Vitamin D Metabolism

Greetings readers,

Today, I will introduce you to the basics of Vitamin D metabolism in the human body. I suspect this will be a bit boring, but it is a necessary step we need to go through in order to fully understand the effects of this vitamin regarding human health, longevity and possibly fitness (controversial reports).

Everybody knows that vitamin D is important for adequate calcium absorption. Since its discovery in the early 20th century and the eradication of nutritional rickets1, many aspects of its beneficial health effects have been elucidated, but many more remain to be investigated. Quite a lot is known about its metabolism. First of all, I would like to point out that vitamin D is not a “real vitamin”.  By definition vitamins are organic compounds that are required for various physiological processes, but cannot be produced by the organism. Vitamin D can be obtained through limited dietary sources (mostly fatty fish) and be made in the skin directly exposed to ultraviolet B light (UVB). Just to clarify, UVB and UVA is ultraviolet light with slightly different wavelengths.

 

Figure 1: Vitamin D Metabolism and Physiology. After synthesis of Vitamin D3 in the skin or its absorption through the diet, it is transported by DBP to liver and kidneys where it undergoes two sequential hydroxilations to yield the hormonally active form, 1,25(OH)2D3. 25(OH)D3 and 1,25(OH)2D3 induces the gene expression of 24-hydroxylase, which results in its degradation.

 

In skin exposed to UVB light, pro-vitamin D3 or 7-dehydrocholesterol, is converted to pre-vitamin D3 (fig. 1)2,3. Chemically, a C-C bond of 7-dehydrocholesterol (pro-vitamin D3) is broken giving rise to pre-vitamin D3. Pre-vitamin D3 then isomerises to vitamin D3 in a process stimulated by heat (fig. 2)4. Vitamin D3 thus produced in the skin or dietary vitamin D3 absorbed in the intestine then enters the circulation3. Vitamin D3 in the circulation does not exist in free form. It is bound by vitamin D3 binding protein (DBP)2. DBP is a Gc-globulin that is abundant in serum. It binds the lipophilic vitamin D3 and transports it through the bloodstream to other organs and tissues5.

 

Figure 2: Vitamin D Metabolism. Under the action of UVB (ultraviolet B) light, a C-C bond in Pro-vitamin D3 (7-dehydrocholesterol) is broken giving rise to Pre-vitamin D3. Under the action of heat, Pre-vitamin D3 is converted to to vitamin D3 relieving steric hindrance. Vitamin D3 then is converted to the hormonally active form, which is 1,25(OH)2D3 or Calcitriol, by the sequential action of a hepatic and renal enzymes as discussed in the text.

Vitamin D3 needs to be activated through chemical modifications. The first one takes place in the liver. The vitamin D3 molecule is hydroxylated at the 25th position to give 25-hydroxyvitamin D3 [25(OH)D3]. This is the major circulating form of vitamin D. It determines the status of vitamin D in the body: sufficiency, insufficiency or deficiency. The enzyme responsible for this modification is a hepatic vitamin D3 25-hydroxylase encoded by the gene CYP27A1 (fig. 1)3. CYP27A1 is a cytochrome P450 enzyme and is mitochondrial. There are other enzymes that perform the same function – e.g. the microsomal CYP2R12.

25(OH)D3 is still not hormonally active. It is bound by DBP and is transported to the kidneys. The DBP/25(OH)D3 complex interacts with the receptor magalin6,7 and is internalized in cells of the proximal tubules where it is hydroxylated at carbon 1. This form of vitamin D, 1,25(OH)2D3 or 1,25-alpha-dihydroxyvitamin D3, is the hormonally active form of vitamin D. The enzyme responsible for the 1-alpha hydroxylation (the 1-alpha-hydroxylase) is encoded by the gene CYP27B1, also a member of cytochrome P450 family. The renal 1-alpha-hydroxylase is regulated by calcium and phosphate homeostatic signals such as parathyroid hormone and FGF23 (a separate post will deal with this). There is ample evidence, however that CYP27B1 is expressed in other tissues enabling the local production of the hormonal form of vitamin D [1,25(OH)2D3]8 from circulating 25(OH)D3 independently of the regulation cues stated above. 1,25(OH)2D3 could be bound to DBP, but with a much lower affinity compared to vitamin D3 or 25(OH)D3.

1,25(OH)2D3 enters freely in the cells through the membrane. It exerts non-genomic effects (minutes to an hour) or genomic effects. The latter take at least 1h to observe and involve gene expression regulation. The Vitamin D Receptor (VDR) is required to mediate the genomic effects. VDR is a member of the nuclear receptor family and is activated by 1,25(OH)2D3 to stimulate or repress target gene expression. One of these target genes is CYP24A1, also a member of the cytochrome P450 family. This gene encodes the enzyme 25(OH)D3/1,25(OH)2D3-24-hydroxylase. 1,25(OH)2D3 or 25(OH)D3 24-hydroxylation is the limiting step in the degradation of vitamin D39. In this context, 1,25(OH)2D3 stimulates its own degradation creating a negative feedback loop. This, along with other regulatory mechanisms, insures a tight control on the actions of vitamin D.

Finally, I would like to discuss the names of the different forms of Vitamin D:

  1. Pro-Vitamin D3=7-dehydrocholesterol
  2. Pre-Vitamin D3
  3. Vitamin D3=cholecalciferol=calciol
  4. 25(OH)D3=25-hydroxyvitamin D3= calcifediol=25-hydroxychelcalciferol=calcidiol= circulating vitamin D
  5. 1,25(OH)2D3=1,25-dihydroxycholecacliferol=calcitriol=hormonal vitamin D

Vitamin D3 is a form of vitamin D produced in vertebrates. I would like to mention that there is another form, vitamin D2, produced in plants, that has similar properties to vitamin D3. I will write about the similarities and differences between the two at a later time, but they seem to be modified in a similar fashion and have similar physiological functions.

I discussed above the basics of Vitamin D metabolism. What I did not mention is what role skin complexion has on vitamin D production and how long the skin should be exposed to UVB to get optimal production of vitamin D. Frankly, I think I will create a new entry in my blog that will deal with this, along with epidemiology of vitamin D deficiency-associated diseases, supplementation and concentrations of circulating forms of vitamin D. For now, I will just say that individuals with darker skin produce vitamin D less efficiently than white.

That’s it for now. Thanks for reading.

 

References:

1              DeLuca, H. F. Evolution of our understanding of vitamin D. Nutrition Reviews 66, S73-S87, doi:10.1111/j.1753-4887.2008.00105.x (2008).

2              Christakos, S., Ajibade, D. V., Dhawan, P., Fechner, A. J. & Mady, L. J. Vitamin D: Metabolism. Endocrinology & Metabolism Clinics of North America 39, 243-253, doi:DOI: 10.1016/j.ecl.2010.02.002 (2010).

3              Doorenbos, C. R. C., van den Born, J., Navis, G. & de Borst, M. H. Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism. Nat Rev Nephrol 5, 691-700 (2009).

4              Jeremy M Berg, J. L. T., Lubert Stryer. Biochemistry.  (2002).

5              Zella, L. A., Shevde, N. K., Hollis, B. W., Cooke, N. E. & Pike, J. W. Vitamin D-Binding Protein Influences Total Circulating Levels of 1,25-Dihydroxyvitamin D3 but Does Not Directly Modulate the Bioactive Levels of the Hormone in Vivo. Endocrinology 149, 3656-3667, doi:10.1210/en.2008-0042 (2008).

6              Negri, A. L. Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein/25-(OH)D3 complex (Review Article). Nephrology 11, 510-515, doi:10.1111/j.1440-1797.2006.00704.x (2006).

7              Rowling, M. J., Kemmis, C. M., Taffany, D. A. & Welsh, J. Megalin-Mediated Endocytosis of Vitamin D Binding Protein Correlates with 25-Hydroxycholecalciferol Actions in Human Mammary Cells. The Journal of Nutrition 136, 2754-2759 (2006).

8              Zehnder, D. et al. Extrarenal Expression of 25-Hydroxyvitamin D3-1{{alpha}}-Hydroxylase. J Clin Endocrinol Metab 86, 888-894, doi:10.1210/jc.86.2.888 (2001).

9              Prosser, D. E. & Jones, G. Enzymes involved in the activation and inactivation of vitamin D. Trends in Biochemical Sciences 29, 664-673, doi:DOI: 10.1016/j.tibs.2004.10.005 (2004).

 

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