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home:pathogenesis:vitamind:mechanisms [01.25.2019] – [Effects of VDR blockage on the PXR, a receptor which converts pre-vitamin D into 25-D] sallieqhome:pathogenesis:vitamind:mechanisms [09.14.2022] (current) – external edit 127.0.0.1
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 Given that the VDR is fundamentally a control system for the innate immune response, the body  upregulates the Receptor's activity by increasing concentrations of 1,25-D and downregulating concentrations of 25-D.  Given that the VDR is fundamentally a control system for the innate immune response, the body  upregulates the Receptor's activity by increasing concentrations of 1,25-D and downregulating concentrations of 25-D. 
  
-One such mechanism is the CYP27B1 pathway.(({{pubmed>long:17290304}})) When the immune system is challenged by pathogens, the body activates a protein called Protein Kinase A (PKA). PKA in turn activates CYP27B1, causing more 25-D to be converted to 1,25-D, which, of course, increases activity of the VDR.(({{pubmed>long:21124742}}))+One such mechanism is the CYP27B1 pathway.(({{pmid>long:17290304}})) When the immune system is challenged by pathogens, the body activates a protein called Protein Kinase A (PKA). PKA in turn activates CYP27B1, causing more 25-D to be converted to 1,25-D, which, of course, increases activity of the VDR.(({{pmid>long:21124742}}))
  
 <blockquote>1α-OHase [CYP27B1] expression is upregulated in macrophages in response to bacterial infection and that 1α-OHase at the site of infection provides 1,25(OH)(2)D(3) for local regulation of vitamin D responsive genes. <blockquote>1α-OHase [CYP27B1] expression is upregulated in macrophages in response to bacterial infection and that 1α-OHase at the site of infection provides 1,25(OH)(2)D(3) for local regulation of vitamin D responsive genes.
  
-**//C.D. Nelson//** (({{pubmed>long:21124742}}))</blockquote>+**//C.D. Nelson//** (({{pmid>long:21124742}}))</blockquote>
 ===== Elevated 1,25-D for extended periods implies a partially blocked VDR ===== ===== Elevated 1,25-D for extended periods implies a partially blocked VDR =====
  
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 ===== Effects of VDR blockage on CYP24A1, an enzyme regulating conversion of 25-D into 1,25-D ===== ===== Effects of VDR blockage on CYP24A1, an enzyme regulating conversion of 25-D into 1,25-D =====
  
-When active, the VDR transcribes CYP24A1 (sometimes referred to as CYP24), which regulates levels of 25-D and 1,25-D. CYP24A1 breaks down excess 1,25-D, ensuring that the level of 1,25-D in the body stays in the normal range.(({{pubmed>long:18200565}})) It is a sensible mechanism for controlling levels of the D metabolites. +When active, the VDR transcribes CYP24A1 (sometimes referred to as CYP24), which regulates levels of 25-D and 1,25-D. CYP24A1 breaks down excess 1,25-D, ensuring that the level of 1,25-D in the body stays in the normal range.(({{pmid>long:18200565}})) It is a sensible mechanism for controlling levels of the D metabolites. 
  
 <blockquote>[The production of CYP24A1] is the best documented of the feedback control systems used by the body to limit the concentration of 1,25-D to just that amount needed for proper transcription and activation of the VDR. <blockquote>[The production of CYP24A1] is the best documented of the feedback control systems used by the body to limit the concentration of 1,25-D to just that amount needed for proper transcription and activation of the VDR.
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 ===== Effects of VDR blockage on the PXR, a receptor which converts pre-vitamin D into 25-D ===== ===== Effects of VDR blockage on the PXR, a receptor which converts pre-vitamin D into 25-D =====
  
-When 1,25-D rises due to the processes described above, it also binds a receptor called the PXR. The PXR subsequently inhibits conversion of pre-vitamin D to 25-D, causing 25-D levels to drop via the CYP27A1 pathway.(({{pubmed>long:16207822}})) (({{pubmed>long:16691293}})) PXR has also been reported to competitively downregulate the VDR-induced expression of CYP24A1, which as we saw above, breaks down excess 1,25-D.+When 1,25-D rises due to the processes described above, it also binds a receptor called the PXR. The PXR subsequently inhibits conversion of pre-vitamin D to 25-D, causing 25-D levels to drop via the CYP27A1 pathway.(({{pmid>long:16207822}})) (({{pmid>long:16691293}})) PXR has also been reported to competitively downregulate the VDR-induced expression of CYP24A1, which as we saw above, breaks down excess 1,25-D.
  
 This mechanism works well when 1,25-D is within normal ranges. But when 1,25-D becomes extremely high, as in the case of chronic diseases, 25-D is downregulated to abnormally low levels, leading some observers to erroneously conclude that vitamin D deficiency causes disease. This mechanism works well when 1,25-D is within normal ranges. But when 1,25-D becomes extremely high, as in the case of chronic diseases, 25-D is downregulated to abnormally low levels, leading some observers to erroneously conclude that vitamin D deficiency causes disease.
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 ===== Recent research ===== ===== Recent research =====
  
-We evaluated whether the ability of M. leprae to induce type I IFN blocks the intrinsic activation of the vitamin D pathway, representing an escape mechanism by which the bacterium evades the host response.    (({{pubmed>long:000}})) +We evaluated whether the ability of M. leprae to induce type I IFN blocks the intrinsic activation of the vitamin D pathway, representing an escape mechanism by which the bacterium evades the host response.    (({{pmid>long:30300363}}))  
 + 
 + 
 +<blockquote>Vitamin D plays a crucial role in the regulation of genes central to protection against microbe invasion, such as the induction of the expression of antimicrobial peptides (also known as host defense peptides) such as CAMP and defensin. These peptides were demonstrated to disrupt the integrity of the microbe membrane, resulting in its death (Gombart, 2009). In addition, Vitamin D regulates the immune system by managing the expression of TNFα (Golovko et al., 2005), one of the most important pro-inflammatory and pro-immune cytokines. Therefore, downregulation of the vitamin D signaling pathway by viruses, can result in decreased production of antimicrobial peptides and cytokines and as a result, to attenuation of the immune response. Several studies have previously indicated that certain viruses can inhibit the Vitamin D signal transduction. 
 +</blockquote> Our in-vitro study showed that Vitamin D does not affect the rate of HBV replication, and downregulates VDR levels in the presence of the virus, thereby attenuating vitamin D signal transduction.   (({{pmid>long:30326825}})) 
 ===== Related publications and presentations ===== ===== Related publications and presentations =====
  
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 {{tag>pathogenesis Science_behind_vitamin_D}} {{tag>pathogenesis Science_behind_vitamin_D}}
 +<nodisp>
 ===== Notes and comments ===== ===== Notes and comments =====
 +
 +  (({{pmid>long:000}})) 
  
   * Legacy content   * Legacy content
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 The progressive decline in kidney function and concomitant loss of renal 1α-hydroxylase (CYP27B1) in chronic kidney disease (CKD) are associated with a gradual loss of circulating 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). However, only the decrease in 1α,25(OH)2D3 can be explained by the decline of CYP27B1, suggesting that insufficiency of both metabolites may reflect their accelerated degradation by the key catabolic enzyme 24-hydroxylase (CYP24). To determine whether CYP24 is involved in causing vitamin D insufficiency and/or resistance to vitamin D therapy in CKD, we determined the regulation of CYP24 and CYP27B1 in normal rats and rats treated with adenine to induce CKD. As expected, CYP24 decreased whereas CYP27B1 increased when normal animals were rendered vitamin D deficient. Unexpectedly, renal CYP24 mRNA and protein expression were markedly elevated, irrespective of the vitamin D status of the rats. A significant decrease in serum 1α,25(OH)2D3 levels was found in uremic rats; however, we did not find a coincident decline in CYP27B1. Analysis in human kidney biopsies confirmed the association of elevated CYP24 with kidney disease. Thus, our findings suggest that dysregulation of CYP24 may be a significant mechanism contributing to vitamin D insufficiency and resistance to vitamin D therapy in CKD.</blockquote> The progressive decline in kidney function and concomitant loss of renal 1α-hydroxylase (CYP27B1) in chronic kidney disease (CKD) are associated with a gradual loss of circulating 25-hydroxyvitamin D3 (25(OH)D3) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). However, only the decrease in 1α,25(OH)2D3 can be explained by the decline of CYP27B1, suggesting that insufficiency of both metabolites may reflect their accelerated degradation by the key catabolic enzyme 24-hydroxylase (CYP24). To determine whether CYP24 is involved in causing vitamin D insufficiency and/or resistance to vitamin D therapy in CKD, we determined the regulation of CYP24 and CYP27B1 in normal rats and rats treated with adenine to induce CKD. As expected, CYP24 decreased whereas CYP27B1 increased when normal animals were rendered vitamin D deficient. Unexpectedly, renal CYP24 mRNA and protein expression were markedly elevated, irrespective of the vitamin D status of the rats. A significant decrease in serum 1α,25(OH)2D3 levels was found in uremic rats; however, we did not find a coincident decline in CYP27B1. Analysis in human kidney biopsies confirmed the association of elevated CYP24 with kidney disease. Thus, our findings suggest that dysregulation of CYP24 may be a significant mechanism contributing to vitamin D insufficiency and resistance to vitamin D therapy in CKD.</blockquote>
  
-===== References =====+===== References =====</nodisp> 
home/pathogenesis/vitamind/mechanisms.1548459148.txt.gz · Last modified: 01.25.2019 by sallieq
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