Is Supplemental Vitamin D Safe? "RENAL POTASSIUM-WASTING INDUCED BY VITAMIN D"

sweetly

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squanch

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Matt Stone has talked about this a lot in his Podcasts. I think it was in one with Dr Garret Smith where they discussed this, basically saying that low vit d levels is often just your body trying to keep mineral ratios in balance.
 
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sweetly

sweetly

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bump
 

milk_lover

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Whenever I supplement high amounts of vitamin D (+6000IU) my biceps become mushy if that makes sense, which is similar to insulin resistance in that the sugar does not reach the muscles. It feels sorta like water retention. I don't know if this is related to potassium deficiency though. After experimentation with vitamin D3 supplements, I've concluded it's not worth it because I am not getting very good results. I'll stick with the sun.
 

XPlus

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I've some doubts about vit. D3.
Suikerbuik voiced some potential concerns with this form of Vit. D throughout the forum before - you can search them if you like.
I think it might be that it's got to be supplemented gradually in small amounts bringing up its levels in the body or supplementation is bad altogether.
Anyway, I keep my supplementation around 1-2k a day and try to get more from the sun.
 

jaa

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The paper states that the renal-potassium wasting is caused by hypercalciema. Seems like supplementing vitamin k2 could help.
 

milk_lover

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jaa said:
post 110731 The paper states that the renal-potassium wasting is caused by hypercalciema. Seems like supplementing vitamin k2 could help.
Could magnesium help also?
 
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jb116

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milk_lover said:
post 110734
jaa said:
post 110731 The paper states that the renal-potassium wasting is caused by hypercalciema. Seems like supplementing vitamin k2 could help.
Could magnesium help also?

Mag works in synergy as well but the K should do best in 'telling' where the cal to go and where NOT to go
 
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Bumping

I have just experienced spleen enlargement/pain for the past few days which has left me sidelined from sports in times of good weather:disrelieved:, and this coincides with increased vit d3 supplementation, anywhere from 4,000-20,000 IU a day for about a week (Carlson's brand). I will rely on the sun for vit d from now on.

Found this: Spleen: A new role for an old player?
a good read in general, but they mention the role of d3 at the very bottom. Says d3 is well know to be immunosupressive! Seems as if bone mineralization is involved in this, and they mention calcium supplementation can reverse the problem... I don't really understand the bottom line tho... any thoughts appreciated!
 

Amazoniac

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@tyw, what are your thoughts on vitamin d from supplements or from sun?
If you search for this on the forum, you'll notice how there's still a lot of confusion on this.
For reasons that I don't understand, it seems easier to overdose with much less when people take supplements, the effects are also very different. Why?
 

tyw

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@tyw, what are your thoughts on vitamin d from supplements or from sun?
If you search for this on the forum, you'll notice how there's still a lot of confusion on this.
For reasons that I don't understand, it seems easier to overdose with much less when people take supplements, the effects are also very different. Why?

Sun exposure is preferred. Fixing of sulfation pathways along with adequate sulfur supply is needed in this case.

Efficacy of supplementation is going to be dependent on liver and kidney function and overall storage and mobilisation capacity. Storage is a hit or miss, and conversion is a hit or miss. Regulation is less controlled with supplemental form. I will support use of supplements during cases of tested deficiency and low sunlight, but that requires the appropriate testing and personal supervision of a medical practitioner.

More details below.

Image for reference: https://www.nap.edu/read/5776/chapter/9#251
upload_2017-4-24_8-32-48.png

----

Active Form


As basic background information, the active form of Vitamin D3 is called calcitriol. This is the compound that will be responsible for vitamin D3's effects, and therefore any disruptions along the pathway to synthesise this compound, or some problem with response to this compound, will prevent the expected effects from Vitamin D3.

----
Supplements vs Natural Synthesis. Sulfation vs not

When we refer to vitamin D3 supplements, we are talking about cholecalciferol, also, we are usually talking about un-sulfated cholecalciferol.

When we make cholecalciferol in the skin, it is made from 7-dehydrocholesterol, and this is usually a sulfated compound. The main difference with sulfation, is that the the sulfated cholecalciferol product from skin production is both water and fat soluble, while most cholecalciferol supplements are not sulfated, and only fat soluble.

We can already see that if a person fails to create enough 7-dehydrocholesterol, or doesn't have enough sulfur, or fails in the needed sulfation pathways, then skin production of cholecalciferol is going to be reduced.

----
Storage and Conversion of Cholecaliferol

In any case, once we have cholecalciferol, much of it is stored, and some of it sent to the liver to be converted to calcifediol / 25(OH)D3.

Storage of cholecalciferol is largely (>70%) in adipose tissue, and I personally think this is even more likely if cholecalciferol is taken through supplements in the un-sulfated, fat-soluble-only form. This means that body fat is a store of cholecalciferol, and the more body fat one has, the more one has potential active Vitamin D3 production from stored precursors. Whether or not this can lead to excess vitamin D3 is unknown, but I have seen cases of people saying that their measured 25(OH)D3 levels shot up dramatically after losing significant levels of body fat.

Another risk here with supplementing in people with lots of body fat, is that supposed high dose supplementation doesn't change 25(OH)D3 levels, and prompts the person to supplement even more, even to the point of overdose. It is storage of cholecalciferol that is causing the lack of impact on 25(OH)D3 levels.

----
25(OH)D

And now we get to 25(OH)D / calcifediol, which is what is usually measured on "Vitamin D serum tests" -- Calcifediol - Wikipedia

This is made in the liver from cholecalciferol, using the enzyme cytochrome P450 2R1 / Vitamin D 25-hydroxylase. Instantly we see potentials for failure ... The liver is yet again the bottleneck for active Vit D3 function, and the CYP450 system is particular dependent on good reducing function -- most of these enzymes have a heme iron center, and require NADPH for function. NAPDH levels need to be constantly replenished by the Pentose Phosphate Pathway.

I speculate that any excessive xenobiotic burden on the liver will also compromise production of 25(OH)D3, but in any case, both supplemental and endogenously synthesis cholecalciferol needs to go through this phase, and if the liver isn't functioning well, then there will be no active Vitamin D3.

In any case, 25(OH)D3 seems to be distributed pretty evenly between all tissues, and can be mobilised at will. Most kinetic studies will say that we have a couple of days, to a week's worth, of 25(OH)D3 ready to be converted to calcitriol.

----
Active D3

The active form of D3 is then calcitriol / 1,25(OH)2D3 -- Calcitriol - Wikipedia

This happens in the kidneys, and note again that the conversion from 25(OH)D to active calcitriol requires another CYP450 family enzyme, 25-Hydroxyvitamin D3 1-alpha-hydroxylase / cytochrome p450 27B1. The same caveats about apply (just substitute kidney over liver).

This conversion is a dynamic process, and as we already know, is tied heavily to calcium metabolism, and thus is expected to vary acutely.

====

At the end of all of that, we can see that endogenous vs exogenous cholecalciferol largely differs in their sulfation characteristics, which has definite implications for storage of cholecalciferol.

As far as I know, it is unknown whether or not the un-sulfated supplementatl cholecalciferol can escape regulation. For example, it may be possible that sulfated, water-soluble, skin-produced cholecalciferol, is capable of signalling to the rest of the system that, "hey, we have enough cholecalciferol", and prevent accumulation of excess.

In any case, it is clear that cholecalciferol synthesis in the skin is regulated, but exogenous supplies are not. In that sense, it is probably wise to supplement only if one is sure that 25(OH)D3 tests continue to come back at deficient levels, where there is no access to sunshine, and that one is relatively weight stable through the period of supplementation.

SIDENOTE: I personally do not like the idea of tanning beds. EMF emission is unknown, and intensity of lights has to be well-known (need to pester the business offering the service to give you all the details).​

Taking care not to overload the liver is something that everyone should already do. Vitamin D3 production is just yet another system that is heavily dependent on this organ.

....
 

TeslaFan

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Vitamin is a nutrient we have to take because our bodies cannot make it. That's exactly what D isn't.

Ditto on sun exposure.

If we begin by understanding that D is a fat soluble hormone, and not a vitamin, many confusions about it will start to resolve. It's one of those things that somehow never got corrected.
 

Amazoniac

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Sun exposure is preferred. Fixing of sulfation pathways along with adequate sulfur supply is needed in this case.

Efficacy of supplementation is going to be dependent on liver and kidney function and overall storage and mobilisation capacity. Storage is a hit or miss, and conversion is a hit or miss. Regulation is less controlled with supplemental form. I will support use of supplements during cases of tested deficiency and low sunlight, but that requires the appropriate testing and personal supervision of a medical practitioner.

More details below.

Image for reference: https://www.nap.edu/read/5776/chapter/9#251
View attachment 5192
----

Active Form


As basic background information, the active form of Vitamin D3 is called calcitriol. This is the compound that will be responsible for vitamin D3's effects, and therefore any disruptions along the pathway to synthesise this compound, or some problem with response to this compound, will prevent the expected effects from Vitamin D3.

----
Supplements vs Natural Synthesis. Sulfation vs not

When we refer to vitamin D3 supplements, we are talking about cholecalciferol, also, we are usually talking about un-sulfated cholecalciferol.

When we make cholecalciferol in the skin, it is made from 7-dehydrocholesterol, and this is usually a sulfated compound. The main difference with sulfation, is that the the sulfated cholecalciferol product from skin production is both water and fat soluble, while most cholecalciferol supplements are not sulfated, and only fat soluble.

We can already see that if a person fails to create enough 7-dehydrocholesterol, or doesn't have enough sulfur, or fails in the needed sulfation pathways, then skin production of cholecalciferol is going to be reduced.

----
Storage and Conversion of Cholecaliferol

In any case, once we have cholecalciferol, much of it is stored, and some of it sent to the liver to be converted to calcifediol / 25(OH)D3.

Storage of cholecalciferol is largely (>70%) in adipose tissue, and I personally think this is even more likely if cholecalciferol is taken through supplements in the un-sulfated, fat-soluble-only form. This means that body fat is a store of cholecalciferol, and the more body fat one has, the more one has potential active Vitamin D3 production from stored precursors. Whether or not this can lead to excess vitamin D3 is unknown, but I have seen cases of people saying that their measured 25(OH)D3 levels shot up dramatically after losing significant levels of body fat.

Another risk here with supplementing in people with lots of body fat, is that supposed high dose supplementation doesn't change 25(OH)D3 levels, and prompts the person to supplement even more, even to the point of overdose. It is storage of cholecalciferol that is causing the lack of impact on 25(OH)D3 levels.

----
25(OH)D

And now we get to 25(OH)D / calcifediol, which is what is usually measured on "Vitamin D serum tests" -- Calcifediol - Wikipedia

This is made in the liver from cholecalciferol, using the enzyme cytochrome P450 2R1 / Vitamin D 25-hydroxylase. Instantly we see potentials for failure ... The liver is yet again the bottleneck for active Vit D3 function, and the CYP450 system is particular dependent on good reducing function -- most of these enzymes have a heme iron center, and require NADPH for function. NAPDH levels need to be constantly replenished by the Pentose Phosphate Pathway.

I speculate that any excessive xenobiotic burden on the liver will also compromise production of 25(OH)D3, but in any case, both supplemental and endogenously synthesis cholecalciferol needs to go through this phase, and if the liver isn't functioning well, then there will be no active Vitamin D3.

In any case, 25(OH)D3 seems to be distributed pretty evenly between all tissues, and can be mobilised at will. Most kinetic studies will say that we have a couple of days, to a week's worth, of 25(OH)D3 ready to be converted to calcitriol.

----
Active D3

The active form of D3 is then calcitriol / 1,25(OH)2D3 -- Calcitriol - Wikipedia

This happens in the kidneys, and note again that the conversion from 25(OH)D to active calcitriol requires another CYP450 family enzyme, 25-Hydroxyvitamin D3 1-alpha-hydroxylase / cytochrome p450 27B1. The same caveats about apply (just substitute kidney over liver).

This conversion is a dynamic process, and as we already know, is tied heavily to calcium metabolism, and thus is expected to vary acutely.

====

At the end of all of that, we can see that endogenous vs exogenous cholecalciferol largely differs in their sulfation characteristics, which has definite implications for storage of cholecalciferol.

As far as I know, it is unknown whether or not the un-sulfated supplementatl cholecalciferol can escape regulation. For example, it may be possible that sulfated, water-soluble, skin-produced cholecalciferol, is capable of signalling to the rest of the system that, "hey, we have enough cholecalciferol", and prevent accumulation of excess.

In any case, it is clear that cholecalciferol synthesis in the skin is regulated, but exogenous supplies are not. In that sense, it is probably wise to supplement only if one is sure that 25(OH)D3 tests continue to come back at deficient levels, where there is no access to sunshine, and that one is relatively weight stable through the period of supplementation.

SIDENOTE: I personally do not like the idea of tanning beds. EMF emission is unknown, and intensity of lights has to be well-known (need to pester the business offering the service to give you all the details).​

Taking care not to overload the liver is something that everyone should already do. Vitamin D3 production is just yet another system that is heavily dependent on this organ.

....
Thanks! @Suikerbuik
 

NathanK

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May 30, 2015
Messages
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Location
Austin, TX
Sun exposure is preferred. Fixing of sulfation pathways along with adequate sulfur supply is needed in this case.

Efficacy of supplementation is going to be dependent on liver and kidney function and overall storage and mobilisation capacity. Storage is a hit or miss, and conversion is a hit or miss. Regulation is less controlled with supplemental form. I will support use of supplements during cases of tested deficiency and low sunlight, but that requires the appropriate testing and personal supervision of a medical practitioner.

More details below.

Image for reference: https://www.nap.edu/read/5776/chapter/9#251
View attachment 5192
----

Active Form


As basic background information, the active form of Vitamin D3 is called calcitriol. This is the compound that will be responsible for vitamin D3's effects, and therefore any disruptions along the pathway to synthesise this compound, or some problem with response to this compound, will prevent the expected effects from Vitamin D3.

----
Supplements vs Natural Synthesis. Sulfation vs not

When we refer to vitamin D3 supplements, we are talking about cholecalciferol, also, we are usually talking about un-sulfated cholecalciferol.

When we make cholecalciferol in the skin, it is made from 7-dehydrocholesterol, and this is usually a sulfated compound. The main difference with sulfation, is that the the sulfated cholecalciferol product from skin production is both water and fat soluble, while most cholecalciferol supplements are not sulfated, and only fat soluble.

We can already see that if a person fails to create enough 7-dehydrocholesterol, or doesn't have enough sulfur, or fails in the needed sulfation pathways, then skin production of cholecalciferol is going to be reduced.

----
Storage and Conversion of Cholecaliferol

In any case, once we have cholecalciferol, much of it is stored, and some of it sent to the liver to be converted to calcifediol / 25(OH)D3.

Storage of cholecalciferol is largely (>70%) in adipose tissue, and I personally think this is even more likely if cholecalciferol is taken through supplements in the un-sulfated, fat-soluble-only form. This means that body fat is a store of cholecalciferol, and the more body fat one has, the more one has potential active Vitamin D3 production from stored precursors. Whether or not this can lead to excess vitamin D3 is unknown, but I have seen cases of people saying that their measured 25(OH)D3 levels shot up dramatically after losing significant levels of body fat.

Another risk here with supplementing in people with lots of body fat, is that supposed high dose supplementation doesn't change 25(OH)D3 levels, and prompts the person to supplement even more, even to the point of overdose. It is storage of cholecalciferol that is causing the lack of impact on 25(OH)D3 levels.

----
25(OH)D

And now we get to 25(OH)D / calcifediol, which is what is usually measured on "Vitamin D serum tests" -- Calcifediol - Wikipedia

This is made in the liver from cholecalciferol, using the enzyme cytochrome P450 2R1 / Vitamin D 25-hydroxylase. Instantly we see potentials for failure ... The liver is yet again the bottleneck for active Vit D3 function, and the CYP450 system is particular dependent on good reducing function -- most of these enzymes have a heme iron center, and require NADPH for function. NAPDH levels need to be constantly replenished by the Pentose Phosphate Pathway.

I speculate that any excessive xenobiotic burden on the liver will also compromise production of 25(OH)D3, but in any case, both supplemental and endogenously synthesis cholecalciferol needs to go through this phase, and if the liver isn't functioning well, then there will be no active Vitamin D3.

In any case, 25(OH)D3 seems to be distributed pretty evenly between all tissues, and can be mobilised at will. Most kinetic studies will say that we have a couple of days, to a week's worth, of 25(OH)D3 ready to be converted to calcitriol.

----
Active D3

The active form of D3 is then calcitriol / 1,25(OH)2D3 -- Calcitriol - Wikipedia

This happens in the kidneys, and note again that the conversion from 25(OH)D to active calcitriol requires another CYP450 family enzyme, 25-Hydroxyvitamin D3 1-alpha-hydroxylase / cytochrome p450 27B1. The same caveats about apply (just substitute kidney over liver).

This conversion is a dynamic process, and as we already know, is tied heavily to calcium metabolism, and thus is expected to vary acutely.

====

At the end of all of that, we can see that endogenous vs exogenous cholecalciferol largely differs in their sulfation characteristics, which has definite implications for storage of cholecalciferol.

As far as I know, it is unknown whether or not the un-sulfated supplementatl cholecalciferol can escape regulation. For example, it may be possible that sulfated, water-soluble, skin-produced cholecalciferol, is capable of signalling to the rest of the system that, "hey, we have enough cholecalciferol", and prevent accumulation of excess.

In any case, it is clear that cholecalciferol synthesis in the skin is regulated, but exogenous supplies are not. In that sense, it is probably wise to supplement only if one is sure that 25(OH)D3 tests continue to come back at deficient levels, where there is no access to sunshine, and that one is relatively weight stable through the period of supplementation.

SIDENOTE: I personally do not like the idea of tanning beds. EMF emission is unknown, and intensity of lights has to be well-known (need to pester the business offering the service to give you all the details).​

Taking care not to overload the liver is something that everyone should already do. Vitamin D3 production is just yet another system that is heavily dependent on this organ.

....
Great reply. I'm on the same side of the fence. D is fairly well regulated. "More" can often turn into "less".

A little background check into the primary researcher that popularized D in the past decade was enlightening as well.
 

Koveras

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Joined
Dec 17, 2015
Messages
720
----
Active Form

As basic background information, the active form of Vitamin D3 is called calcitriol. This is the compound that will be responsible for vitamin D3's effects, and therefore any disruptions along the pathway to synthesise this compound, or some problem with response to this compound, will prevent the expected effects from Vitamin D3.

----
Storage and Conversion of Cholecaliferol

In any case, once we have cholecalciferol, much of it is stored, and some of it sent to the liver to be converted to calcifediol / 25(OH)D3.

Another risk here with supplementing in people with lots of body fat, is that supposed high dose supplementation doesn't change 25(OH)D3 levels, and prompts the person to supplement even more, even to the point of overdose. It is storage of cholecalciferol that is causing the lack of impact on 25(OH)D3 levels.
....

H/T to Chris Masterjohn for the lead here

I would add that calcium: phosphorous balance, other nutrients such as vitamin C, vitamin K, niacinamide, various hormones, and likely anything that impacts cAMP in the relevant tissues (coffee, forskolin, aforementioned hormones) can impact this system..

The storage form of vitamin D (25-OH-D) is converted to the more active form (1,25-(OH)2-D) by the enzyme 1a-hydroxylase (CYP27B1). This enzyme is stimulated by cAMP and uses vitamin C as a cofactor.

During periods of low calcium intake, PTH rises, PTH increases cAMP and increases/maintains the activity of 1a-hydroxylase and the levels of 1,25-(OH)2-D as a result - which has the effect of increasing intestinal calcium absorption and helping to maintain balance in the system.

Low calcium intakes may cause the blood levels of 25-OH-D to stay low despite supplementation due to an increased rate of conversion to 1,25-(OH)2-D in the presence of higher PTH.

Dietary phosphorous independently raises PTH and a high phosphorous intake or high phosphorous to calcium ratio may cause PTH to remain higher despite otherwise adequate calcium and/or vitamin D.

Phosphorous increases also increases FGF23 however which decreases 1a-hydroxylase activity. Niacinamide promotes phosphorous excretion so may benefit active vitamin D production. Advanced Glycation End Products (AGEs) increase FGF23 so there's likely a role for PUFA and the whole antioxidant defence system there (vitamin C, vitamin E, Glutathione) and the rest of the B-vitamins.

Additionally when 1a-hydroxylase activty is low for whatever reason, more of the 25-OH-D is likely to be converted to 24,25-(OH)2-D which can have antagonistic effects in certain tissues and may explain some of the negative effects of higher dose vitamin D in certain individuals.

Arch Biochem Biophys. 2000 Sep 1;381(1):143-52.
Regulation of 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression by parathyroid hormone and 1,25-dihydroxyvitamin D3.
Brenza HL1, DeLuca HF.
The conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) takes place mainly in the kidney and is catalyzed by the enzyme 1alpha-hydroxylase. Parathyroid hormone (PTH) and 1,25-(OH)2D3 are well-known regulators of this tightly controlled step, but the mechanisms by which they modulate 1alpha-hydroxylase activity have not been fully delineated. Northern analysis showed PTH and forskolin rapidly and transiently increase 1alpha-hydroxylase expression in AOK-B50 cells and HKC-8 cells. Actinomycin D treatment blocks the increase, but cycloheximide does not. No decrease of 1alpha-hydroxylase transcript by 1,25-(OH)2D3 was observed in either cell line, although 24-hydroxylase levels were strongly induced by 1,25-(OH)2D3 treatment. 1,25-(OH)2D3 suppressed the 1alpha-hydroxylase transcript in vivo both in the presence and absence of exogenously supplied PTH. These results suggest that the stimulatory action of PTH is directly on the 1alpha-hydroxylase gene, while the repressive action of 1,25-(OH)2D3 does not involve the parathyroid gland but is nevertheless indirect.

Endocrinology. 1985 Feb;116(2):503-10.
Parathyroid hormone modulation of 25-hydroxyvitamin D3 metabolism by cultured chick kidney cells is mimicked and enhanced by forskolin.
Henry HL.
In order to determine whether cAMP mediates the effects of PTH on the metabolism of 25-hydroxyvitamin D3 (25-OH-D3) on chick kidney cells in primary culture, the effect of forskolin on the production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] was assessed. In 4-h incubations with [3H]25-OH-D3 and forskolin, (1-10 microM) [3H]1,25-(OH)2D3 accumulation was increased 50-100%, and that of [3H]24,25-(OH)2D3 was decreased 30-60%. PTH (1-10 ng/ml) brought about identical changes. Similar results were observed when cultures were preincubated with nonradioactive 25-OH-D3 for 4 h in the presence of PTH and forskolin, followed by a 30-min incubation with radioactive substrate. At a low concentration (0.05 microM), forskolin alone had no effect on the metabolism of [3H]25-OH-D3 but markedly enhanced that of PTH. At maximal concentrations of PTH (10 ng/ml) and forskolin (10 microM), the effects of the two on 25-OH-D3 metabolism were not additive. Both PTH and forskolin decreased the further metabolism of [3H]1,25-(OH)2D3, probably by inhibiting its 24-hydroxylation, but there are also cycloheximide-sensitive steps in the metabolism of 1,25-(OH)2D3 that are not affected by PTH and forskolin. In time course experiments, increased [3H]1,25-(OH)2D3 accumulation could be observed before the detection of 24-hydroxylase activity suggesting that the primary effect of PTH and forskolin is on the production of [3H] 1,25-(OH)2D3 rather than its catabolism. Raising the calcium concentration of the medium to 2.5 mM from the normal 1.8 mM or lowering it to 0.5 mM for 24 h in serum-free medium did not alter the response of 25-OH-D3 metabolism to these agents. The results of these studies indicate that the effects of PTH on the metabolism of 25-OH-D3 by chick kidney cells are mediated by cAMP, since they can be enhanced and mimicked by forskolin, that they are exerted at the level of both 1- and 24-hydroxylase activity, and that they are not dependent on the calcium concentration of the medium.
In Vitro Cell Dev Biol Anim. 1997 Apr;33(4):310-4.


Endocrinology. 1978 Dec;103(6):2035-9.
Synergistic effect of progesterone, testosterone, and estradiol in the stimulation of chick renal 25-hydroxyvitamin D3-1alpha-hydroxylase.
Tanaka Y, Castillo L, Wineland MJ, DeLuca HF.
Castrate male chickens have low levels of renal 25-hydroxyvitamin D3-1 alpha-hydroxylase (13 pmol 1,25-dihydroxyvitamin D3/200 mg tissue . 10 min). This activity is markedly increased by the administration of 5 mg/kg estradiol and 5-20 mg/kg testosterone 24 h before in vitro measurement of the enzyme. Both hormones are required for this stimulation. The testosterone, but not estradiol, requirement for the stimulation can also be satisfied by progesterone. Progesterone (12.5 mg/kg) given in addition to estradiol and testosterone stimulates even further the 25-hydroxyvitamin D3-1 alpha-hydroxylase activity to very high levels (388 pmol 1,25-dihydroxyvitamin D3/200 MG tissue . 10 min). This is accompanied by a 3-fold increase in plasma 1,25-dihydroxyvitamin D3 (from 55 to 170 pg/ml), which provides in vivo evidence for the stimulation of the 1 alpha-hydroxylase by sex hormones in birds.

Endocrinology. 1993 Jan;132(1):133-8.
Insulin-like growth factor-I regulation of renal 25-hydroxyvitamin D-1-hydroxylase activity.
Nesbitt T1, Drezner MK.
Controversy exists regarding the role of GH and insulin-like growth factor-I (IGF-I) in the modulation of calcitriol production. While their administration increases serum levels of 1,25-dihydroxyvitamin D, the mechanism remains unknown. Investigations have also implicated GH as a causal factor underlying renal 25-hydroxyvitamin D-1 alpha-hydroxylase activity [1(OH)ase] secondary to phosphate depletion. Thus, we investigated the effects of IGF-I on 1(OH)ase and the relationships between these actions and those of phosphate depletion. Our studies indicate that IGF-I administration to normal mice results in a dose-dependent (0-10 micrograms/h) increase in 1(OH)ase with maximum effects evident after 24 h, independent of changes in serum calcium, phosphorus, and glucose levels. Similarly, hormone administration to phosphate-depleted mice increases enzyme activity (6.06 +/- 0.96 vs. 13.97 +/- 1.67 fmol/mg.min) but to a level significantly greater than that achieved in normals (2.72 +/- 0.4 vs. 5.01 +/- 0.56 fmol/mg.min). Furthermore, the response represents an additive increment of the effects elicited by maximum doses of IGF-I and phosphate depletion, suggesting that the hormone- and phosphate-dependent enzyme stimulation occur by different mechanisms. Thus, our data establish that IGF-I stimulates renal 1(OH)ase activity in a time- and dose-dependent fashion. However, they do not support the hypothesis that IGF-I modulates the effects of phosphate-depletion on 1(OH)ase activity. Regardless, the documentation that IGF-I stimulates enzyme function provides an explanation for many observed physiological states associated with concomitant alterations of hormone levels and calcitriol production.

J Nutr. 1990 Oct;120(10):1185-90.
Ascorbic acid effects on vitamin D hormone metabolism and binding in guinea pigs.
Sergeev IN1, Arkhapchev YP, Spirichev VB.
Ascorbic acid deficiency in guinea pigs fed a vitamin D-replete diet caused a moderate reduction of Ca level in serum and bone; 25-hydroxy-cholecalciferol or 25-hydroxyergocalciferol (25-OHD) serum concentration tended to decline; renal 25-hydroxycholecalciferol-1-hydroxylase (1-OHase) activity decreased 50%; and 25-hydroxycholecalciferol-24-hydroxylase activity increased 1.6-fold. Chromatin 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] receptor concentration in the intestinal mucosa decreased 20-30%, and the percentage of occupied receptors decreased from 12-15% to 6-8%. Receptor affinity for 1,25-(OH)2D3 did not change (Kd = 0.24-0.26 nmol/L, Kd2 = 0.06-0.10 nmol/L), but the cooperativity coefficient decreased from 1.7 to 1.4. Vitamin C deficiency potentiated effects of vitamin D deprivation and impaired a restorative action of vitamin D. It was accompanied by a marked delay in the elevation of 25-OHD concentration in serum as well as decreased 1-OHase activity in kidneys and a lower concentration of occupied 1,25-(OH)2D3 receptors in the intestinal mucosa. The data demonstrate a critical role for ascorbic acid in vitamin D metabolism and binding.

Clin Rheumatol. 1991 Jun;10(2):162-7.
The importance of vitamin C for hydroxylation of vitamin D3 to 1,25(OH)2D3 in man.
Cantatore FP1, Loperfido MC, Magli DM, Mancini L, Carrozzo M.
The effects of vitamin C on 1,25(OH)2D3 synthesis in humans were evaluated; the study included 20 females. They were divided into 2 groups. The first of the 10 subjects (age range 55-71) received ascorbic acid at a dose of 150 mg/die i.v. for 10 days; the second 10 subjects (age range 55-69) received a placebo i.v. for 10 days. In a later study (after a 30-day washout) the same two groups were tested for the second time with ascorbic acid at a dose of 1,000 mg/die i.v. for 10 days and placebo i.v. for 10 days. Serum calcium and phosphorus, serum Ca++, serum proteins, blood and urinary pH, serum 25(OH)D3 and 1,25(OH)2D3, serum PTH, urinary hydroxyprolin were tested before and after the treatments. In the first study a significant increase in serum 1,25(OH)2D3 was observed after ascorbic acid while no significant variation was observed for the other parameters. In the second study, a significant increase in serum Ca++ and a significant decrease in serum 1,25(OH)2D3 were observed after ascorbic acid while no significant variation was observed for the other parameters. The authors conclude that ascorbic acid promotes 1,25(OH)2D3 synthesis at a paraphysiologic dose (150 mg/die) in humans but this synthesis is inhibited at higher doses (1,000 mg/die). The latter effect by Ca++ or by an effect of ascorbate on 1 alpha-hydroxylase enzyme could be mediated.

J Bone Miner Res. 2013 Jan;28(1):46-55. doi: 10.1002/jbmr.1740.
Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes.
Bacchetta J1, Sea JL, Chun RF, Lisse TS, Wesseling-Perry K, Gales B, Adams JS, Salusky IB, Hewison M.
Vitamin D is a potent stimulator of monocyte innate immunity, and this effect is mediated via intracrine conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)(2) D). In the kidney, synthesis of 1,25(OH)(2) D is suppressed by fibroblast growth factor 23 (FGF23), via transcriptional suppression of the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). We hypothesized that FGF23 also suppresses CYP27B1 in monocytes, with concomitant effects on intracrine responses to 1,25(OH)(2) D. Healthy donor peripheral blood mononuclear cell monocytes (PBMCm) and peritoneal dialysate monocyte (PDm) effluent from kidney disease patients were assessed at baseline to confirm the presence of mRNA for FGF23 receptors (FGFRs), with Klotho and FGFR1 being more strongly expressed than FGFR2/3/4 in both cell types. Immunohistochemistry showed coexpression of Klotho and FGFR1 in PBMCm and PDm, with this effect being enhanced following treatment with FGF23 in PBMCm but not PDm. Treatment with FGF23 activated mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) pathways in PBMCm, demonstrating functional FGFR signaling in these cells. FGF23 treatment of PBMCm and PDm decreased expression of mRNA for CYP27B1. In PBMCm this was associated with downregulation of 25OHD to 1,25(OH)(2) D metabolism, and concomitant suppression of intracrine induced 24-hydroxylase (CYP24A1) and antibacterial cathelicidin (LL37). FGF23 suppression of CYP27B1 was particularly pronounced in PBMCm treated with interleukin-15 to stimulate synthesis of 1,25(OH)(2) D. These data indicate that FGF23 can inhibit extra-renal expression of CYP27B1 and subsequent intracrine responses to 1,25(OH)(2) D in two different human monocyte models. Elevated expression of FGF23 may therefore play a crucial role in defining immune responses to vitamin D and this, in turn, may be a key determinant of infection in patients with chronic kidney disease (CKD).

Vet Pathol. 2015 Sep;52(5):770-84. doi: 10.1177/0300985815586222. Epub 2015 May 27.
Fibroblast Growth Factor 23: A New Dimension to Diseases of Calcium-Phosphorus Metabolism.
Hardcastle MR1, Dittmer KE2.
Traditionally, control of phosphorus in the body has been considered secondary to the tighter control of calcium by parathyroid hormone and vitamin D. However, over the past decade, substantial advances have been made in understanding the control of phosphorus by the so-called phosphatonin system, the lynchpin of which is fibroblast growth factor 23 (FGF23). FGF23 binds to the klotho/FGFR1c receptor complex in renal tubular epithelial cells, leading to upregulation of Na/Pi cotransporters and subsequent excretion of phosphorus from the body. In addition, FGF23 inhibits parathyroid hormone and the renal 1α-hydroxylase enzyme, while it stimulates 24-hydroxylase, leading to decreased 1,25-dihydroxyvitamin D3. FGF23 is intimately involved in the pathogenesis of a number of diseases, particularly the hereditary hypophosphatemic rickets group and chronic kidney disease, and is a target for the development of new treatments in human medicine. Little work has been done on FGF23 or the other phosphatonins in veterinary medicine, but increases in FGF23 are seen with chronic kidney disease in cats, and increased FGF23 expression has been found in soft tissue sarcomas in dogs.

J Bone Miner Metab. 2016 Mar;34(2):132-9. doi: 10.1007/s00774-015-0651-9. Epub 2015 Mar 21.
Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells.
Hori M1, Kinoshita Y1, Taguchi M1, Fukumoto S2.
Fibroblast growth factor 23 (FGF23) has been shown to work as a phosphotropic hormone. Although FGF23 reduces the serum phosphate level, it has not been established that phosphate directly regulates FGF23 production. In this study, we investigated whether phosphate can enhance Fgf23 expression using the rat osteoblastic cell line UMR-106, which has been shown to express Fgf23 in response to 1,25-dihydroxyvitamin D [1,25(OH)2D]. Phosphate increased Fgf23 expression in a dose- and time-dependent manner in the presence of 1,25(OH)2D. Phosphate also increased Fgf23 promoter activity, but showed no effect on the half-life of Fgf23 messenger RNA. Phosphonoformic acid and PD98059, an inhibitor of MEK, inhibited the effects of phosphate on Fgf23 expression and promoter activity. In addition, phosphate enhanced production of reactive oxygen species (ROS) in UMR-106 cells, and hydrogen peroxide enhanced FGF23 production in a dose- and time-dependent manner. Hydrogen peroxide also enhanced Elk1 reporter activity, a target of the MEK-extracellular-signal-regulated kinase (ERK) pathway. Furthermore, the effect of phosphate on ROS production and Fgf23 expression was inhibited by apocynin, an inhibitor of NADPH oxidase. These results indicate that phosphate directly enhances Fgf23 transcription without affecting the stability of Fgf23 messenger RNA by stimulating NADPH-induced ROS production and the MEK-ERK pathway in UMR-106 cells.

Advanced glycation end products stimulate gene expression of fibroblast growth factor 23.
Mol Nutr Food Res. 2017 Jan 28;:
Authors: Bär L, Wächter K, Wege N, Santos AN, Simm A, Föller M
Abstract
SCOPE: Osteoblasts produce fibroblast growth factor 23 (FGF23), a hormone inhibiting renal phosphate reabsorption and the formation of biologically active vitamin D, calcitriol. FGF23-deficient mice age rapidly and develop age-associated diseases at least in part due to massive calcification. Elevated FGF23 serum levels are detected in patients suffering from acute and chronic renal, cardiovascular, inflammatory, and metabolic diseases. Advanced glycation end products (AGEs) are sugar-modified proteins, nucleic acid, and lipids which contribute to these disorders. Here, we studied the significance of AGEs for the generation of FGF23.
METHODS AND RESULTS: As AGE sources, bread crust extract (BCE) and ribose-modified bovine serum albumin (r-BSA) were used. UMR106 osteoblast-like cells were exposed to BCE and r-BSA, and Fgf23 transcripts were determined by qRT-PCR. UMR106 cells express the receptor for AGEs, RAGE. BCE and r-BSA were powerful stimulators of Fgf23 transcription. NFκB inhibitor wogonin and store-operated calcium entry (SOCE) antagonist 2-APB attenuated the r-BSA and BCE effects on FGF23 synthesis.
CONCLUSIONS: Source of AGEs induce the transcription of Fgf23 in UMR cells. At least in part, the effect is mediated through up-regulation of NFκB and subsequent SOCE. AGE-induced FGF23 production may contribute to increased FGF23 serum levels observed in chronic disease. This article is protected by copyright. All rights reserved.
 

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"Male Sprague-Dawley rats weighing between 250 and 400 g were used in all the experiments. Animals were kept in individual metabolic cages which permitted the collection of urine without contamination by feces. Urine was collected under mineral oil, with thymol used as a preservative. The animals were rendered hypercalcemic by the intraperitoneal injection of 200,000 U of vitamin D2 (calciferol) dissolved in 0.5 ml of peanut oil daily for 4 consecutive days."

"[Exp. 1] Twenty-two rats were placed on a diet containing 133 mEq of Na+ per kg but no potassium (10) for 7 days. At the end of this time, when the urinary excretion of potassium had declined to very low levels, half of the animals were given vitamin D for 4 days."

That's insane, but they could still handle the first hit with class, just like Sheila would:

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