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Natural Ways to Increase Calcitriol and Activate The Vitamin D Receptor Gene

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.

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Active Vitamin D vs Vitamin D3

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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 of toxins black 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 is particularly good for Th1 and Th17 dominant people.

Vitamin D’s Anti-Inflammatory Role

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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. (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.

Low blood levels of vitamin D3 are associated with lower bone density (R). Clinical trials have shown that Calcitriol is helpful for people with lower bone density (R).

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 (R).

The Vitamin D Receptor is important for hair growth and loss of VDR is associated with hair loss in experimental animals (R).

The VDR regulates intestinal transport of calcium, Iron and other minerals (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 dopamine by increasing the enzyme that’s the rate limiting step for dopamine production (tyrosine hydroxylase) (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 GAD67 and therefore increases GABA (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).

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 (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)

High levels of the enzyme that breaks down active D is found in lung cancer (R) and breast cancer (R).  This would suggest that increasing its levels are good for breast and lung cancer.

Active vitamin D increases prolactin production (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

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  • 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-their-role-in-chronic-health-issues/”>SIRT1 -potentiates VDR (RR2) – 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),

DHAEPA, linoleic acid and arachidonic acid are all 10,000X less capable than 1,25 D3 at activating the VDR (R).

Curcumin is 1,000X less capable than 1,25 D3 in inducing VDR gene expression (R).

Curcumin and bile have similar binding ability to the VDR and similar levels of gene expression (R).

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

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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.
  • Tuberculosis – Reduces VDR 3.3-fold. (R)
  • “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 protein which breaks apart the VDR structure and thus limits the ability of VDR to perform gene transcription. (R)
  • 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)

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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).

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

Testing Calcitriol/Active Vitamin D

Click here to check your active Vitamin D levels by taking a simple blood test. 

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.

VDR Snps

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.

  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.

 

Comments

  1. Aaron_c

    Hi Joseph,

    First of all, thank you for the list of pathogens that inhibit VDRs (with citations!). Very helpful.

    I do have two comments regarding the item that reads: “Ubiquitin (R) – autophagy stops this.”

    First of all, ubiquitin isn’t a pathogen, it is “a small protein that is found in almost all cellular tissues in humans and other eukaryotic organisms, which helps to regulate the processes of other proteins in the body.” (news-medical.net)

    Secondly, the article that you linked to appears to disagree with the second source it cites. The article you linked to claims: “At the receptor level, calcitriol induces ubiquitination of the VDR leading to its degradation by the ubiquitin-proteasomal pathway (38,39).” The first source details how calcitriol binding is necessary for SUG1 to degrade VDRs. So far so good, but I mention this mostly because it is important to note that it does not look at the net effect of calcitriol on VDR levels.

    The second article that was cited appears to have been misunderstood. Far from claiming that calcitriol induces ubiquitination of VDRs (which then leads to VDR degredation and fewer VDRs) the study is titled “1,25-Dihydroxyvitamin D3 INCREASES nuclear vitamin D3 receptors by BLOCKING ubiquitin/proteasome-mediated degradation in human skin.” [emphasis added] We should also note that this second, misrepresented study looks at the net effect of calcitriol on VDR levels–and found that calcitriol increases VDR levels both by increasing VDR transcription and by decreasing VDR degradation.

  2. RC

    Should I (a eczema patient) take vitamin D supplements if Vitamin D promotes Treg but also shift TH1 to TH2 which increase allergic response ?

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