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Vitamin D Receptor Gene: Activation, Calcitriol, Benefits

Written by Joe Cohen, BS | Last updated:
Jonathan Ritter
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology) | Written by Joe Cohen, BS | Last updated:
Vitamin D

The Vitamin D Receptor has many very 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


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 be converted 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 to 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 [1].

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) [1].

The Benefits of Vitamin D3

The active form of vitamin D (calcitriol) has many benefits.

Vitamin D protects against:

  • Osteoporosis [2]
  • Cancer [3]
  • Diabetes [4] – Type 1 and 2 [5]
  • Heart disease [6]
  • Neurological diseases [7]
  • Psoriasis [8]
  • Infections [9]
  • Multiple sclerosis [10]
  • Asthma [11, 12]
  • Kidney inflammation and kidney disease death. (It should lower your creatinine levels) [13].
  • High Blood Pressure (Decreases Renin/angiotensin system) [14].
  • Lupus/SLE [5]
  • Arthritis [5]
  • Scleroderma [5]
  • Sarcoidosis [5]
  • Sjogren’s [5]
  • Autoimmune thyroid disease (Hashimoto’s, Grave’s) [5]
  • Ankylosing spondylitis [5]
  • Reiter’s syndrome [5]
  • Uveitis [5]

Vitamin D is particularly good for Th1 and Th17 dominant people.

Vitamin D’s Anti-Inflammatory Role

Vitamin D mainly lowers the “adaptive” immune system.

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 [18].
  • Increase CD8+ T Cells, which is important in controlling viral infections.
  • Increases Natural Killer T Cells [19] – good for preventing autoimmune disease, but bad for asthma.
  • Increases NK cells [20]
  • Releases Antimicrobials in response to an infection such as cathelicidin and beta-defensin 4 [20].

Other Benefits of the Vitamin D Receptor

The most popular benefits of vitamin D3 is its role in bone health.

Low blood levels of vitamin D3 are associated with lower bone density [21]. Clinical trials have shown that Calcitriol is helpful for people with lower bone density [22].

VDR activation induces the expression of liver and intestinal phase I detox enzymes (e.g., CYP2C9 and 3A4) that play major roles in metabolizing drugs and toxins [23].

The Vitamin D Receptor is important for hair growth and loss of VDR is associated with hair loss in experimental animals [24].

The VDR regulates the intestinal transport of calcium, iron and other minerals [25].

Since many infections block the Vitamin D Receptor, our body can’t fight them off well. Researchers 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 [5].

Calcitriol/VDR increases dopamine by increasing the enzyme that’s the rate-limiting step for dopamine production (tyrosine hydroxylase) [26].

Calcitriol/VDR increases tyrosine hydroxylase in the hypothalamus [27], adrenal glands [28], substantia nigra [29] 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 [30].

Calcitriol increases GAD67 and therefore increases GABA [31].

Calcitriol increases glial-derived neurotrophic factor (GDNF) (in vitro), which protects dopamine neurons [32].

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 [33].

A high prevalence of vitamin D deficiency has been reported in Parkinson’s patients and Parkinson’s has been associated with decreased bone mineral density [33].

Active D has different effects on 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) [34].

High levels of the enzyme that breaks down active D is found in lung cancer [35] and breast cancer [36]. This would suggest that increasing its levels are good for breast and lung cancer.

Active vitamin D increases prolactin production [37].

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 [1].

Natural Ways to Increase Calcitriol and Vitamin D Receptor Gene Expression

  • Exercise [38] – increases calcitriol, but not aerobic exercise [39].
  • RXR (and retinol) is needed to produce proteins with the VDR. 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 [40] and PTH-related peptide [41],
  • SIRT1 – potentiates VDR [42, 43] – acetylation of VDR lessens 1,25D/VDR signaling. SIRT1 increased the ability of VDR to associate with RXR.
  • PGC-1a [44] – potentiates VDR. It is a coactivator of the VDR, but it still needs 1,25D3.
  • Dopamine [45]
  • Bile – specifically Lithocholic acid orLCA [46], 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 facilitate disposal from the cell via the ABC efflux transporter [47].
  • Omega-3: DHA, EPA [47], – Fish oil/DHA
  • Omega-6: γ-Linolenic acid, Arachidonic acid [47],
  • Curcumin [1] – 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 [42] – Potentiates VDR by: (1) potentiating 1,25D binding to VDR; (2) activating RXR; (3) stimulating SIRT1
  • Forskolin [40] – increases 1,25D3 from 25D3 in-vitro
  • Gamma Tocotrienol [47] – Tocotrienols or Tocopherols (IHERB)
  • Vitamin E/alpha-tocopherol [47] – doesn’t compete with calcitriol for the VDR.
  • Dexamethasone [47] – 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 1,25 D binding to the VDR or nuclear VDR levels. IFN-γ impairs VDR-RXR binding to VDRE through a Stat1-mediated mechanism) [48].
  • Estradiol increases VDR expression [49, 50] and calcitriol levels [51].
  • Phytoestrogens [52]
  • Testosterone [53]
  • Prostaglandins
  • Bisphosphonates

DHA, EPA, linoleic acid and arachidonic acid are all 10,000X less capable than 1,25 D3 at activating the VDR [47].

Curcumin is 1,000X less capable than 1,25 D3 in inducing VDR gene expression [47].

Curcumin and bile have a similar binding ability to the VDR and similar levels of gene expression [47].

Curcumin, Bile, DHA, EPA, Arachidonic acid all compete with 1,25 D3 for binding. Dexamethasone and alpha-tocopherol don’t compete [47].

A natural question to pose would be that if these are competitive binders and have a 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 [47].

Excess Bile/LCA given to rats caused the same effect that 1,25D3 would cause (in particular calcium transport activation) [47].

Kidney glandular might contain some 1,25 vitamin D.

What Inhibits The Vitamin D Receptor (VDR) or Calcitriol

  • Caffeine decreases VDR production [54]
  • Cortisol/Glucocorticoids decreases VDR production [25]
  • Prolactin [55]
  • Thyroid hormones repress VDR activation [56]
  • TGF-beta reduces the activation of VDR/RXR combination, which results in VDR-mediated gene expression [57]
  • TNF [58] (inhibits osteocalcin interaction with VDR, but not osteopontin)
  • Corticosteroids decrease calcitriol [59]
  • Phosphatonin, Ketoconazole, Heparin, and Thiazides decrease calcitriol [59]
  • Ubiquitin [60] – 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” [61]. Antibiotics don’t work well [62].
  • H. pylori (responsible for stomach ulcers). 50% of the global population has this. Produces “Sulfonolipid ligand capnine” [61].
  • Lyme/Borrelia – Live Borrelia reduces VDR by 50 times (in monocytes) and “dead” Borrelia reduces it by 8 times [63] – This could explain why people develop autoimmune conditions after Lyme infection.
  • Tuberculosis – Reduces VDR 3.3-fold [64]
  • “Gliding” biofilm bacteria have been shown to create Capnine – Capnine (Cytophaga, Capnocytophaga, Sporocytophaga, and Flexibacter)
  • Chlamydia (trachomatis)
  • Shigella – bacteria in stool and causes intestinal problems and diarrhea. It increases Caspase-3, which is a protein which breaks apart the VDR structure and thus limits the ability of VDR to perform gene transcription [65].
  • Mycobacterium leprase – produces mir-21 to target multiple genes associated with the VDR [64].
  • Epstein-Barr virus (EBV) – Decreases VDR by a factor of about five [66] EBV also blocks the ability of VDR to produce products [67].
  • HIV – binds to the VDR [68] and inhibits conversion to active D [69].
  • 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 [70].
  • Hepatitis C virus – Inhibits CYP24A1, the enzyme responsible for breaking down excess 1,25-D [71]

Screenshot 2015-01-14 15.57.25

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 [72].

Studies show a strong association between these autoimmune conditions and levels of 1,25-D greater than 110 pmol/L (46 pg/mL [73]), 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 [73]) [72].

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 [72].

Acquired hormone resistance has also been recognized with insulin, thyroid, steroid, and GHRH and elevated levels of hormones are seen in some autoimmune conditions [72].

Figuring Out Calcitriol Levels Of 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
  • Higher blood calcium and phosphorous [41]
  • Higher albumin [74]
  • Higher creatinine [75]
  • Lower alkaline phosphatase [76]

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.


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.

  1. RS11574143 (VDR) CC
  2. RS1540339 (VDR) CC
  3. RS1544410 (VDR) CT
  4. RS2107301 (VDR) GG
  5. RS2228570 (VDR) AG
  6. RS2238136 (VDR) CC
  7. RS2239182 (VDR) CC
  8. RS2239185 (VDR) AA
  9. RS2239186 (VDR) AA
  10. RS3782905 (VDR) CG
  11. RS3819545 (VDR) AA
  12. RS4516035 (VDR) TT
  13. RS7041 (VDR) AC
  14. RS731236 (VDR) AG
  15. RS757343 (VDR) CT
  16. RS7975232 (VDR) AA

CYP24A1 breaks down the active form of vitamin D (Calcitriol). Check out the CYP24A1 gene that breaks down calcitriol.

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen flipped the script on conventional and alternative medicine…and it worked. Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs.
Joe is a thriving entrepreneur, with a mission of empowering people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time.


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