Vitamin D Deficiency

[Persej]

I think that these articles support my theory that if you consume cholecalciferol every day, you will suppress the production of calcitriol in your body.

Feedback regulation of 25-hydroxycholecalciferol metabolism by vitamin D3 - PubMed

1. In vitamin D-deficient chicks both vitamin D3 and 1alpha-hydroxycholecalciferol markedly decrease renal 1-hydroxylase activity and induce 24-hydroxylase activity. 2. Actinomycin D abolishes both effects. 3. These results are consistent with feedback regulation of vitamin D3 metabolism by a...

pubmed.ncbi.nlm.nih.gov

Regulation and its refractoriness of 25-hydroxyvitamin D3 metabolism in vitamin D deficiency - PubMed

The time course of change in plasma calcium levels and renal metabolism of 25-hydroxyvitamin D3 [25(OH)D3] was investigated in chicks maintained on a vitamin D-deficient diet for 4 weeks. Plasma calcium concentrations dropped sharply between the 7th and 14th day of the feeding period. Renal...

pubmed.ncbi.nlm.nih.gov

The Regulation of Vitamin D Metabolism - Nature

VITAMIN D is hydroxylated in the liver to 25-hydroxychole-calciferol (25-HCC)1, and this relatively inactive metabolite is further hydroxylated in the kidney to 1,25-dihydroxychole-calciferol (1,25-DHCC)2 (Fig. 1), the most active form, or to 24,25-dihydroxycholecalciferol (24,25-DHCC)3, a less...

www.nature.com

Vitamin D metabolism in pregnant rabbits: differences between the maternal and fetal response to administration of large amounts of vitamin D3 - PubMed

Maternal and fetal metabolism of vitamin D was examined in term pregnant rabbits fed a normal diet and in those supplemented with a large amount of vitamin D3. Term pregnant rabbits (27--30 days of gestation) fed the normal diet showed lower levels of plasma calcium, 25-hydroxyvitamin D3...

pubmed.ncbi.nlm.nih.gov

https://www.sciencedirect.com/science/article/pii/0014579374806782

https://www.sciencedirect.com/science/article/abs/pii/0006291X78912056

 

[Persej]

I managed to find one study where they followed cholecalciferol all the way down to calcitriol. It's done on cows and it was a big dose. But it's still interesting what they found. Unlike everything else that went first up and then down, calcitriol went up, then down, then up again.

Metabolism of orally administered [3H]ergocalciferol and [3H]cholecalciferol by dairy calves - PubMed

Concentrations of ergocalciferol, cholecalciferol, and their metabolites in plasma were determined after a single oral dose of [3H]ergocalciferol or [3H]cholecalciferol was given to 95- to 105-kg Jersey bull calves. One group (three calves) was given 365 muCi of [3H]ergocalciferol (1.2 Ci/mmol)...

pubmed.ncbi.nlm.nih.gov

 

[Persej]

High fat diet increases the production of calcitriol.

As a fat-soluble vitamin, vitamin D3 relies on fat to perform its biological function, affecting lipid metabolism and innate immunity. This study used different percentages of lipid and vitamin D3 diets to evaluate the synergistic effects on the growth, lipid metabolism and immunity of juvenile Eriocheir sinensis (5.83 ± 0.01 g) for 56 days, including low lipid (LL, 1.5%) and normal lipid (NL, 7.5%) and three levels of vitamin D3: low (LVD, 0 IU/kg), medium (MVD, 9000 IU/kg) and high (HVD, 27,000, IU/kg). The synergistic effect of lipid and vitamin D3 was not significant on growth but significant on ash content, total protein, hepatopancreas lipid content, hemolymph 1α,25-hydroxy vitamin D3 [1α,25(OH)2D3] content, hepatopancreas lipolysis and synthesis genes. Crabs fed normal lipid (7.5%) and medium vitamin D3 (9000 IU/kg) had the highest hepatopancreas index, hemolymph 1α,25(OH)2D3 content, antibacterial ability, immune-related genes and hepatopancreatic lipid synthesis genes expression, but down-regulated the lipolysis genes expression. In contrast, crabs fed diets with low lipid percentage (1.5%) had low growth performance, hemolymph 1α,25(OH)2D3, mRNA levels of lipid synthesis genes, antibacterial ability and immune-related gene expression. At the 1.5% lipid level, excessive or insufficient vitamin D3 supplementation led to the obstruction of ash and protein deposition, reduced growth and molting, aggravated the reduction in antioxidant capacity, hindered antimicrobial peptide gene expression and reduced innate immunity, and resulted in abnormal lipid accumulation and the risk of oxidative stress. This study suggests that diets' lipid and vitamin D3 percentage can enhance antioxidant capacity, lipid metabolism and innate immunity in E. sinensis. A low lipid diet can cause growth retardation, reduce antioxidant capacity and innate immunity, and enhance lipid metabolism disorder.

https://www.sciencedirect.com/science/article/abs/pii/S1050464824000998

Low serum 25(OH)D concentrations have been reported in obese humans. Inadequate sun exposure and impaired hepatic 25-hydroxylation have been suggested as possible reasons for obesity-associated vitamin D deficiency; however, the underlying mechanism has not been elucidated. We investigated the effects of high fat diet-induced obesity on vitamin D status and vitamin D metabolizing enzyme expression. Male C57BL mice (4 weeks old) were fed control diet containing 10% energy from fat (control group) or high fat diet containing 45% energy from fat (obese group) for 18 weeks. There were no differences in serum 25(OH)D concentrations between two groups, while serum 1,25(OH)2D concentrations were significantly higher in obese mice. Hepatic mRNA levels of 25-hydroxylases (Cyp2r1, Cyp27a1, and Cyp2j3) were lower in the obese group (31, 30, and 48% lower, respectively). Renal 1α-hydroxylase (Cyp27b1) mRNA levels were higher and 24-hydroxylase (Cyp24) mRNA levels were lower in the obese group. Serum 1,25(OH)2D concentrations correlated positively with renal Cyp27b1 expression levels and negatively with renal Cyp24 expression levels. Serum PTH concentrations were higher in obese mice. In visceral adipose tissue, Cyp27a1, Cyp2j3, and vitamin D receptor mRNA levels were higher in obese mice. Overall, vitamin D metabolizing enzyme expression was influenced by high fat diet-induced obesity, which might partly explain the mechanisms of the altered vitamin D endocrine system associated with obesity. Higher serum PTH and 1,25(OH)2D concentrations in obese mice suggest abnormal regulation of serum 1,25(OH)2D concentrations due to hyperparathyroidism, which might have contributed to lower hepatic 25-hydroxylase mRNA levels.

https://iubmb.onlinelibrary.wiley.com/doi/abs/10.1002/biof.1211

Bicarbonate also increases the production of calcitriol.

https://portlandpress.com/clinsci/article-abstract/68/1/97/73465/Effect-of-Bicarbonate-Feeding-on-Intestinal

 

[Persej]

It is interesting that many people are still not interested in looking at calcitriol, even though many studies showed that calcitriol is the most important aspect of vitamin D and not its precursors:

Although the elevation in serum calcium levels was similar in the 1,000 μg/kg 25(OH)D3- and 2.5 μg/kg 1,25(OH)2D3-treated groups, only 1,25(OH)2D3 prevented the induction of EAE (Fig. 3A). Thus, even at doses that dramatically elevated serum calcium levels and caused weight loss, 25(OH)D3 provided only modest suppression of EAE. It is known that at high plasma levels of 25(OH)D3, it acts as an analog of 1,25(OH)2D3 and increases serum calcium levels. Although 25(OH)D3 may act as an analog elevating serum calcium levels, it may not express all of the functions of 1,25(OH)2D3, such as immunomodulation.

UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production - PMC

Although the exact cause of multiple sclerosis (MS) is unknown, a number of genetic and environmental factors are thought to influence MS susceptibility. One potential environmental factor is sunlight and the subsequent production of vitamin D. A ...

pmc.ncbi.nlm.nih.gov

In the eighties, some scientists were experimenting with calcitriol, and what is interesting is that they were using it every other day and not every day:

In vitro addition of the active vitamin D3 metabolites every other day is as effective, if not more effective, than daily addition in inhibiting human breast cancer cell (T47D) replication. This is despite the fact that, in these cells in vitro, there is rapid induction of 1,25D metabolism upon exposure of the cells to the hormone, such that virtually all the hormone has been metabolized within 8 h of its addition. Treatment every other day with the vitamin D, compounds was elected on the basis of these studies and also for simplicity of the treatment protocol.

Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3 - PubMed

It has been demonstrated previously that several human cancer cell lines possess specific, high affinity receptors for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3, calcitriol] and that 1,25-(OH)2D3 and certain of its metabolites inhibit the growth in vitro of several human breast cancer and malignant...

pubmed.ncbi.nlm.nih.gov

I looked for studies about that, and I found a couple which talk about the temporal relationship between calcitriol and its receptor. Like this one:

We have studied the interaction of the vitamin D hormone with its receptor in these intact human target cells. Specific binding of tritium-labeled 1,25-(OH)2D3 by these cells reaches a maximum with 3-9 h depending on hormone concentration; subsequently there is a rapid loss of hormone-binding activity to virtually undetectable levels by 12-24 h. Although the hormone induces its own metabolism in these cells, binding cannot be restored by the addition of fresh hormone. This loss of hormone-binding activity of the receptor, is analogous to the processing of the estrogen receptor in estrogen receptor-positive cells. Two inhibitors of DNA transcription, actinomycin D and cordycepin, delay the onset and slow the processing of receptor if added with the hormone. They are ineffective if added after hormone binding is maximal. Inhibitors of protein synthesis have no protective effect at all and, in fact, these agents inhibit both the attainment of maximum specific binding and the recovery of receptor over the subsequent 24-72 h. These data demonstrate for the first time that the 1,25-(OH)2D3 receptor undergoes regulation in the intact human target cell. This event, which resembles processing of the estrogen receptor and down-regulation of peptide-hormone receptors, likely represents a nuclear mechanism for the control of cellular responsiveness to hormone in the intact cell.

Regulation of the 1,25-dihydroxyvitamin D3 receptor by 1,25-dihydroxyvitamin D3 in intact human cancer cells - PubMed

Human breast cancer cells have been shown to be targets of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]action with specific dose-dependent effects on growth in vitro. These cells possess specific, high affinity receptors for 1,25-(OH)2D3. We have studied the interaction of the vitamin D hormone with...

pubmed.ncbi.nlm.nih.gov

So it seems that even if you take the active form of vitamin D, it would still be useless to take it every day, since the next day the vitamin D receptor would have become unresponsive to it.

Little more about the mechanism of vitamin D regulation:

Therefore, evidence from the CYP24-null mouse seems to confirm our hypothesis that the C-24 oxidation pathway is a complex, self-induced mechanism for limiting the action of 1,25-(OH)2D3 in vitamin D target cells once the initial wave of gene expression has been initiated.

Several of the hydroxylase enzymes that act directly on 1,25-(OH)2D3 formation and degradation have been shown to be controlled at the transcriptional level by 1,25-(OH)2D3. In particular, the hydroxylase enzyme CYP24 is one of the most highly regulated genes that responds to vitamin D. This enzyme represents the major means by which 1,25-(OH)2D3 is catabolized in vivo, and its importance is emphasized by recent gene knockout experiments in which loss of the enzyme was found to be lethal to at least 50% of the recipient mice. The CYP24 gene is highly upregulated by 1,25-(OH)2D3.

In contrast to the preceding example, the hydroxylase enzyme CYP1α, which is responsible for catalyzing the formation of 1,25-(OH)2D3, is highly downregulated by its product. This enzyme, expressed in the proximal convoluted tubule of the kidney, is regulated with extreme stringency, although the exact details of the way in which this regulation is exerted are unclear.

The metabolism of vitamin D by target cells has been shown to occur in a number of tissues, including kidney, intestine, and bone. In kidney and intestine in particular, upregulation of the 24-hydroxylase enzyme in response to 1,25-(OH)2D3 treatment is rapid, occurring within 4 h, as shown by both Northern and enzymatic analyses. Cultured bone cells have also been shown to possess highly inducible 24-hydroxylase activity. These cells have been used to isolate catabolic products of 1,25-(OH)2D3 that can be placed in a logical order on a degradative pathway leading from the active compound to inactive excretion products. Thus it appears that the target cells for vitamin D contain the means to regulate its activity at the cellular level. The additional level of control that this target cell metabolism provides over local concentrations of 1,25-(OH)2D3 may be an important means by which tissues regulate the responsiveness of genes to vitamin D.

As stated in section I, much evidence has accumulated to support the hypothesis that 1,25-(OH)2D3 is subject to target-cell catabolism and side chain cleavage via a 24-oxidation pathway to calcitroic acid. CYP24 carries out multiple steps in the C-24 oxidation process, is vitamin D inducible, and is present in many (if not all) vitamin D target cells. We have postulated that the purpose of this catabolic pathway is to desensitize the target cell to continuing hormonal stimulation by 1,25-(OH)2D3.

https://journals.physiology.org/doi/full/10.1152/physrev.1998.78.4.1193

So after every wave of gene expression, there is a period of downregulation of receptor sensitivity to calcitriol and downregulation of production of calcitriol.

Now, if you take cholecalciferol or calcifediol, you also have to take into account the time lag to produce calcitriol, though it's much smaller in the case of calcifediol, so in those cases perhaps taking vitamin D every third day might be more optimal, but I said before, nobody has ever tested this, so I am not sure about proper timing. But at least every other day, if not more, would be preferred.