convert carotene, and shellfish (especially clams, but also oysters and mussels) are great sources of this.

The last thing I thought about is the needed for extra vitamin D, most likely via sunlight and not supplementation, as vitamin D and A work synergistically, and if my theory holds weight that a person has too much vitamin A, they would need to match this with D (or fix this imbalance). I have a feeling supplemental vitamin D on a fat person would too easily get stored in tissue but I dont have science to back this up.

 

[Recoen]

I havent read the whole thread, I have about 1,000 posts left to read (...) but the snippets I skimmed made me wonder something. If there is a similar sentiment posted previously, I apologize for bumping the thread.

Vitamin A is essential for growth, steroid hormone production, immunity, bone health, and etc. But it is necessary for it to be balanced with other things.

Vitamin A is fat soluble, excesses are stored in body fat. Excessive vitamin A can slow metabolism.

I do believe getting adequate vitamin A is important, but less talked about is vitamin A metabolism - I'm sure its possible that a person can have plenty of vitamin A in their system but are lacking the co-factors needed to utilize it fully.

I theorize that fatter or more hypothyroid people, especially those "eating healthy", have too much vitamin A in their fat stores, and not enough co-factors for its metabolism. Conversely, thinner people struggling to gain weight (another form of hypothyroidism) would do better adding additional sources of vitamin A. Truly healthy people would thrive on the standard RP diet advice - and having their eggs, butter, milk, liver, carrot (carotene), orange juice (carotene), maybe sweet potato (carotene), shellfish, etc.

The implication for heavier people might be to chill with the vitamin A, and replace fats with coconut oil. Nathan Hatch wrote that coconut oil can deplete vitamin A, but I dont think the claim was referenced and I dont understand how that could be true.

Another implication would be for heavier people to drastically increase their B12, to convert carotene, and shellfish (especially clams, but also oysters and mussels) are great sources of this.

The last thing I thought about is the needed for extra vitamin D, most likely via sunlight and not supplementation, as vitamin D and A work synergistically, and if my theory holds weight that a person has too much vitamin A, they would need to match this with D (or fix this imbalance). I have a feeling supplemental vitamin D on a fat person would too easily get stored in tissue but I dont have science to back this up.

So many have glucuronidation issues which is needed for the fat solubles too.

 

[Amazoniac]

- Carotenoid metabolism and regulation in horticultural crops

Spoiler

- Regulation of Carotenoid Biosynthesis During Fruit Development

Spoiler

 

[tallglass13]

I think Grant’s contribution are valid in the sense that he allowed us to refine our understanding of vitamin A. But at the same time, it’s pretty clear that it is not a toxin in the strict sense, and seeing it as such is pretty reductionist. I share your perspective, I suspect Grant is probably not producing much of the protective steroids anymore, but simultaneously he maybe benefiting from low endotoxins and low PUFAs in his system.

I felt good on this diet, my waist got smaller and my thinking what's clear and precise. I would be 100% sold if Grant did more labs and showed everyone his thyroid function and his testosterone levels. Because the 110 cholesterol level may not be all that bad. I mean 50 more points and he would be normal to most people. Ray has said 170 would be very good as long as the person has good hormone profile. If @tim333 knows Grant maybe he can get him to do a full hormonal lab.

 

[tim333]

Grant's diet is nutritionally unsound, nobody should be following it. It will certainly lead to health problems. A low VA diet doesn't have to exclude any food groups.

 

[Vinero]

Grant's diet is nutritionally unsound, nobody should be following it. It will certainly lead to health problems. A low VA diet doesn't have to exclude any food groups.

What kind of health problems would people get who just eat rice, beans and beef? What nutrients do you think are important that Grant is not getting?

 

[tim333]

What kind of health problems would people get who just eat rice, beans and beef? What nutrients do you think are important that Grant is not getting?

In addition to being vA deficient it is low in Vit C, Vit E, Vit K, calcium, potassium, DHA and iodine.

Vitamin A deficient rats develop thyroid hormone resistance where TSH, T3 and T4 are all high. Low vA will cause a range of issues after many years from being vA deficient before one gets to the point of xeropthalmia.

Lack of iodine will put further stress on the thyroid. The only reliable sources of some nutrients are animal foods, some of these nutrients are not found in beef. The ancestral diet included lizards, insects, eggs, freshwater fish and freshwater shellfish. These foods contain selenium, iodine, DHA and K2. This is why I very strongly emphasize fish consumption.

There is basically a whole textbook of issues that can arise from being deficient in the nutrients I listed long term.

 

[md_a]

Modification of Hepatic Folate Metabolism in Rats Fed Excess Retinol

Discussion

lhe ability of rats to oxidize hlstldlne or formate to CO 2 depends on the status of folate metabolism In the liver and, specifically, the availability of tetrahydrofolate needed In those oxidations. That the increased capacity to oxidize these substrates to CO 2 In rats given excess dietary retlnol was accompanied by an increase in hepatic tetrahydrofolate concentration is therefore not surprising.

The increased tetrahydrofolate levels may be explalned by a decrease tn the synthesis of 5-methyltetrahydrofolate, resultlng from the suppression of methylenetetrahydrofolate reductase activity. The decreases in concentrations of both 5-methyltetrahydrofQlate and AdoMet in ltvers of hlgh-retlnol Fed rats support this view. Thus, the increased oxidation of one-carbon units to CO2 occurs at the expense of methyl group production, resulting in a relatlve deficiency of labile methyl groups needed for transmethylatlon. The ramifications of this deficiency are currently under investigation.

Although it is uncertain whether a physiological function of vitamin A or an unrelated consequence of retlnol toxicity is responsible for the observed effects, it is clear that retlnol given at lO00 IU/g diet influences hepatic folate metabolism. The suppression of methylene-tetrahydrofolate reductase activity in hlgh-retlnol fed rats may well be the primary effect since this perturbation alone is adequate to explain the resulting influence on hlstldlne and formate oxidation and tetrahydrofolate, 5-methyltetrahydrofolate and AdoMet concentrations in liver. It has been documented that a decrease in hepatic methylenetetrahydro folate reductase activity (27) and an increase in hepatic tetrahydrofolate concentration (28) result after thyroldectomy in rats. Considering the observation that feeding rats excess retlnol dramatically decreases their serum levels of thyroid hormones (29, 30), the investigation of thyroid function in our model might provide insight into the mechanism by which retlnol affects folate metabolism.

Modification of Hepatic Folate Metabolism in Rats Fed Excess Retinol - PubMed

...

FOLATE-RETINOID INTERACTIONS: IMPLICATIONS IN LIVER DISEASE

Goals / Objectives

Our long range goal is to understand how the metabolic interaction between nutrients influences the development of liver disease. The objective of this research proposal is to identify the mechanism by which vitamin A compounds and derivatives cause hepatotoxicity. Our hypothesis is that specific retinoids mediate the abnormal metabolism of methyl groups and other lipotropes (e.g., folate), thereby leading to methyl group wastage and deficiency, exacerbating conditions in the development of liver disease. First, we will determine how retinoids influence methyl group and folate metabolism by focusing on key components, coenzymes, and proteins that control the ability of these pathways to function properly. Second, we will determine the role of diet and hormonal status to mediate retinoid-induced hepatotoxicity.Project Methods

The primary model we will use to study the interaction of folate and retinoids in liver disease will be the male Sprague-Dawley rat. Rats will be maintained on a control (10% casein + 0.3% methionine) diet and administered various levels of two retinoids, 13-cis-retinoic acid and all-trans-retinoic acid. To determine how retinoids modulate lipotrope metabolism, we will measure the hepatic levels of specific metabolites, coenzymes, and enzymes involved in folate and methyl group metabolism. The retinoid-induced increase in a key enzyme, glycine N-methyltransferase, will be a focus of this objective. Using both the rat model as well as cell culture models, we will determine the transcriptional/translational mechanisms underlying the induction of this protein by retinoids. In addition, hepatotoxicity will be addressed, in part, by determining hepatic lipid concentrations, including the determination of phosphatidylcholine. To determine the role of diet and hormones in mediating and/or exacerbating the ability of retinoids to down-regulate folate/methyl group metabolism, we will continue to use the rat model. Rats will be provided diets containing various levels of protein to determine how exogenous lipotrope sources prevent retinoid-induced hepatotoxicity. For hormonal involvement, studies will be performed using adrenalectomized rats, because previous work suggests that the ability of retinoids to induce hepatic steatosis is adrenal-mediated. Cell culture models will also be utilized when appropriate.

Progress 12/01/00 to 11/30/04


Outputs

We have shown that all-trans-retinoic acid (RA) induced the hepatic enzyme glycine N-methyltransferase (GNMT), a key regulatory protein that controls both folate and methionine metabolism to optimize the availability of methyl groups for transmethylation reactions. Retinoid-mediated alterations in GNMT were liver-specific and resulted in a diminished ability to methylate DNA, an epigenetic process that is critical in a number of pathological states. Moreover, we have shown that the minimum dose of RA required to perturb methyl group metabolism was well within the level used therapeutically by humans. RA also enhances the catabolism of methionine and the folate-dependent remethylation of homocysteine. We have extended our RA findings to explore a gluconeogenic state, namely treatment with the glucocorticoid dexamethasone or a diabetic condition. Treatment of rats or hepatic cells in culture with dexamethasone perturbed GNMT similar to, but independent of RA. GNMT was also induced using a streptozotocin-induced diabetic rat model, a condition that promoted folate-independent remethylation of homocysteine. It appeared that the catabolism of homocysteine was also enhanced, and that treatment of diabetic rats with RA prevented many of the changes observed in homocysteine metabolism in diabetic-only animals. Recently, we have found that the induction of GNMT protein in diabetic rats was associated with increased abundance of GNMT mRNA, indicating that the regulation of this protein was at the transcriptional/translational level. Moreover, the changes in methyl and homocysteine metabolism were exacerbated under dietary folate restriction, whereas inclusion of folate in the diet attenuated many of the observed changes. This data with respect to diabetes and perturbation of methyl group metabolism is in contrast to our recent report examining these pathways, with and without RA administration, using a hyperthyroid rat model, as alterations in thyroid status have been reported to disrupt the normal metabolism of folate and methyl groups. Treatment with triiodothyronine prevented the increase in GNMT activity, but only partially attenuated the accumulation of GNMT protein, indicating that its ability to restore normal metabolism of methyl groups was at a posttranslational level, possibly by altering the levels of the known folate coenzymes that allosterically regulate GNMT activity. Taken together, these results clearly indicate that physiologic/hormonal conditions (i.e., gluconeogenic; hyperthyroid) as well as the administration of RA have profound adverse effects on hepatic methyl group metabolism and exhibit a distinct interaction when manipulated together. Because these pathways are vital in maintenance of health, understanding how nutritional and hormonal factors is important in preventing potential pathologies associated with their disruption. The results of this research indicates that the dietary recommendations with respect to ensuring optimal folate function and methyl group metabolism may be significantly influenced by potential changes in hormonal profiles, such as diabetes or altered thyroid function.


Impacts

The proper metabolism of folate and methyl groups is critical to health, as perturbation of these pathways is associated with a number of pathologies, including cardiovascular disease, cancer development, and birth defects. Understanding how hormonal and nutritional factors, such as retinoid compounds and/or a diabetic state, perturb these metabolic pathways is important for future dietary recommendations directed at optimizing human health and preventing disease. Moreover, this research will begin to identify individuals that are more sensitive to moderate nutritional deficiencies, hormonal imbalances, or retinoid toxicity.


Publications


Tanghe, K.A., Garrow, T.A. & Schalinske, K.L. (2004) Triiodothyronine treatment attenuates the induction of hepatic glycine N-methyltransferase by retinoic acid and elevates plasma homocysteine concentrations in rats. J. Nutr. 134: 2913-2918.

Nieman, K.M., Rowling, M.J., Garrow, T.A. & Schalinske, K.L. (2004) Modulation of methyl group metabolism by streptozotocin-induced diabetes and all-trans-retinoic acid. J. Biol. Chem. 279: 45708-45712.


Progress 01/01/03 to 12/31/03


Outputs

To date, we have shown that all-trans-retinoic acid (ATRA) induced the hepatic enzyme glycine N-methyltransferase (GNMT), a key regulatory protein that controls both folate and methionine metabolism to optimize the availability of methyl groups for transmethylation reactions. Retinoid-mediated alterations in GNMT were liver-specific and resulted in a diminished ability to methylate DNA, an epigenetic process that is critical in a number of pathological states. During the past year, we have extended these findings on several fronts, in particular linking perturbation of methyl group metabolism with a diabetic condition. First, the induction of GNMT by ATRA was demonstrated at levels equivalent to those utilized therapeutically by humans. Second, treatment with ATRA resulted in a decrease in both plasma homocysteine and methionine concentrations, indicating that the catabolism of homocysteine was enhanced by retinoids and perturbation of hepatic methyl group metabolism may compromise the availability of methyl groups for other cells and tissues. Moreover, the reduction of homocysteine appears to be largely due to an increase in folate-dependent remethylation of homocysteine, whereas folate-independent remethylation was not affected. Third, the induction of GNMT by ATRA was exacerbated in both diabetic rats and rats treated with the glucocorticoid, dexamethasone. We have confirmed this finding in a cell culture model, indicating that the ability of ATRA or diabetes/ glucocorticoids to perturb methyl group metabolism was direct and mechanistically distinct from each other. In support of this finding, we have found that a diabetic condition enhances homocysteine metabolism by increasing catabolism through the transsulfuration pathway and enhancing folate-independent remethylation. Fourth, we have found that supplementation of folate-deficient rats with dietary folate attenuated the increase in GNMT activity, but ATRA did not prevent the hyperhomocysteinemia owing to folate deficiency. Fifth, we have found that treatment of ATRA-treated rats with thyroid hormone prevented the increase in GNMT activity, but not induction of GNMT protein, indicating that triiodothyronine was likely altering the folate coenzyme levels known to inhibit GNMT activity at a posttranslational level. Taken together, these results clearly indicate that the administration of ATRA and a diabetic condition have profound adverse effects on hepatic methyl group metabolism, thereby having significant implications for millions of individuals that are diabetic and/or receive therapeutic retinoids.


Impacts

The proper metabolism of folate and methyl groups is critical to health, as perturbation of these pathways is associated with a number of pathologies, including cardiovascular disease, cancer development, and birth defects. Understanding how nutrients and/or physiological conditions, such as retinoid compounds and a diabetic state, perturb these metabolic pathways is important for future dietary recommendations directed at optimizing human health and preventing disease. Moreover, this research will begin to identify individuals that are more sensitive to retinoid toxicity due to unsupervised or therapeutic use of retinoid compounds or hormonal imbalances.


Publications


Rowling, M.J. & Schalinske, K.L. (2003) Retinoic acid and glucocorticoid treatment induces hepatic glycine N-methyltransferase and lowers plasma homocysteine concentrations in the rat and rat hepatoma cells. J. Nutr. 133: 3392-3398.

Schalinske, K.L. (2003) Interrelationship between diabetes and homocysteine metabolism: hormonal regulation of cystathionine b-synthase. Nutr. Rev. 61: 136-138.

Ozias, M.K. & Schalinske, K.L. (2003) All-trans-retinoic acid rapidly induces glycine N-methyltransferase in a dose-dependent manner and reduces circulating methionine and homocysteine levels in rats. J. Nutr. 133: 4090-4094.


Progress 01/01/02 to 12/31/02


Outputs

During year 1, we demonstrated that the administration of retinoid compounds (30 mmol/kg body weight) to rats profoundly altered the metabolism of methionine in the liver. In particular, all-trans-retinoic acid (ATRA) induced the enzyme glycine N-methyltransferase (GNMT), a key regulatory protein that controls both folate and methionine metabolism to optimize the availability of methyl groups for transmethylation reactions. Retinoid-mediated alterations in GNMT were liver-specific and resulted in a diminished ability to methylate DNA, an epigenetic process that is critical in a number of pathological states. We have extended these findings on several fronts. First, the induction of GNMT by ATRA was dose-dependent as more physiological levels of retinoid compounds (5 mmol/kg body weight) were also effective. This is a key finding, as it demonstrates that retinoid levels that are achievable by supplementation and/or therapeutic uses are sufficient to perturb methyl group metabolism. Second, treatment with ATRA resulted in a decrease in the plasma homocysteine concentrations, indicating that the catabolism of homocysteine was enhanced by retinoids. The enhanced catabolism of homocysteine was also evident by the increase in taurine synthesis, at the expense of plasma glutathione and urinary inorganic sulfate. Third, the induction of GNMT by ATRA was exacerbated in diabetic rats, a condition known to perturb homocysteine metabolism. Fourth, increasing the protein (i.e., casein) content of the diet exacerbated the induction of GNMT by ATRA; however, substituting soy protein for casein attenuated this effect. This indicates that the level of dietary cysteine may serve as a viable intervention strategy to abrogate the adverse effects of retinoid administration on methyl group and homocysteine metabolism. Taken together, these results clearly indicate that the administration of ATRA has profound adverse effects on hepatic methyl group metabolism, thereby having significant implications for liver toxicity, cancer development, cardiovascular disease, and birth defects.


Impacts

The proper metabolism of folate and methyl groups is critical to health, as perturbation of these pathways is associated with a number of pathologies, including hepatotoxicity and cancer development. Understanding how nutrients such as retinoid compounds perturb these metabolic pathways is important for future dietary recommendations directed at optimizing human health and preventing disease. Moreover, this research will begin to identify individuals that are more sensitive to retinoid toxicity due to unsupervised or therapeutic use of retinoid compounds.


Publications


Rowling MJ, MH McMullen and KL Schalinske. 2002. Vitamin A and its derivatives induce hepatic glycine N-methyltransferase and hypomethylation of DNA in rats. J. Nutr. 132:365-369.

McMullen MH, MJ Rowling, MK Ozias and KL Schalinske. 2002. Activation and induction of glycine N-methyltransferase by retinoids are tissue- and gender-specific. Arch. Biochem. Biophys. 401:73-80.

Rowling MJ, MH McMullen, DC Chipman and KL Schalinske. 2002. Hepatic glycine N-methyltransferase is up-regulated by methionine in rats. J. Nutr. 132:2545-2549.


Progress 01/01/01 to 12/31/01


Outputs

The oral administration of retinoid compounds to rats had profound effects on the hepatic metabolism of methyl groups. All-trans-retinoic acid and 13-cis-retinoic acid elevated the hepatic activity of glycine N-methyltransferase more than 2-fold following a 10-day treatment at 30 mmol retinoid/kg body weight. Moreover, changes in GNMT activity were reflected in the abundance of the protein, suggesting that retinoids mediate GNMT modulation at a transcriptional/translational level. GNMT is a key protein that regulates folate and methyl group metabolism, two interrelated metabolic pathways that are important in preventing liver disease and cancer development. The administration of vitamin A (i.e., retinyl palmitate) was also effective in inducing modulation of GNMT, but to a lesser degree. The ability of retinoids to modulate changes in methyl group metabolism appears to be tissue- and gender-specific. The activity and abundance of GNMT was not altered in renal or pancreatic tissue, the only other known localizations of the protein. Hepatic GNMT activity and abundance was elevated by retinoids in female as well as male rats, however, the degree to which it was increased was significantly less in female rats. Furthermore, the ability of retinoid compounds to alter methyl group metabolism does not appear to be dependent on adrenal function, as has been shown for retinoid-mediated alterations in lipid metabolism. The retinoid-mediated increase in GNMT function and subsequent loss of methyl groups was evident for a number of transmethylation-dependent processes. Rats receiving all-trans-retinoic acid exhibited a significant decrease in DNA methylation and creatinine synthesis. In contrast, glutathione synthesis, a product of transmethylation and transsulfuration, was not compromised. Taken together, these results clearly indicate that retinoid compounds, including vitamin A, has a profound affect on hepatic methyl group metabolism. These results are significant, because alterations in this pathway are known to be associated with hepatic steatosis, liver disease, and neoplastic development.


Impacts

Abnormal functioning of methyl group metabolism is associated with liver disease and cancer development, as well as cardiovascular disease and birth defects. Understanding the interaction between retinoid compounds and methyl group metabolism will impact future dietary recommendations directed towards optimal health. Moreover, it will provide a basis for the evaluation of current and new therapeutic retinoid compounds.


Publications


Rowling MJ and KL Schalinske. 2001. Retinoid compounds activate and induce hepatic glycine N-methyltransferase in rats. J. Nutr. 131:1914-1917.

Rowling MJ, MH McMullen and KL Schalinske. 2002 Vitamin A and its derivatives induce hepatic glycine N-methyltransferase and hypomethylation of DNA in rats. J. Nutr. 132in press).


Folate-Retinoid Interactions: Implications in Liver Disease - IOWA STATE UNIVERSITY

 

[Amazoniac]

Listened to the whole thing. The part about the autopsied liver biopsies was really convincing.Would be great to find out why exaclty were those people liver toxic. The only thing I don't understand is that how can a molecule that is so ubiquitous in foods be toxic in this context? Toxicity is a broadly loaded term in this case.

They sampled the livers of a population whose average age was something around 70 years, and while this isn't old, there were people up to 101 years. They didn't narrow the selection criteria to accidental deaths, if I'm not wrong, they were from (hospitalized?) subjects who were dealing with varied diseases and only a few conditions were excluding. And yet, out of 27 persons analyzed (7 ages 21-54 y; 10 ages 55-74 y; 10 age 75 y and beyond), 6 had clean, 11 had acceptable, 1 had contaminated, and 9 heavily contaminated livers. If everyone was to adhere to this detox fad, a great deal of people could be compromised by it, in particular those that are taking countermeasures (such as shoving down methyl donors) as opposed to Grant's hibernation approach.

I thought that it was going to be gone by now, but the terrorization continues.

 

[tim333]

@Amazoniac Nah... studies clearly show that Hypervitaminosis A is an epidemic and has been for a long time. Smith is on point with this. In his latest video he goes through a number of studies proving the epidemic. Here are a couple:

Vitamin A reserve of liver in health and coronary heart disease among ethnic groups in Singapore

https://www.researchgate.net/public...eart_disease_among_ethnic_groups_in_Singapore

40% of Caucasians had over 300 mg/kg. Their mean age was 48.6.

Vitamin A content of human liver from autopsies in New Zealand

https://www.cambridge.org/core/serv...human_liver_from_autopsies_in_new_zealand.pdf

Mean liver vA was 278 mg/kg (928 IU/g) for 11-20 year olds.

 

[meatbag]

@Amazoniac Nah... studies clearly show that Hypervitaminosis A is an epidemic and has been for a long time. Smith is on point with this. In his latest video he goes through a number of studies proving the epidemic. Here are a couple:

Vitamin A reserve of liver in health and coronary heart disease among ethnic groups in Singapore

https://www.researchgate.net/public...eart_disease_among_ethnic_groups_in_Singapore

40% of Caucasians had over 300 mg/kg. Their mean age was 48.6.

Vitamin A content of human liver from autopsies in New Zealand

https://www.cambridge.org/core/serv...human_liver_from_autopsies_in_new_zealand.pdf

Mean liver vA was 278 mg/kg (928 IU/g) for 11-20 year olds.

Why does the liver store vitamin a?

 

[tim333]

Why does the liver store vitamin a?

Because the first animal that crawled the earth precognitively perceived Genereux's eBooks and made a conscious effort to avoid carotenes thus the body adapted by storing vA as much as possible.

Seriously though, vA and vD are both used to make hormones so that might have something to do with why both are able to be stored for considerable periods of time. Lots of it is depleted during infectious disease, the body likes to have some reserves handy.

 

[Amazoniac]

@Amazoniac Nah... studies clearly show that Hypervitaminosis A is an epidemic and has been for a long time. Smith is on point with this. In his latest video he goes through a number of studies proving the epidemic. Here are a couple:

Vitamin A reserve of liver in health and coronary heart disease among ethnic groups in Singapore

https://www.researchgate.net/public...eart_disease_among_ethnic_groups_in_Singapore

40% of Caucasians had over 300 mg/kg. Their mean age was 48.6.

Vitamin A content of human liver from autopsies in New Zealand

https://www.cambridge.org/core/serv...human_liver_from_autopsies_in_new_zealand.pdf

Mean liver vA was 278 mg/kg (928 IU/g) for 11-20 year olds.

They report mean and median to give a clearer picture, or else a few obscene concentrations tend to distort it.

- Vitamin A reserve of liver in health and coronary heart disease among ethnic groups in Singapore

Spoiler: Actual distribution

- Vitamin A content of human liver from autopsies in New Zealand

Spoiler: Actual distribution

The round numbers are multiples of 90 mcg: 0, 90 (300), 180 (600)..

The word 'epidemic' is alarmist, sometimes used by these charlatans as one more artifice to leave people scared and susceptible to the following suggestions, not so much warn them. If it's a common problem (and I never denied that our liver reserves might be greater than in the past due to decline in metabolism and fortification/supplementation), the solution is not to go around instilling terror that people have their livers contaminated (especially because you can tell that it doesn't apply to everyone, it can be detrimental for many to restrict it), requiring years of dedicated work and a strict regimen to purge it out, preferably with guidance.


- Iron Toxicity Post #73: Why I detest hormone-D supplementation.

"In conclusion, supplementing with this “poison,” because you think you have a dearth of this storage hormone in your blood, could very well be the stimulus for the death of your vitality, in ways you never imagined possible."

​

 

[tim333]

"In conclusion, supplementing with this “poison,” because you think you have a dearth of this storage hormone in your blood, could very well be the stimulus for the death of your vitality, in ways you never imagined possible."