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Increased activation of vitamin D (1,25D/25D ratio) is likely to be linked to disruption of the bone-kidney-parathyroid endocrine axis.

aliml

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The results of the present study suggested that vitamin D activities had relevance to clinical parameters, especially bone turnover, with gender-specific correlations with features in age and BMI. The ratio of serum 1,25D/25D as a marker for activation of vitamin D was significantly lower in male patients than in female patients, particularly in older females (≧50 years of age), who are considered to be menopausal women. On the other hand, bone mineral density was significantly lower in older female patients (≧50 years of age) than in male patients. The serum 1,25D/25D ratio was found to be negatively correlated with bone mineral density, negatively correlated with serum inorganic phosphate, and positively correlated with intact PTH, ALP, and BAP in all patients. Of interest, the ratio was negatively correlated with age in male patients but was positively correlated with BMI in female patients, suggesting that vitamin D activation is involved in bone metabolism in a gender-specific manner.

The 1,25D/25D ratio is a putative index of CYP27B1 activity and is considered to be a useful tool for the diagnosis of ocular sarcoidosis [17]. In cases of sarcoidosis or lymphomas, type II IFN enhances the activity of 1α-hydroxylase in macrophages, resulting in increased production of 1,25D and hypercalcemia [1]. Excessive vitamin D activity also has a stimulatory effect on bone turnover and an inhibitory effect on bone mineralization [18]. Vitamin D is a key component of the bone-kidney-parathyroid endocrine axis. 1,25D produced in the kidney binds to VDR in the bone and also activates FGF-23 gene expression. Secreted FGF-23 acts on the Klotho-FGF receptor complex in the kidney and parathyroid gland. In the kidney, FGF-23 down-regulates the Cyp27b1 gene and up-regulates the Cyp24 gene, resulting in suppression of vitamin D activity. In the parathyroid gland, FGF-23 suppresses the expression of PTH, which has the potential function of promoting Cyp27b1 gene expression. Since there is a closed negative feedback loop for vitamin D homeostasis, disruption of the loop regulating CYP27B1 induction results in an increase in 1,25D level [19-21].

Vitamin D level in serum has been reported to decline with aging due to a reduction in the production of vitamin D in the skin [22,23]. In general, a hormonal decline of sex steroids such as androgen and estrogen is important in the aging process [24]. Total testosterone level has been reported to have a slight but significant positive association with serum 25D level, suggesting that both testosterone and vitamin D can be health-related markers for males [25]. A meta-analysis showed that vitamin D status has an inverse relationship with BMI in both diabetic and non-diabetic subjects [26]. Another meta-analysis showed that serum vitamin D level had an inverse association with the risk of abdominal obesity in a dose-response manner [27]. Vitamin D deficiency has been considered to be associated with obesity and metabolic dysregulation by modulating the expression of genes related to adipogenesis and inflammatory and oxidative stress in mature adipocytes [28].

In the present study, it was also shown that serum levels of creatinine and free thyroxin were negatively correlated with the serum 1,25D/25D ratio. In this regard, patients with chronic kidney disease (CKD) usually have secondary hyperparathyroidism and a low serum 1,25 level [29]. Patients in an advanced stage of CKD have high levels of serum FGF-23 and PTH and a low level of Klotho expression, so-called FGF-23 resistance, leading to impaired activation of vitamin D [19]. Vitamin D also acts on the thyroid through VDR; however, there is no clear consensus about a relationship between vitamin D status and thyroid function in healthy humans [30], although a study on the role of vitamin D in thyroid diseases indicated that vitamin D deficiency might be an increased risk of autoimmune thyroid diseases [30]. However, based on the present findings, it seems likely that thyroid function is involved in the activation of vitamin D.

Vitamin D activity should be evaluated when vitamin D-related disorders such as hyperparathyroidism or granuloma-forming disorders are suspected. However, our findings presented here indicate the importance of assessing vitamin D activity from the ratio of 1,25D to 25D in general clinical settings. Considering that vitamin D activation can be linked to aging and obesity as well as bone mineral metabolism, measurement of serum 1,25D/25D ratio can be useful for suspecting bone loss, fractures, sarcopenia, or other clinical outcomes associated with frailty. Since the present study showed a negative correlation between serum 1,25D/25D ratio and bone mineral density, serum 1,25D/25D ratio might be a marker for determining the necessity for vitamin D supplementation. However, when a high serum 1,25D/25D ratio is related to increased PTH as in primary hyperparathyroidism, vitamin D supplementation may promote the progression of hypercalcemia. Nevertheless, our findings suggest that a high serum 1,25D/25D ratio is a clue for considering the loss of bone mineral density. There are some limitations of the present study. Patients included in the present study had various pathological conditions possibly associated with hypovitaminosis D. Since we focused on BMI and age, which are physiological parameters potentially influenced by pathological conditions, our study could not show a direct interrelationship between vitamin D metabolism and BMI/age. However, we consider that it is meaningful to assess real-world data obtained from clinical practice in general medicine. Also, serum vitamin D levels can be affected by seasonal changes, lifestyles related to sunlight exposure, nutritional intake, and human race [5,23]. In the present study, serum vitamin D levels might have been affected by seasonal changes or sunlight exposure. All of the patients included in this study were Japanese.

Technically, although free vitamin D and albumin-bound vitamin D (10-15%) are bioavailable, current assays cannot distinguish free vitamin D from vitamin D-binding protein-bound (DPB) vitamin D (85-90%) and albumin-bound vitamin D, the amounts of which are affected by the capability for DPB and albumin synthesis [31]. Another limitation of this study is that it was performed retrospectively at a single center with a relatively small number of patients, and it is, therefore, difficult to draw a solid conclusion. To clarify the precise interaction between vitamin D activity and bone turnover, another study with a larger sample size including a general population or a prospective study using age- and gender-matched cohorts as a multi-center study will be needed.

In the present study, it was notable that the 1,25D/25D ratio is conceivably a useful tool for suspecting bone loss, fractures, or other clinical outcomes associated with frailty.
 

aliml

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Active Vitamin D vs. Vitamin D3​

c2pp25194a-f2


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]
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.
 

youngsinatra

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Really interesting article.

Interesting that Ray‘s recommendations match with many of the things that inhibit the VDR, while things that activate the VDR are things that Ray does warn against.

The only thing that baffles me is that infections also inhibit VDR which is sort of bad from my POV. I had Epstein-Barr Virus in the past and I know that my vitamin D always poorly responded to supplementation and that higher doses were needed to feel good and reach the desired level.
 
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frannybananny

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Really interesting article.

Interesting that Ray‘s recommendations match with many of the things that inhibit the VDR, while things that activate the VDR are things that Ray does warn against.

The only thing that baffles me is that infections also inhibit VDR which is sort of bad from my POV. I had Epstein-Barr Virus in the past and I know that my vitamin D always poorly responded to supplementation and that higher doses were needed to feel good and reach the desired level.
This is confusing because ideally you would want to stimulate or activate the VDR....right?
 

Kris

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Isn't being in the sun enough to give you all the vitamin D that you need? And can someone explain in laymen terms, what would interfere with creating vitamin D in the body, even if one is exposed a lot to the sunlight?
 
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Kris

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no, sun is enough. RP is against supplements. anyone one who says anyways is is an imbecile.
 

Ben.

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Isn't being in the sun enough to give you all the vitamin D that you need? And can someone explain in laymen terms, what would interfere with creating vitamin D in the body, even if one is exposed a lot to the sunlight?

I once read that a excessive feedback from the paraventricular nucleus of the brainstem forcefully reduces the vitamin d one gets from the sun because of excess intracellular calcium which might be due to many reasons but most prominently EMF/blue light from screens.

Not sure if thats correct, but if it was magnesium as a calcium channel blocker would help. And ofcourse the usual ray peat stuff, increasing atp/energy production, having good metabolism, warm temperature, maybe k2 and taurin ... so on and so forth.
 
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no, sun is enough. RP is against supplements. anyone one who says anyways is is an imbecile.
RP did say in the winter he uses vitamin D on his skin. He says when using on the skin use 10 times the internal dosage.
 

Kris

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yes, supplementing vitamin D in winter makes sense. I live now in thailand, so I have too much sun. by the way, black folks living in the west have issues with getting vitamin D from sun. this is why, as we moved to colder climates, we developed whiter skin.
 
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yes, supplementing vitamin D in winter makes sense. I live now in thailand, so I have too much sun. by the way, black folks living in the west have issues with getting vitamin D from sun. this is why, as we moved to colder climates, we developed whiter skin.
I read that recently that black skinned people need to be in the sun 6 times longer to get the same amount of vitamin D as white skin. That is interesting about the skin getting whiter moving to colder climates.
 

Kris

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I read that recently that black skinned people need to be in the sun 6 times longer to get the same amount of vitamin D as white skin. That is interesting about the skin getting whiter moving to colder climates.

it is pretty obvious. they absorb less vitamin D from the sun.
 
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Isn't being in the sun enough to give you all the vitamin D that you need? And can someone explain in laymen terms, what would interfere with creating vitamin D in the body, even if one is exposed a lot to the sunlight?
I am agreeing with you.
 

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