The Vitamin D Receptor has many really important functions. People mistakenly believe that to get Vitamin D related benefits, they need to supplement with Vitamin D3. Often, vitamin D3 isn’t enough.
- Active Vitamin D vs Vitamin D3
- The Benefits of Vitamin D3
- Vitamin D’s Anti-Inflammatory Role
- Other Benefits of the Vitamin D Receptor
- Natural Ways to Increase Calcitrol and Vitamin D Receptor Gene Expression
- What Inhibits The Vitamin D Receptor (VDR) or Calcitriol
- Pathogens That Inhibit The Vitamin D Receptor
- High Levels of Calcitriol Indicate Inflammatory/Autoimmune Disease
- Calcitriol/Active Vitamin D on SelfDecode
- Figuring Out Calcitriol Levels From Vitamin D3
- VDR Snps
Active Vitamin D vs Vitamin D3
We think of vitamin D3 as causing a bunch of health effects, but vitamin D3 is mainly just the beginning of the process that leads to its health benefits.
Vitamin D3 needs to convert to Calcitriol, the active form.
Then, Calcitriol needs to attach to a specific receptor – the Vitamin D Receptor or VDR. Some infections or toxins block these receptors. If this happens, you won’t get the health effects of Calcitriol or vitamin D3.
After Calcitriol binds to the VDR, for many bodily functions, this complex then needs to go to the nucleus and bind with another protein such as RXR.
After that, there are cell-specific responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D (R).
In some cases, various steps can be left out. For example, in skin cells, the Vitamin D Receptor can have effects without Calcitriol to increase hair growth (via Wnt). (R)
The Benefits of Vitamin D3
The active Vitamin D (calcitriol) has many benefits…
Vitamin D protects against:
- Osteoporosis (R)
- Cancer (R)
- Diabetes (R) – Type 1 and 2 (R)
- Heart disease (R)
- Neurological diseases (R)
- Psoriasis (R)
- Infections (R)
- Multiple sclerosis (R)
- Asthma (R)
- Sun damage (R)
- Kidney inflammation and kidney disease death. (It should lower your creatinine levels.) (R)
- High Blood Pressure (Decreases Renin/angiotensin system). (R)
- Lupus/SLE (R)
- Arthritis (R)
- Scleroderma (R)
- Sarcoidosis (R)
- Sjogren’s (R)
- Autoimmune thyroid disease (Hashimoto’s, Grave’s) (R)
- Ankylosing spondylitis (R)
- Reiter’s syndrome (R)
- Uveitis (R)
Vitamin D’s Anti-Inflammatory Role
Vitamin D mainly lowers the “adaptive” immune system.
- Inhibits B cell proliferation. (R)
- Inhibits immunoglobulin (Ig) secretion. (R)
- Inhibits T cell proliferation. (R)
- Shift from Th1 to Th2. (R, R2)
- Inhibits Th17. (R)
- Increases Tregs and IL-10. (R)
- Decreases inflammatory cytokines (IL-1, IL-6, IL-8, IL-12, TNFα, IL-17, IL-21). (R)
- Decreases TGF-beta (R)
- Decreases expression of MHCII and co-stimulatory molecules, which inhibits Dendritic Cell differentiation and maturation. (R)
Vitamin D also boosts the immune system:
Vitamin D mainly stimulates the “innate” immune system.
- Crucial for T Cell activation. In this sense it’s an immune booster. (R)
- Increase CD8+ T Cells, which is important in controlling viral infections.
- Increases Natural Killer T Cells. (R) – good for preventing an autoimmune disease, but bad for asthma.
- Increases NK cells. (R) ( are associated with…)
- Releases Antimicrobials in response to an infection such as cathelocidin and beta defensin 4. (R)
Other Benefits of the Vitamin D Receptor
The most popular benefits for vitamin D3 is it’s role in bone health.
The Vitamin D Receptor is important for hair growth and loss of VDR is associated with hair loss in experimental animals (R).
Since many infections block the Vitamin D Receptor, our body can’t fight them off well. Researches are using a combination of Calcitriol (active D) and antibiotics with good effects in many conditions. It’s a good idea to gradually eliminate pathogens over several years to minimize immune reactions. (R)
Calcitriol/VDR increases tyrosine hydroxylase in the hypothalamus (R), adrenal glands (R), substantia nigra (R) and likely other areas. This means that it increases productions of dopamine, adrenaline and noradrenaline. Although having more neurotransmitters is a good thing, Tyrosine hydroxylase also increases oxidative stress, so it doesn’t provide a free lunch. (R)
Calcitriol increases glial derived neurotrophic factor (GDNF) (in vitro), which protects dopamine neurons. (R)
Researchers hypothesize that inadequate levels of circulating vitamin D could lead to dysfunction in the substantia nigra, an area of the brain in which the characteristic dopaminergic degeneration occurs in parkinsonian disorders (R).
Active D has different effects in cancer. In breast cancer cells, estrogen (and aromatase) production decreased, while Testosterone/androgens increased (both GOOD). In adrenal cancer cells, it decreased DHT (GOOD). In prostate cancer cells, the production of testosterone and DHT increased (BAD). (R)
Technical: 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP(9k), and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate kidney calcium and phosphate reabsorption (R).
Natural Ways to Increase Calcitrol and Vitamin D Receptor Gene Expression
- Exercise (R)- increases calcitriol, but not aerobic exercise (R).
- RXR (and retinol) is needed to produce proteins with the VDR (R). 1,25D3 binds to the VDR, which then combines with RXR to activate gene expression. (Not all VDR dependent genes need RXR.)
- Parathyroid hormone (PTH) – increases Calcitriol/1,25 D3 (R) and PTH -related peptide (R),
- SIRT1 -potentiates VDR (R, R2) – acetylation of VDR lessens 1,25D/VDR signaling. SIRT1 increased the ability of VDR to associate with RXR.
- PGC-1a (R) – potentiates VDR. It is a coactivator of the VDR, but it still needs 1,25D3.
- Dopamine (R)
- Bile – specifically Lithocholic acid or LCA (R),
The VDR evolved from its ancient role as a detoxification nuclear receptor. LCA is produced from the gut bacteria (metabolizing liver derived chenodeoxycholic acid). LCA travels to the colon, where the VDR binds to LCA or 1,25 D and activates the CYP3A4 and SULT2A genes facilitates disposal from the cell via the ABC efflux transporter (R).
- Omega-3: DHA, EPA (R), – Fish oil/DHA
- Omega-6: Linolenic acid, Arachidonic acid (R),
- Curcumin (R) – Curcumin is more active than LCA/Bile in driving VDR-mediated
transcription and that it binds to VDR with approximately the same affinity as LCA.
- Resveratrol (R) – Potentiates VDR by: (1) potentiating 1,25D binding to VDR; (2) activating RXR; (3) stimulating SIRT1.
- Forskolin (R), – increases 1,25D3 from 25D3 in-vitro.
- Gamma Tocotrienol (R)- Tocotrienols or Tocopherols (IHERB)
- Vitamin E/alpha-tocopherol (R)- doesn’t compete with calcitriol for the VDR.
- Dexamethasone (R) – doesn’t compete with 1,25
- Interferon gamma -IFN-γ treatment inhibited 1,25D3 induction of 24-hydroxylase, the enzyme that breaks down 1,25 D3. This means 1,25D3 increased. (Technical: IFNy did not change the base level activity of the promoter, or change 1,25D binding to the VDR or nuclear VDR levels. IFN-γ impairs VDR-RXR binding to VDRE through a Stat1-mediated mechanism) (R),
- Estradiol increases VDR expression (R, R2) and calcitriol levels (R).
- Phytoestrogens (R),
- Testosterone (R),
- Prostaglandins (R),
- Bisphosphonates (R),
DHA, EPA, linoleic acid and arachidonic acid are all 10,000X less capable than 1,25 D3 at activating the VDR (R).
Curcumin and bile have similar binding ability to the VDR and similar levels of gene expression (R).
A natural question to pose would be that if these are competitive binders and have much lower binding capacity for the VDR, are they of use? The answer seems to be yes.
High concentrations of PUFAs could occur in select cells or tissues and exert bioactivity (R).
Excess Bile/LCA given to rats caused the same effect that 1,25D3 would cause (in particular calcium transport activation) (R).
Kidney glandular might contain some 1,25 vitamin D.
What Inhibits The Vitamin D Receptor (VDR) or Calcitriol
- Caffeine decreases VDR production (R),
- Cortisol/Glucocorticoids decreases VDR production (R),
- Prolactin (R),
- Thyroid hormones repress VDR activation (R),
- TGF-beta reduces the activation of VDR/RXR combination, which results in VDR-mediated gene expression (R).
- TNF (R) (inhibits osteocalcin interaction with VDR, but not osteopontin)
- Corticosteroids decrease calcitriol (R),
- Phosphatonin, Ketoconazole, Heparin and Thiazides decrease calcitriol (R).
- Ubiquitin (R) – autophagy stops this
Pathogens That Inhibit The Vitamin D Receptor
Many pathogens inhibit some aspect of the vitamin D system – either the VDR, the ability of molecules to bind to it or the ability of VDR to cause gene expression.
These are some examples, but I’m sure I haven’t covered all of them known to the body of science.
- P. aeruginosa (often hospital acquired). Produces “Sulfonolipid ligand capnine.”(R) Antibiotics don’t work well (R).
- H. pylori (responsible for stomach ulcers). 50% of the global population has this. Produces “Sulfonolipid ligand capnine.”(R)
Lyme/Borrelia – Live Borrelia reduces VDR by 50 times (in monocytes) and “dead” Borrelia reduces it by 8 times (R) – This could explain why people develop autoimmune conditions after lyme infection.
“Gliding” biofilm bacteria have been shown to create Capnine – Capnine (Cytophaga, Capnocytophaga, Sporocytophaga, and Flexibacter)
- Mycobacterium leprase – produces mir-21 to target multiple genes associated with the VDR. (R)
- Epstein-Barr virus (EBV) – Decreases VDR by a factor of about five (R) EBV also blocks the ability of VDR to produce products. (R)
- HIV – binds to the VDR (R) and inhibits conversion to active D (R)
- Aspergillus fumigatus – In cystic fibrosis patients, the fungus A. fumigatus has been shown to secrete gliotoxin, a toxin which dose-dependently decreases VDR.
- Cytomegalovirus – CMV decreases VDR 2.2 fold. (R)
- Hepatitis C virus – Inhibits CYP24A1, the enzyme responsible for breaking down excess 1,25-D. (R)
When bacterial products block the VDR, less of the CYP24A1 is produced, which results in excess active vitamin D – as is the case in many autoimmune conditions.
High Levels of Calcitriol Indicate Inflammatory/Autoimmune Disease
As bacterial products compromise the activity of the VDR, the receptor is prevented from expressing an enzyme (CYP24) that breaks the calcitriol/1,25-D down into its inactive metabolites. This allows 1,25-D levels to rise without a feedback system to keep them in check, resulting in the elevated levels of the hormone (R).
Studies show a strong association between these autoimmune conditions and levels of 1,25-D greater than 110 pmol/L (46 pg/mL (R)), even though there were no apparent cases of high blood calcium. 38 of the 100 people in a group of people with autoimmune conditions had over 160 pmol/L (66.6 pg/mL (R)) (R).
I see clients with chronic inflammation often have active vitamin D levels between 50-80 pg/mL.
However, there was little association with vitamin D deficiency or the other inflammatory markers, meaning that the results challenge the assumption that blood levels of vitamin D3 or 25-D are a sensitive measure of the autoimmune disease state (R).
Calcitriol/Active Vitamin D on SelfDecode
Figuring Out Calcitriol Levels From Vitamin D3
Common blood tests measure a variety of markers that indicate how much active vitamin D you have.
The following indicate higher calcitriol:
- Higher Parathyroid hormones (R)
- Higher blood calcium and phosphorous (R)
- Higher albumin (R)
- Higher creatinine (R)
- Lower alkaline phosphatase (R)
Since at least some of these (maybe all) require the vitamin D receptor, checking Calcitriol Active/Vitamin D (1,25 Hydroxy) blood levels in combination with the other tests might indicate the degree of VDR resistance.
You need to order your 23andme to find out what your genotype is.
If you want to interpret your genes, you can use SelfDecode, the best SNP analyzer around.
The program has a bunch of SNPs in the VDR Gene.
- RS11574143 (VDR) CC
- RS1540339 (VDR) CC
- RS1544410 (VDR) CT
- RS2107301 (VDR) GG
- RS2228570 (VDR) AG
- RS2238136 (VDR) CC
- RS2239182 (VDR) CC
- RS2239185 (VDR) AA
- RS2239186 (VDR) AA
- RS3782905 (VDR) CG
- RS3819545 (VDR) AA
- RS4516035 (VDR) TT
- RS7041 (VDR) AC
- RS731236 (VDR) AG
- RS757343 (VDR) CT
- RS7975232 (VDR) AA
CYP24A1 breaks down the active form of vitamin D (Calcitriol). Check out the CYP24A1 gene that breaks down calcitriol.
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