Vitamin D and Zinc / Manganese

[percyval577]

the gene investigated here is chiefly expressed in the liver, brain, testis and small intestine

Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor.
da Silva et al 2016


from the Abstract (my paragraphing)

Vitamin D3 regulates genes critical for human health and its deficiency is associated with an increased risk for osteoporosis, cancer, diabetes, multiple sclerosis, hypertension, inflammatory and immunological diseases.

To study the impact of vitamin D3 on genes relevant for the transport and metabolism of nutrients and drugs, we employed next-generation sequencing (NGS) and analyzed global gene expression of the human-derived Caco-2 cell line treated with 500nM vitamin D3. Genes involved in neuropeptide signaling, inflammation, cell adhesion and morphogenesis were differentially expressed.

Notably, genes implicated in zinc, manganese and iron homeostasis were largely increased by vitamin D3 treatment. An ∼10-fold increase in ceruloplasmin and ∼4-fold increase in haptoglobin gene expression suggested a possible association between vitamin D and iron homeostasis. SLC30A10, the gene encoding the zinc and manganese transporter ZnT10, was the chiefly affected transporter, with ∼15-fold increase in expression. SLC30A10 is critical for zinc and manganese homeostasis and mutations in this gene, resulting in impaired ZnT10 function or expression, cause manganese intoxication, with Parkinson-like symptoms.

...

In conclusion, we have shown that vitamin D3 transactivates the SLC30A10 gene in a VDR-dependent manner, resulting in increased ZnT10 protein expression. Because SLC30A10 is highly expressed in the small intestine, it is possible that the control of zinc and manganese systemic levels is regulated by vitamin D3 in the intestine. Zinc, manganese and vitamin D are important for bone metabolism and brain health.

Future examination of a possible role for supplementation or chelation of zinc and manganese, alongside vitamin D3 administration, will further our understanding of its potential benefit in the treatment of specific illnesses, such as osteoporosis and Parkinson's disease.

open access
J Steroid Biochem Mol Biol. 2016 Oct;163:77-87. doi: 10.1016/j.jsbmb.2016.04.006. Epub 2016 Apr 20. ​

 

[percyval577]

Modulation effects of Zinc on the formation of vitamin D receptor and retinoid X receptor alpha-DNA transcription complex: analysis by microelectrospray mass spectrometry.
Craig et al 2001


Abstract (my paragraphing)

The vitamin D receptor (VDR) binds zinc, and the activity of vitamin D dependent genes in cells is influenced by intracellular zinc concentrations. To determine whether zinc influences vitamin D action in cells by modulating the formation of VDR and retinoid x receptor alpha (RXR alpha) heterodimer-DNA complexes, we used microelectrospray ionization mass spectrometry (microESI-MS) to assess receptor-DNA interactions in the presence of varying amounts of zinc.

In the absence of DNA, VDR and RXR alpha proteins were primarily monomeric with small amounts of protein homodimers also observed. Zn(2+) (up to 300 microM) did not change VDR or RXR alpha monomer/homodimer ratios. Mass spectra of VDR combined with RXR alpha were a sum of individual protein spectral data. Zn(2+) had no effect on the interactions of receptors.

With increasing amounts of Zn(2+), additional Zn(2+) ions were detected bound to VDR and RXR alpha. microESI-MS analyses of RXR alpha in the presence of an osteopontin vitamin D DNA response element (OP-VDRE) showed RXR alpha homodimer/OP-VDRE complexes. DNA-protein complex formation increased on addition of Zn(2+) up to 200 microM;

at 300 microM, Zn(2+) dissociation of the RXR alpha homodimer/OP-VDRE complexes occurred, coincident with the appearance of RXR alpha monomeric protein. When microESI-MS analyses were carried out with VDR and OP-VDRE, VDR homodimer/OP-VDRE complexes were not detected. Addition of Zn(2+) did not result in VDR/OP-VDRE complex formation. Heterodimeric VDR/RXR alpha complexes with OP-VDRE were detected by microESI-MS.

Addition of 300 microM Zn(2+) resulted in dissociation of the heterodimeric VDR/RXR alpha/OP-VDRE complex. Addition of Mg(2+) in place of Zn(2+) did not alter protein/OP-VDRE complexes. Our results show that zinc modulates steroid hormone receptor-DNA interactions.

paywalled
Rapid Commun Mass Spectrom. 2001;15(12):1011-6. ​

 

[percyval577]

Heme Oxygenase-1 might be an interesting link between Mn and vitD.

Manganese Potentiates LPS-Induced Heme-Oxygenase 1 in Microglia but not Dopminergic Cells: Role in Controlling Microglial Hydrogen Peroxide and Inflammatory Cytokine Output.
Dodd and Filipov 2011


from the Discussion (my splitting)

The major findings of our current study are that

(1) Mn up to 250 μM does not induce HO-1 on its own, but it does potentiate LPS-induction of HO-1 in microglia cells,

(2) HO-1 activity appears to be important in regulating Mn-induced H2O2 release,

(3) increased HO-1 plays a role in the enhancement of inflammatory mediator output, particularly TNF-α, in Mn+LPS-exposed microglia as inhibition of HO-1 activity resulted in decreased inflammatory cytokines,

(4) NO is not the key regulator of HO-1 induction by Mn+LPS, as iNOS inhibition did not significantly alter Mn-potentiated HO-1 induction,

(5) small Maf proteins appear to be transcriptional regulators targeted by Mn for potentiation of HO-1, and

(6) the increased HO-1 by Mn+LPS appears to be glia-specific as, neither Mn, LPS, or combined Mn+LPS induced HO-1 in N27 dopaminergic neurons.

open access
Neurotoxicology. 2011 Dec;32(6):683-92. doi: 10.1016/j.neuro.2011.09.002. Epub 2011 Sep 25​

The protective role of vitamin D3 in a murine model of asthma via the surpression of TGF-beta/Smad signaling and activation of the Nrf2/HO-1 pathway.
Wang et al 2016


from the Abstract (my paragraphing)

The results demonstrated that OVA‑induced airway inflammation and immunoglobulin E overexpression were significantly reduced by vitamin D3 treatment. In addition, treatment with vitamin D3 decreased α‑SMA expression, collagen deposition and goblet cell hyperplasia, and inhibited TGF‑β/Smad signaling in the asthmatic airway.

The upregulated levels of malondialdehyde, and the reduced activities of superoxide dismutase and glutathione in OVA‑challenged mice were also markedly restored following vitamin D3 treatment.

Furthermore, treatment with vitamin D3 enhanced activation of the Nrf2/HO‑1 pathway in the airways of asthmatic mice. In conclusion, these findings suggest that vitamin D3 may protect airways from asthmatic damage via the suppression of TGF‑β/Smad signaling and activation of the Nrf2/HO‑1 pathway; however, these protective effects were shown to be accompanied by hypercalcemia.

open access
Mol Med Rep. 2016 Sep;14(3):2389-96. doi: 10.3892/mmr.2016.5563. Epub 2016 Jul 27​

Vitamin D Improves Intestinal Barrier Function in Cirrosis Rats by Upregulating Heme Oxygenase-1 Expression
Wang et al 2019


from the Abstract

We found that vitamin D could maintain intestinal epithelial proliferation and turnover, inhibit intestinal epithelial apoptosis, alleviate structural damage, and prevent BT and intestinal barrier dysfunction. These were achieved partly through restoration of HO-1 and inhibition of oxidative stress. Taken together, our results suggest that vitamin D ameliorated intestinal epithelial turnover and improved the integrity and function of intestinal barrier in CCl4-induced liver cirrhotic rats. HO-1 signaling activation was involved in these above beneficial effects.

open access
Biomol Ther (Seoul). 2019 Mar 1;27(2):222-230. doi: 10.4062/biomolther.2018.052​

 

[percyval577]

Google gives vitD related genetics as a predisposition for obesity, a review only on insufficiency: Zakharova et al 2019
Mn intake may be related to metabolic disease in an u-shaped manner, judges this meta-analysis: Li and Yang 2018


Heme Oxygenase-1 Drives Metainflammation and Insulin Resistance in Mouse and Man.
Jais et al 2014


from the Introduction

The concept of metaflammation was born out of the discovery that tumor necrosis factor-alpha (TNF-α) potently inhibits adipose insulin signaling (Hotamisligil et al., 1993). Subsequent work implicated additional hallmark activities including inhibitor of kB kinase (Yuan et al., 2001), c-Jun amino-terminal kinases (Hirosumi et al., 2002), and protein kinase R (Nakamura et al., 2010). Two landmark papers described macrophage infiltrates in adipose as the source of insulin-resistance inducing TNF-α (Weisberg et al., 2003; Xu et al., 2003). Such infiltrates have since been characterized as classically activated, proinflammatory M1-like macrophages (Lumeng et al., 2007; Solinas et al., 2007), which have proven pivotal to the emergence of metabolic disease (Patsouris et al., 2008). Importantly, studies now implicate metaflammation as a central feature of human insulin resistance (Capel et al., 2009; Qatanani et al., 2013).
...
Here, using conditional mouse genetics we show that HO-1 is in fact proinflammatory, potently and independently driving insulin resistance in the hepatic and macrophage compartments. Against expectations, we find that HO-1 is among the top predictors of metabolic disease in humans and mice and, intriguingly, that hepatocyte and macrophage loss-of-function leads to resistance to diet-induced metaflammation, insulin resistance, and steatosis. The results indicate that HO-1 is in fact necessary for the development of metaflammation and metabolic disease, and call for a re-evaluation of numerous findings in the field. They identify HO-1 as a candidate biomarker for stratification of metabolically healthy and unhealthy obesity and provide a framework for selective, personalized therapy.

page 8

Interestingly, qPCR analysis revealed clear and widespread upregulation of the entire mitochondrial reactive oxygen species (ROS) detoxification system, from glutathione processing to the mitochondrial-specific superoxide dismutase 2 (Sod2), again in both systems (Figure 6B), indicating that the increased mitochondrial flux was coupled to the induction of ROS quenching machinery. Notably, these changes were confirmed directly, with the findings of increased SOD activity (Figure 6C) and indirectly, with an ~50% increase in intracellular H2O2, the product of SOD, and an increase of cytosolic ROS, again in both knockout cell types (Figures 6D and S5F). Recent studies have suggested that mild ROS elevations activate mitochondrial respiration (Mailloux et al., 2013). If ROS balance was altering oxidative capacity (Figure 6A) then mitochondrial function in the knockout cells should be particularly sensitive to antioxidants. In line with this idea, 1 hr preadministration of the potent ROS quencher N-acetyl-cysteine (NAC) reverted HO-1-deficient mitochondrial functional parameters to control levels (Figure 6E). Thus, HO-1 regulates acute ROS thresholding of mitochondrial respiration.

from the Discussion

Along similar lines, our data suggest a trigger-like role for HO-1 in metaflammation and insulin resistance and thus indicate high prognostic value for detecting disease onset. The observations are certainly generalizable, corroborated by multiple independent patient cohorts including human diabetes (Misu et al., 2010), generalized obesity (Qatanani et al., 2013), and obese monozygotic twins (Pietiläinen et al., 2008). These data and our own, show that liver and adipose HO-1 predict disease severity independently of age, sex, and degree of adiposity, and that they correlate specifically with pro- but not anti-inflammatory markers.

open access
Cell. 2014 Jul 3; 158(1): 25–40. doi: 10.1016/j.cell.2014.04.04​

 

[percyval577]

Mn makes phosphatase high, at least in rachitogenic diet which probably means VitD-deficient:

Interrelationship of Manganese Phospatase and Vitamin D in Bone Development
Combs et al 1942

Summary (my paragraph)

In rachitic chicks it was found that the bone phosphatase is increased to an abnormally high level the same as in the rachitic rat. By omitting manganese from the rachitogenic diet, the bone phosphatase was decreased to approximately the normal amount.

The difference in the phosphatase levels in the bones of groups of chicks fed rachitogenic diets, with and without an adequate quantity of manganese, was found to be much greater than the difference in the phosphatase levels in the bones of groups of chicks fed a non-rachitogenic diet, with and without an adequate quantity of manganese.

still paywalled
The Journal of Nutrition, Volume 23, Issue 2, February 1942, Pages 131-140, https://doi.org/10.1093/jn/23.2.131 ​

 

[percyval577]

Referring to the fist post (ZnT10 expression is dependent on ViD receptor):

The Physiological, Biochemical, And Molecular Roles of Zinc Transporters In Zinc Homeostasis And Metabolism
Kambe et al 2015

Figure 4.

I. ZnT10
ZnT10 is a zinc transporter localized to early/recycling endosomes or the Golgi apparatus (37, 312), which is altered to the plasma membrane at higher extracellular zinc concentrations (37). Expression of ZnT10 is downregulated by IL-6 (108) and is suggested to be under the control of ZTRE, as in ZnT5 (63). The downregulation of ZnT10 along with ZnT3 by angiotensin II may be associated with cellular senescence in vascular smooth muscle cells (312). Homozygous mutations of the ZnT10 gene cause Parkinsonism and dystonia with hypermanganesemia, polycythemia, and hepatic cirrhosis (OMIM 613280) (341, 417). In these patients, not zinc, but systemic and cellular manganese homeostasis was disturbed (341, 417), suggesting that the primary function of ZnT10 is manganese transport (see sect. IIIA). The ability of ZnT10 to transport manganese has been shown recently at the molecular level (237). ZnT10 mRNA expression is high in the liver and brain, which is consistent with high manganese accumulation in these tissues for patients with ZnT10 mutations (341, 417).

open access
01 JUL 2015https://doi.org/10.1152/physrev.00035.2014
​

The Functions of Metallothionein and ZIP and ZnT Transporters: An Overview and Perspective
Kimura et al 2016

open access
Int J Mol Sci. 2016 Mar; 17(3): 336. Published online 2016 Mar 4. doi: 10.3390/ijms17030336​

This would mean that Mn accumulates in the cell when the VitD Receptor is blocked. Therefore, if the triggers of ME/CFS had indeed such a VitaminD action (thread), too much Mn in the cell could be one consequence.

Interestingly, the Golgi Apparatus and Endosomes would lack Mn.

 

[Kadar]

Can this mean vitamin D depletes manganese and zinc?


P. S. : I found some info it says vitamin D does deplete manganese. SUPER INFO ABOUT MINERALS INTERACTION!

https://www.google.com/url?sa=t&sou...FjARegQICBAC&usg=AOvVaw2pdriPuolFTF9Nb7Zxxhtc