Vitamin D Receptor stops mitochondria respiration [Why vit D can cause problems] [1,25 vitamin D]
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- in response to stimulation with 1,25[OH]₂ D, upregulation of the inactivating enzyme CYP24A1 curtailed the functional effects of vitamin D in DCs, but not macrophages.
rifampin fixes 1,25 excess in sarcoidosis through inducing CYP 3a4 enzyme
- So CYP 3a4 can be used to lower the 1,25 excess coming from macrophages
side note 24,25 vit D increases bone strength / fracture repair where 1,25 does not have this effect https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063485/
Insightful studies below that highlight 24,25 aka 24r,25 looks to be the commonly desirable form of vitamin D.
If in good health it's supposed to rise in ratio to 1,25 as 25 vit D goes up, https://www.nature.com/articles/s41598-019-43462-624r,25 form of vit D is likely protective in MS / brain atrophy https://pubmed.ncbi.nlm.nih.gov/21047880/ lower 24,25 compared to 25 = worse outcome
and it actually DECREASES the VD Receptor
Vitamin D3 is metabolized in the liver and kidney in addition to localized tissue-specific biosynthesis. Bone cells are known to metabolize 25(OH)D3 into both 1α,25(OH)2D3 and 24R,25(OH)2D3 via 1α-OHase and 24-OHase, respectively
24,25 DECREASES vdr expression and can lower 1,25,
it inhibits stem cell proliferation like 1,25 also does, but unlike 1,25 it stimulates stem cell maturation / enables their differentiation ,
increasing bone repair / strength https://pubmed.ncbi.nlm.nih.gov/24597546/(but by my experience cannot get this increased enough simply through vit D without worsening the issue from extra 1,25 in people with this excess issue,
was thinking maybe there isnt enough 24a1 enzyme producing 24,25 here, but upregulating doesnt work to counter 1,25 in macrophages)targeting less 1,25 through CYP 3a4 should have effect but also degrades 25 vit D though, so losing 24,25.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310418/Thyroid hormone also increases cyp3a4
(another connection to hypothyroid & vitamin D problems)
and also decreases CYP27B1 , lowering 1,25 (at least in the kidneys, wonder if this also has effect in macrophages keratinocytes etc https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077994/table/T1/?report=objectonly)lowering Cyp27b1 is a major target for lowering 1,25, it stays expressed even when macrophages are removed from IFN-y inducing environment https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077994/
How was it that synthetic 1-hydroxylating activity in macrophages harvested from humans with active disease persisted ex vivo in culture even in the absence of conditioning IFNs? Some of the questions have been answered and some are still coming to light. For example, it is now known that there exists a single gene that encodes the 1-hydroxylase, CYP27B1 [11] and the 24-hydroxylase, CYP24A1 [12]. Further, it is now clear that persistence of mTB in macrophages is an explanation for the continual expression of the CYP27B1 in human macrophages even after their removal from the host and conditioning cytokines present in the inflammatory microenvironment in the host.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508960/
(thyroid hormone & iron key players) & upping 24,25- In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvβ3 and the activation of signalling pathways through Stat1 and NF-κB.
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L LucH referenced this topic on
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@cs3000
You had mentioned relative lack of copper in this context of Mg and Zn and VDR activation making things worse and exacerbating underlying mitochondrial energy impairments.
Did you eventually supplement copper and did it profoundly fix these conditions for you?
Very interested in reading about this.
Thanks for having found and reported the 1,25D/VDR effect of inhibiting cellular copper uptake.
Have you made any approach in the meantime into resolving your underlying causes of elevated chronic inflammation/PAMPS/TLR?@cs3000 said in:
Th1 activity leads to paracrine extra-renal conversion of inactive 25D to active 1,25D, often depleting serum levels of measured 25D in order to increase active vitamin D (how can It deplete if theres 100x more 25 than 1,25 in plasma?) <←- NOT DIRECT DEPLETION , THE 1,25 EXCESS CAUSES ENZYME ELEVATION THAT METABOLISES 25
Afaik by drawing upon some of the same sources you've been using:
By measurements of serum levels (extracellular) of these hormones we only get a one-sided and distorted view on their balance between each other.
Since conversion to and activity of 1,25D are both predominantly intracellular processes there are concentration gradients to be accounted for.
I.e. only 1/10 of circulating serum 25D seeps across the cellular membranes and only 1/10 of intracellular 1,25D seeps outside, roughly. Both 25D3 and 1,25D3 are then essentially in the same potency range, could even be equimolar, with regard to exertion of their nuclear receptor binding intracellularly. -
i had similar symptoms than cs3000 described in the link above from drinking mostly raw milk and direct sun exposure(never had these symptoms from sunlight before i started drinking raw milk, and i have experienced these symptoms afterward in winter just from the raw milk), eating very good dattes temporary make me experience 0 bad effects from sunlight and if i have keep eating it at a certain point body even crave sunlight and sunlight exposure feel exhalting
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Apparently, 25D which is the metabolite of D3, inhibits 1-25D production
“...With high dose cholecalciferol therapy... PTH is physiologically down-regulated and therefore the synthesis of 1,25-D and dietary calcium absorption are reduced.” — Vaidya, et al. (2015)" -
Methylene Blue should be able to inhibit 1,25 conversion too if hydroxychloriquine can.
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@bio3nergetic Interdasting, we should get a list of inhbitors / factors that influence the conversion
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Thanks @user1. Do you mean dates as in the fruit, like medjool dates? Because of their c. 0.3mg/100gr copper content?
I remember I had sort of kept myself afloat for many months by consuming a few hundred grams of dates every day and had assumed their delayed sugar release and balancing potassium content to be the major reason. -
@CrumblingCookie said in Vitamin D Receptor stops mitochondria respiration [Why vit D can cause problems] [1,25 vitamin D]:
Thanks @user1. Do you mean dates as in the fruit, like medjool dates? Because of their c. 0.3mg/100gr copper content?
I remember I had sort of kept myself afloat for many months by consuming a few hundred grams of dates every day and had assumed their delayed sugar release and balancing potassium content to be the major reason.Yes this fruit, yet much softer and moistyer thab typical medjool or dattes
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@alfredoolivas Progesterone lowers 1,25 as well
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Is it possible to have copper deficiency, but normal levels of serum copper and ceruloplasmin, and serum free copper abnormally high?
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@BearWithMe estrogen can increase free copper while PUFA can increase estrogenic activity in inducing free copper or directly damaging enzymes related to copper utilization. Free copper is what contributes to toxicity. Total copper in a healthy system is what yields robust copper status.
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@BearWithMe Can it be lack of retinols as cofactor for ceruloplasmin synthesis, or general liver damage?
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@CrumblingCookie yes, liver damage will look like Wilson's in some cases. And Retinol is the rate limiting factor for copper status. Copper becomes very unusable without it.
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@CrumblingCookie Retinol deficiency is very possible, but wouldn't that imply low ceruloplasmin? Mine is right in the middle of reference range (0,22 g/l)
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@BearWithMe said in Vitamin D Receptor stops mitochondria respiration [Why vit D can cause problems] [1,25 vitamin D]:
Retinol deficiency is very possible, but wouldn't that imply low ceruloplasmin? Mine is right in the middle of reference range (0,22 g/l)
By what I've learnt about copper homeostasis it's not as straightforward with the reference ranges. Cpl 0.22g/l looks alright and not too low yet.
But in various disease states, total copper and Cpl seriously rises. Which is directly associated with higher disease severity and death but appears to me to nevertheless be a necessary function in response to the underlying cause.
If you were to assume that your retinol is low and therefore Cpl not as high as physiologically requested and reflected by abnormally high free copper, you'll co-imply that you have a chronic infection of a likely intracellular kind with impeded autophagic clearance and vice versa. -
@CrumblingCookie Makes a lot of sense, thank you. What kind of infection may cause this? I've had elevated ESR and CRP for no apparent reason pretty much since I was born.
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@cs3000
My thought chain goes like… supplementing D3 raises T4 production in the gut. And not T3. Maybe you are getting too much t4 production going and maybe you have a sluggish liver, not converting to excess t4 to t3, so it gets converted to reverse t3 and your feeling a peculiar form of hypothyroidism.
https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2025.1559608/abstract
Do you take magnesium as well?
https://medicalxpress.com/news/2025-09-magnesium-inhibits-colorectal-cancer-carcinogenesis.html
