In this article we look at the metabolism of Vitamin D, more precisely D3, the one that is synthesized in the skin when exposed to sunlight. The oral supplement form is called D2 and will be studied in a different post.
We describe the synthesis of D3, its conversion to a usable form, and how it is transported and used in the body. We also highlight the genes which play the main role in this story.
The main genes in this process are the GC gene, which encodes the vitamin D-binding protein (DBP), and the VDR gene, which encodes the Vitamin D Receptor. The DBP is responsible for transporting vitamin D metabolites in the bloodstream. The VDR is like a lock for the Vitamin D molecule. When vitamin D binds to the VDR, it can regulate the expression of numerous genes involved in calcium and phosphate homeostasis, immune response, and cell proliferation.
Mechanisms of action of vitamin D
Synthesis and conversion
Our skin converts sunlight into vitamin D, but the active form, Calcitriol, is the result of several transformations in the organism. Calcitriol regulates calcium levels in the body, hence the name “calcitriol”, where “triol” means that the molecule has three hydroxyl groups.
Synthesis in the skin
Our skin contains 7-dehydrocholesterol, a precursor molecule synthesized from cholesterol. Exposure to UVB radiation converts 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3 (cholecalciferol) through a process called thermal isomerization.
Thermal isomerization is a chemical reaction caused by heat exposure, which changes the structure of a molecule without altering its chemical composition. When two molecules differ in their structure but not in their chemical composition, they are called isomers, hence the name isomerization.
Conversion to active form
Once synthesized, vitamin D3 enters the bloodstream and is transported to the liver, where it is transformed into a first metabolite, 25-hydroxyvitamin, which is the result of adding a hydroxyl group (-OH). The enzyme responsible for this first transformation is 25-hydroxylase, encoded by the CYP2R1 gene.
The process of adding a hydroxyl group to an organic compound is called hydroxylation.
The second step happens in the kidneys, where a different enzyme, 1-alpha-hydroxylase (encoded by the CYP27B1 gene), converts 25-hydroxyvitamin D to its active form, calcitriol. Calcitriol is then released into the bloodstream to exert its magic everywhere in the body (well, everywhere there is a Vitamin D receptor, as we’ll see).
Variations in the levels of these two critical enzymes can effect the chain of reactions and ultimately impact the levels of active vitamin D in the body.
Cellular mechanisms
Role of vitamin D receptor (VDR)
Vitamin D receptor is a nuclear receptor found in various tissues, e.g. bones, intestines, brain, immune celles. When Vitamin D binds to this receptors, it triggers a conformational change (an alteration of its shape), enabling it to interact with yet another kind of receptor, retinoid X receptors (RXRs).
Nuclear receptors are proteins within cells that regulate gene expression in response to hormones. Retinoid X receptors and vitamin D receptors are examples of nuclear receptors.
The VDR and RXR form a complex that can, in turn, bind to specific DNA sequences known as vitamin D response elements (VDREs), located in the promoter regions of vitamin D-responsive genes.
A promoter region is a DNA sequence located at the start of a gene that controls the initiation of its transcription, the first step in gene expression.
This is how Vitamin D is ultimately responsible for some degree of gene expression.
Biological pathways
Role in bone health
Calcitriol enhances the absorption of calcium and phosphate in the intestines and works with parathyroid hormone (PTH) to release calcium from bones when serum levels are low. Chronic low calcium levels can cause conditions such as rickets and osteoporosis.
Role in immune system
Some ways in which calcitriol influences the immune system include:
- Promoting the production of antimicrobial peptides
- Modulating the activity of T cells and dendritic cells
Antimicrobial peptides are small proteins that can kill microbes by destabilizing their membranes. They are actively studied for their potential therapeutic applications.
T cells are a type of lymphocyte that play a central role in cell-mediated immunity. Dendritic cells are antigen-presenting cells that process antigen material and present it on their surface to T cells, initiating an immune response.
Genetic polymorphisns and vitamin D metabolism
The VDR gene
Variations of the VDR gene can affect the receptor’s function and expression, influencing calcium absorption, bone density, and immune response. For example, certain VDR polymorphisms have been associated with increased risk of osteoporosis, cancer, and autoimmune diseases.
Impact of genetic variants in the CYP2R1, CYP27B1, and CYP24A1 genes
The CYP2R1, CYP27B1, and CYP24A1 genes encode enzymes that are critical for the metabolism of vitamin D.
- CYP2R1 (chromosome 11): This gene encodes the enzyme 25-hydroxylase, which is responsible for the first hydroxylation step in the liver, converting vitamin D3 to 25-hydroxyvitamin D. Variants in CYP2R1 such as rs117576073 can affect the efficiency of this conversion.
- CYP27B1 (chromosome 12): This gene encodes the enzyme 1-alpha-hydroxylase, which converts 25-hydroxyvitamin D to the active form, calcitriol, in the kidneys. Polymorphisms in CYP27B1 can impact the production of calcitriol.
- CYP24A1 (chromosome 20): This gene encodes the enzyme 24-hydroxylase, which deactivates calcitriol by converting it to calcitroic acid. Variations in CYP24A1 can alter the breakdown of calcitriol.
The GC gene
The GC gene (chromosome 4) encodes the vitamin D-binding protein (DBP), which is crucial for the transportation and bioavailability of vitamin D metabolites in the bloodstream. Genetic variants in the GC gene can affect the concentration and binding affinity of DBP. For example, the alternative allele for rs2282679 (T > G) is linked to lower levels of circulating vitamin D by several studies.
Main variants affecting vitamin D levels
In the table below, Ref stands for “reference allele,” while Alt stands for “alternative allele.” The effect indicates whether the variant is associated with increased or decreased vitamin D levels.
| Gene | rsID | Ref | Alt | Effect |
|---|---|---|---|---|
| VDR | rs2228570 (Fokl) | A | G | Increased |
| GC | rs7041 | A | C | Increased |
| GC | rs2282679 | T | G | Decreased |
| CYP2R1 | rs10741657 | A | G | Decreased |
| CYP27B1 | rs10877012 | G | T | Decreased |
| CYP24A1 | rs6013897 | T | A | Decreased |