It is now becoming clear that attempting to test for and correct Vitamin D deficiencies is far more involved than simply looking at levels of 25-hydroxyvitamin D and using supplemental Vitamin D3. That approach fails to recognize the fact that many factors will mediate how 25-hydroxyvitamin D is converted into the active secosteroid hormone Calcitriol (1,25-dihydroxyvitamin D). Furthermore, numerous pathogenic influences will alter the course of calcitriol intracellular transport and nuclear binding to the Vitamin D receptor (VDR). Without investigating these influences, clinicians overlook the underlying origins of aberrant Vitamin D activities.
Essentiality of VDR Activation: Neuro-Endocrine-Immune
Vitamin D in its active form, calcitriol is of great importance for many physiological functions. These functions are activated when calcitriol binds to the nuclear VDR receptor site.
Vitamin D Receptor (VDR) Activation is Essential for:
- Modulation of Immune T-cell & B-cell Behavior – T-cell lymphocytes are a crucial component of the immune defenses. They can be both pro and anti-inflammatory. Calcitriol (1,25 dihydroxyvitamin D) can reduce the proliferation of pro-inflammatory cytokines (interferon gamma, and IL-17). Calcitriol can activate more of a TH2-type response through IL-4 and IL-10, as well as promote the anti-inflammatory T-regulatory cells (TREGs) (5).
- Mast Cell Inhibitory Effects – Calcitriol has been shown in vitro to inhibit mast cell behavior (6). Mast cells are a type of immune cell in the tissues, which among other functions release histamine, an inflammatory molecule. MCAS (mast cell activation syndrome) involves increased degranulation of mast cells, and the associated symptoms.
- Activation of CYP3a4 – VDR can activate CYP3a4. CYP3a4 is the most abundant cytochrome P450 enzyme in the liver. Approximately 60% of hydroxylation reactions in the liver involve CYP3a4. Thus CYP3a4 plays a significant role in hepatic metabolism, detoxification reactions, and drug metabolism. CYP3a4 also plays an essential role in the formation of the sex hormones estriol (E3), and 16OHE1 and 16OHE2. The VDR has shown to influence hepatic CYP3a4 activation (8, 10), as well as in intestinal CYP3a4 (9).
- Calcium & Phosphate Metabolism – Calcitriol interacts with PTH (parathyroid hormone) in order to absorb calcium from the gut and reabsorption of calcium in the kidneys, as well as regulate the excretion of inorganic phosphate.
- Bile Acid Formation – The bile acid Lithocholic acid can activate the vitamin D receptor (VDR) (15). Lithocholic acid is capable of inhibiting the TH1 branch of the immune system (16).
- Neuronal Growth & Integrity – NGF (nerve growth factor) is enhanced by VDR receptor activation. This is significant because ß-amyloid plaque inhibits VDR (17).
- Dopamine Pathway Activation – Calcitriol and VDR activation leads to dopamine pathway activation via tyrosine hydroxylase (18).
- Testosterone, Sperm Count & Fertility – VDR activation interacts with sexual reproductive processes, including androgen receptor function, testosterone synthesis and gonadal sufficiency (19).
The War Over The Vitamin D Receptor (VDR)
Calcitriol (1,25-dihydroxyvitamin D) is the active hormone that binds to the vitamin D receptor (VDR) in the cell nucleus. Once calcitriol binds to the VDR, the Vitamin A (retinol) receptor (RXRA and RXRB) is involved in activation of the VDR targets. Hence, Vitamin D and Vitamin A are truly joined at the hip, so to speak.
The VDR has an important role to play in mitochondrial function and in cell programmed death. BCL-2, is a protein that is involved to the apoptosis pathways (cell programmed death), and for the regulation of the mitochondrial membrane. Up-regulation of BCL-2 is found in cancer, where it prevents cancer cells from undergoing apoptosis. BCL-2 interacts with the VDR, leading to its reduced expression (11). The significance here is that apoptosis is necessary for inhibiting cancer cell division and growth.
Pathogenic influences are known to negatively influence the function of the Vitamin D receptor. This is especially true of:
- EBV (epstein barr virus) (1)
- CMV (cytomegalovirus) (2)
- Borrelia burgdorferi (Lyme bacteria) (3)
- Wifi radiation (electrosmog) has shown to adversely affect the VDR (4)
- Gliotoxin, a virulence factor and mycotoxin of fungi (20). Gliotoxins are produced by numerous fungi. Though the study cited identified gliotoxin release from aspergillus fumigatus, it is known that gliotoxins can also be produced by penicillium and trichoderma
Autoimmune Thyroid & The VDR
In Hashimoto’s autoimmune thyroiditis, a common symptom is hair loss. One likely cause of this is the inactivation of the Vitamin D receptor (VDR). In alopecia (hair loss), very strong associations were found with VDR inactivation (12). One theory about why this is taking place in Hashimoto’s is related to the strong association between epstein barr virus (EBV) and autoimmune thyroid (13). Remember that EBV can cause an inactivation of the VDR (1), and studies have found strong associations between EBV and autoimmune thyroid. Another relationship between Hashimoto’s thyroiditis and the VDR is through the exposure to endotoxins from gram negative bacteria. Endotoxins can induce a cell danger response (CDR), which causes an up-regulation of an enzyme known as 24α-hydroxylase (CYP24a1). 24α-hydroxylase activation leads to the formation of an inactive form of calcitriol known as 24,25-dihydroxyvitamin D3 (14).
Hashimoto’s Hypothyroidism & VDR Genetics
A recent study identified the VDR gene as associated with Hashimoto’s. Carriers of the AA genotype of VDR FOKI had an increased prevalence of Hashimoto’s, compared to controls. Interestingly, carriers of the genotype had higher levels of 25-OHD, compared to non-hypothyroid controls. This once again illustrates the futility of 25-OHD level testing (21).
Abnormal Conversion of Calcitriol (1,25 dihydroxyvitamin D)
Immune macrophages in Sarcoidosis, a granulomatous disease, were shown to be involved in hyperconverting calcitriol, leading to elevations in the serum (7).
An interesting clinical finding is that among individuals with chronic illness such as Lyme disease and autoimmune disease, there’s a tendency for calcitriol levels to be significantly higher than 25OH D levels. It is plausible to consider the effect of cell danger signaling occurring in response to intracellular pathogens such as borrelia and EBV. The inactivation of the VDR would in theory disrupt the intracellular conversion and transport of Vitamin D to calcitriol and its subsequent VDR target.