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home:pathogenesis:vitamind:metabolism [01.01.2019] – [Metabolism of vitamin D and the Vitamin D Receptor] sallieq | home:pathogenesis:vitamind:metabolism [09.14.2022] (current) – external edit 127.0.0.1 | ||
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- | According to a 2010 analysis, the VDR significantly affects 229 human genes. Many of these genes have long been associated with autoimmune diseases and cancers including, for example, the genes IRF8 (linked to multiple sclerosis), and PTPN2 (connected to Crohn' | + | According to a 2010 analysis, the VDR significantly affects 229 human genes. Many of these genes have long been associated with autoimmune diseases and cancers including, for example, the genes IRF8 (linked to multiple sclerosis), and PTPN2 (connected to Crohn' |
However, bacteria create ligands, which like 25-D, inactivate the VDR and, in turn, the innate immune response. This allows the microbes to proliferate. In response, the body increases production of 1,25-D from 25-D, leading to one of the hallmarks of chronic inflammatory disease: a low 25-D and a high 1, | However, bacteria create ligands, which like 25-D, inactivate the VDR and, in turn, the innate immune response. This allows the microbes to proliferate. In response, the body increases production of 1,25-D from 25-D, leading to one of the hallmarks of chronic inflammatory disease: a low 25-D and a high 1, | ||
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- | A general appreciation for how 25-D and 1,25-D compete for nuclear receptors gets to the heart of their opposing roles in the body. According to the Marshall Pathogenesis, | + | A general appreciation for how 25-D and 1,25-D compete for nuclear receptors gets to the heart of their opposing roles in the body. According to the Marshall Pathogenesis, |
- | Further underscoring this role for these two D metabolites is that 25-D and 1,25-D " | + | Further underscoring this role for these two D metabolites is that 25-D and 1,25-D " |
As mentioned before, exposure to injury and infection enhances production of 1,25-D, which in turn leads to the creation of antimicrobial peptides and activation of TLR2. | As mentioned before, exposure to injury and infection enhances production of 1,25-D, which in turn leads to the creation of antimicrobial peptides and activation of TLR2. | ||
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However, certain feedback mechanisms are also in place, which allow the body to limit the production of 1,25-D to just that amount needed for proper transcriptional activation of the VDR. | However, certain feedback mechanisms are also in place, which allow the body to limit the production of 1,25-D to just that amount needed for proper transcriptional activation of the VDR. | ||
* When the VDR is activated, it transcribes the gene for the enzyme CYP24A1, which increases conversion of 1,25-D into inactive metabolites. | * When the VDR is activated, it transcribes the gene for the enzyme CYP24A1, which increases conversion of 1,25-D into inactive metabolites. | ||
- | * An activated VDR also controls 1,25-D concentration by limiting transcription of the gene CYP27B1, which converts 25-D into 1,25-D.(({{pubmed> | + | * An activated VDR also controls 1,25-D concentration by limiting transcription of the gene CYP27B1, which converts 25-D into 1,25-D.(({{pmid> |
===== Bacteria and the VDR ===== | ===== Bacteria and the VDR ===== | ||
- | The [[http:// | + | The [[https:// |
Pathogenic bacteria are likewise driven by evolutionary impetus: it's in their interest to disrupt the proteins, which interfere with their growth. | Pathogenic bacteria are likewise driven by evolutionary impetus: it's in their interest to disrupt the proteins, which interfere with their growth. | ||
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< | < | ||
- | //**Michael Zasloff**// (({{pubmed> | + | //**Michael Zasloff**// (({{pmid> |
However, what if it were possible to disrupt the expression of the Vitamin D Receptor by secreting ligands, which bind to and inactivate the receptor? Such bacteria would have an undeniable reproductive advantage. | However, what if it were possible to disrupt the expression of the Vitamin D Receptor by secreting ligands, which bind to and inactivate the receptor? Such bacteria would have an undeniable reproductive advantage. | ||
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[{{ : | [{{ : | ||
- | In the arms race of host–microbe co-evolution, | + | In the arms race of host–microbe co-evolution, |
< | < | ||
- | //**Jun Sun**// (({{pubmed> | + | //**Jun Sun**// (({{pmid> |
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In keeping with evolutionary theory, a growing number of substances and species have been shown to downregulate the activity of the VDR: | In keeping with evolutionary theory, a growing number of substances and species have been shown to downregulate the activity of the VDR: | ||
- | * **// | + | * **// |
- | * **// | + | * **// |
- | * Mycobacterium tuberculosis enzyme involved in vitamin D and 7-dehydrocholesterol metabolism (({{pubmed> | + | * Mycobacterium tuberculosis enzyme involved in vitamin D and 7-dehydrocholesterol metabolism (({{pmid> |
- | * **// | + | * **// |
- | * **" | + | * **" |
* **// | * **// | ||
The following substances reduce the number of VDR, without which immune function is limited: | The following substances reduce the number of VDR, without which immune function is limited: | ||
- | * **Caspase-3** – A protein which cleaves (breaks apart) the VDR structure and thus limits the ability of VDR to perform gene transcription.(({{pubmed> | + | * **Caspase-3** – A protein which cleaves (breaks apart) the VDR structure and thus limits the ability of VDR to perform gene transcription.(({{pmid> |
| | ||
According to the Marshall Pathogenesis, | According to the Marshall Pathogenesis, | ||
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One can see the effects of a dysfunctional VDR in knockout mice, mice genetically engineered to be born without the receptor. These mice demonstrate what it is like to have a VDR completely blocked by bacterial ligands. | One can see the effects of a dysfunctional VDR in knockout mice, mice genetically engineered to be born without the receptor. These mice demonstrate what it is like to have a VDR completely blocked by bacterial ligands. | ||
- | Mice without a VDR have been shown in separate studies to be born with alopecia, an inflammatory condition in which organisms have no hair(({{pubmed> | + | Mice without a VDR have been shown in separate studies to be born with alopecia, an inflammatory condition in which organisms have no hair(({{pmid> |
- | Further validating the Marshall Pathogenesis model is this: other research in VDR knockout mice has shown a marked increase, by a factor of ten, in serum 1,25-D and a clear reduction - to almost undetectable levels - in serum 25-D. Such levels persisted at seven weeks until the mice eventually died.(({{pubmed> | + | Further validating the Marshall Pathogenesis model is this: other research in VDR knockout mice has shown a marked increase, by a factor of ten, in serum 1,25-D and a clear reduction - to almost undetectable levels - in serum 25-D. Such levels persisted at seven weeks until the mice eventually died.(({{pmid> |
==== Mechanisms by which bacteria affect levels of 25-D and 1,25-D ==== | ==== Mechanisms by which bacteria affect levels of 25-D and 1,25-D ==== | ||
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===== Viruses and fungi also affect the VDR ===== | ===== Viruses and fungi also affect the VDR ===== | ||
- | * **Epstein-Barr virus (EBV)** – shown to downregulate expression of the VDR (and by the VDR) by a factor of about five, inducing " | + | * **Epstein-Barr virus (EBV)** – shown to downregulate expression of the VDR (and by the VDR) by a factor of about five, inducing " |
- | * **HIV** – binds to the VDR(({{pubmed> | + | * **HIV** – binds to the VDR(({{pmid> |
- | * **// | + | * **// |
- | * **Cytomegalovirus** – Cytomegalovirus affects hundreds of genes including downregulating the VDR 2.2 fold.(({{pubmed> | + | * **Cytomegalovirus** – Cytomegalovirus affects hundreds of genes including downregulating the VDR 2.2 fold.(({{pmid> |
- | * **Hepatitis C virus** – Gal-Tanamy //et al.// showed that HCV infections interfere with the VDR by inhibiting the creation of CYP24A1, the enzyme responsible for breaking down excess 1,25-D.(({{pubmed> | + | * **Hepatitis C virus** – Gal-Tanamy //et al.// showed that HCV infections interfere with the VDR by inhibiting the creation of CYP24A1, the enzyme responsible for breaking down excess 1,25-D.(({{pmid> |
===== Evidence for high 1,25-D in patients with chronic disease ===== | ===== Evidence for high 1,25-D in patients with chronic disease ===== | ||
- | Under most normal conditions, | + | Under most normal conditions, |
==== At the site of infection ==== | ==== At the site of infection ==== | ||
- | It is sometimes thought that the liver and kidney are the only sites for conversion of 25-D into 1,25-D, but there is evidence that this process happens outside those organs – not coincidentally, | + | It is sometimes thought that the liver and kidney are the only sites for conversion of 25-D into 1,25-D, but there is evidence that this process happens outside those organs – not coincidentally, |
- | * **skin cells of sarcoidosis patients** – Sarcoidosis patients have a variety of skin symptoms including bumps, ulcers, or discolored skin. Zehnder //et al// found increased expression of the enzyme 1 α-hydroxylase – the enzyme which converts 25-D into 1,25-D – in the skin cells of sarcoidosis patients.(({{pubmed> | + | * **skin cells of sarcoidosis patients** – Sarcoidosis patients have a variety of skin symptoms including bumps, ulcers, or discolored skin. Zehnder //et al// found increased expression of the enzyme 1 α-hydroxylase – the enzyme which converts 25-D into 1,25-D – in the skin cells of sarcoidosis patients.(({{pmid> |
< | < | ||
- | * **synovial fluid surrounding the joints of patients with rheumatoid arthritis** – Mawer //et al// found that 1,25-D levels were particularly elevated in the synovial fluid surrounding the joints of patients with rheumatoid arthritis (RA).(({{pubmed> | + | * **synovial fluid surrounding the joints of patients with rheumatoid arthritis** – Mawer //et al// found that 1,25-D levels were particularly elevated in the synovial fluid surrounding the joints of patients with rheumatoid arthritis (RA).(({{pmid> |
- | * **immune cells including macrophages** – Research has also shown that 1,25-D is synthesized in cells of the immune system, including the T cells and antigen-presenting cells(({{pubmed> | + | * **immune cells including macrophages** – Research has also shown that 1,25-D is synthesized in cells of the immune system, including the T cells and antigen-presenting cells(({{pmid> |
< | < | ||
- | // | + | // |
- | * **respiratory epithelial cells** – The primary lung epithelial cells, which play an important role in the defense against airborne pathogens, have been shown to express high baseline levels of activating 1 α-hydroxylase and low levels of inactivating 24-hydroxylase. This activity leads to increased expression of genes by the Vitamin D Receptor.(({{pubmed> | + | * **respiratory epithelial cells** – The primary lung epithelial cells, which play an important role in the defense against airborne pathogens, have been shown to express high baseline levels of activating 1 α-hydroxylase and low levels of inactivating 24-hydroxylase. This activity leads to increased expression of genes by the Vitamin D Receptor.(({{pmid> |
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A number of studies have demonstrated that the level of the hormone 1,25-D rises in patients with certain chronic diseases. | A number of studies have demonstrated that the level of the hormone 1,25-D rises in patients with certain chronic diseases. | ||
- | * **autoimmune disease** – Greg Blaney MD, a physician who practices in Vancouver, British Columbia (a setting with relatively infrequent sunlight), found that of a group of 100 patients with a variety of chronic inflammatory diseases, 85 had elevated measures of 1,25-D, which was defined as greater than or equal to 110 pmol/L.(({{pubmed> | + | * **autoimmune disease** – Greg Blaney MD, a physician who practices in Vancouver, British Columbia (a setting with relatively infrequent sunlight), found that of a group of 100 patients with a variety of chronic inflammatory diseases, 85 had elevated measures of 1,25-D, which was defined as greater than or equal to 110 pmol/L.(({{pmid> |
- | * **Crohn' | + | * **Crohn' |
- | * **obesity** – Moan //et al.// showed that, in contrast to healthy people, patients with a high body mass index (BMI) had a significant seasonal variation in, not only 25(OH) vitamin D, but also of 1,25-D.(({{pubmed> | + | * **obesity** – Moan //et al.// showed that, in contrast to healthy people, patients with a high body mass index (BMI) had a significant seasonal variation in, not only 25(OH) vitamin D, but also of 1,25-D.(({{pmid> |
- | * **sarcoidosis** – Kavathia //et al// found that in patients with sarcoidosis, | + | * **sarcoidosis** – Kavathia //et al// found that in patients with sarcoidosis, |
- | * **asthma** – Liu //et al.// showed that levels of vitamin D metabolites, | + | * **asthma** – Liu //et al.// showed that levels of vitamin D metabolites, |
- | Bell listed the following diseases and conditions, which manifest with high levels of 1, | + | Bell listed the following diseases and conditions, which manifest with high levels of 1, |
===== Effect of high 1,25-D on nuclear receptors ===== | ===== Effect of high 1,25-D on nuclear receptors ===== | ||
< | < | ||
- | //**Saveria Aquila** et al.//(({{pubmed> | + | //**Saveria Aquila** et al.//(({{pmid> |
</ | </ | ||
- | At normal levels, the active vitamin D metabolite, 1,25-D, serves an important role in host defense, | + | At normal levels, the active vitamin D metabolite, 1,25-D, serves an important role in host defense, |
- | Molecular modeling data show that at high levels, 1,25-D not only binds the VDR but also has a strong affinity for other key receptors that control the body's major hormonal systems including those that regulate the body's sex, thyroid, and adrenal hormones. | + | Molecular modeling data show that at high levels, 1,25-D not only binds the VDR but also has a strong affinity for other key receptors that control the body's major hormonal systems including those that regulate the body's sex, thyroid, and adrenal hormones. |
- | Molecular research also shows that, like the VDR, several of these nuclear receptors (including the alpha/beta thyroid receptors, glucocorticoid receptor, and androgen receptor) also express many families of antimicrobial peptides. A recent analysis of AmP expression by Brahmachary showed that the glucocorticoid receptor, the androgen receptor, and the Vitamin D Receptor, seem to be in control of 20, 17 and 16 families respectively, | + | Molecular research also shows that, like the VDR, several of these nuclear receptors (including the alpha/beta thyroid receptors, glucocorticoid receptor, and androgen receptor) also express many families of antimicrobial peptides. A recent analysis of AmP expression by Brahmachary showed that the glucocorticoid receptor, the androgen receptor, and the Vitamin D Receptor, seem to be in control of 20, 17 and 16 families respectively, |
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- | [{{ : | + | [{{ : |
===== End-stage disease ===== | ===== End-stage disease ===== | ||
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- | As patients become sicker, their immune system becomes increasingly unable to mount a defense against infection. For example, Kanchwala //et al.// showed that patients with sarcoidosis expressed the antimicrobial peptide cathelicidin less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all.((Kanchwala, | + | As patients become sicker, their immune system becomes increasingly unable to mount a defense against infection. For example, Kanchwala //et al.// showed that patients with sarcoidosis expressed the antimicrobial peptide cathelicidin less than healthy subjects, and that sicker sarcoidosis patients expressed it least of all.((Kanchwala, |
One of the hallmarks of late-stage inflammatory diseases is a very low 1,25-D with HIV/AIDS being the most commonly cited example. | One of the hallmarks of late-stage inflammatory diseases is a very low 1,25-D with HIV/AIDS being the most commonly cited example. | ||
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HIV is a viral infection, and AIDS is the syndrome, which results – according to the Marshall Pathogenesis – in a dysregulated vitamin D metabolism. As evidenced by the subset of people who survive for decades with HIV, the virus itself is not necessarily deadly. Instead, it is the co-infections which are the proximate cause of the disease. One can define the breadth of AIDS-related complications by the extent and number of co-infections such as pneumonia, herpes, // | HIV is a viral infection, and AIDS is the syndrome, which results – according to the Marshall Pathogenesis – in a dysregulated vitamin D metabolism. As evidenced by the subset of people who survive for decades with HIV, the virus itself is not necessarily deadly. Instead, it is the co-infections which are the proximate cause of the disease. One can define the breadth of AIDS-related complications by the extent and number of co-infections such as pneumonia, herpes, // | ||
- | Supporting this hypothesis, a number of terminal AIDS patients have neglible levels of 1,25-D. 18 of 29 patients in a study of AIDS patients had undetectable levels of the metabolite.(({{pubmed> | + | Supporting this hypothesis, a number of terminal AIDS patients have neglible levels of 1,25-D. 18 of 29 patients in a study of AIDS patients had undetectable levels of the metabolite.(({{pmid> |
The exact mechanism by which 1,25-D is downregulated is not entirely known, but it is highly likely that it is caused by pathogens. | The exact mechanism by which 1,25-D is downregulated is not entirely known, but it is highly likely that it is caused by pathogens. | ||
- | Haug //et al// theorized that TNF-alpha and possibly other cytokines – which pathogens are known to create(({{pubmed> | + | Haug //et al// theorized that TNF-alpha and possibly other cytokines – which pathogens are known to create(({{pmid> |
- | A second factor is that HIV disables D-Binding protein (DBP).(({{pubmed> | + | A second factor is that HIV disables D-Binding protein (DBP).(({{pmid> |
==== Cancer ==== | ==== Cancer ==== | ||
< | < | ||
- | Higher levels of CYP24A1, the enzyme which breaks down excess 1,25-D, is associated with poorer survival in lung adenocarcinoma. In a 2011 study, CYP24A1 mRNA was elevated 8-50 fold in lung cancer (compared to normal non-cancerous lung) and significantly higher in less severe cancers.(({{pubmed> | + | Higher levels of CYP24A1, the enzyme which breaks down excess 1,25-D, is associated with poorer survival in lung adenocarcinoma. In a 2011 study, CYP24A1 mRNA was elevated 8-50 fold in lung cancer (compared to normal non-cancerous lung) and significantly higher in less severe cancers.(({{pmid> |
Lopes //et al.// showed that CYP24A1 expression was increased in metastatic breast cancer: 53.7% in invasive carcinomas compared to 19.0% of benign lesions. | Lopes //et al.// showed that CYP24A1 expression was increased in metastatic breast cancer: 53.7% in invasive carcinomas compared to 19.0% of benign lesions. | ||
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< | < | ||
- | //**N. Lopes**, | + | //**N. Lopes**, |
===== Related publications and presentations ===== | ===== Related publications and presentations ===== | ||
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{{tag> | {{tag> | ||
+ | < | ||
===== Notes and comments ===== | ===== Notes and comments ===== | ||
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Description of Jun Sun's work: | Description of Jun Sun's work: | ||
- | http:// | + | https:// |
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< | < | ||
- | Not sure where this should go. Here? Psoriasis? Innate immunity? | + | Not sure where this should go. Here? Psoriasis? Innate immunity? |
PLoS One. 2009 Jul 22; | PLoS One. 2009 Jul 22; | ||
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Peric M, Koglin S, Dombrowski Y, Gross K, Bradac E, Büchau A, Steinmeyer A, Zügel U, Ruzicka T, Schauber J. | Peric M, Koglin S, Dombrowski Y, Gross K, Bradac E, Büchau A, Steinmeyer A, Zügel U, Ruzicka T, Schauber J. | ||
- | Department of Dermatology and Allergology, | ||
- | Abstract | ||
- | Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory " | ||
PMID: 19623255 | PMID: 19623255 | ||
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For a very long time it has been known that EBV delays cell-death, an obvious way of allowing the microbiota to form stable communities within human cells. Here is a 1991 paper: | For a very long time it has been known that EBV delays cell-death, an obvious way of allowing the microbiota to form stable communities within human cells. Here is a 1991 paper: | ||
- | http:// | + | https:// |
Another early paper showed Sarcoidosis was also associated with reduced cell-death (I met one of the authors of this paper last week at the Microbiome conference, and he was surprised when I told him how important it had been in helping me formulate the early MP pathogenesis): | Another early paper showed Sarcoidosis was also associated with reduced cell-death (I met one of the authors of this paper last week at the Microbiome conference, and he was surprised when I told him how important it had been in helping me formulate the early MP pathogenesis): | ||
- | http:// | + | https:// |
Well, a new paper is out showing that EBV not only down-regulates expression of the VDR protein itself, but also acts to block transcription by the VDR: | Well, a new paper is out showing that EBV not only down-regulates expression of the VDR protein itself, but also acts to block transcription by the VDR: | ||
- | http:// | + | https:// |
Here are some of the key points from the fulltext of this paper: | Here are some of the key points from the fulltext of this paper: | ||
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PMID: 17113648 | PMID: 17113648 | ||
- | Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, | + | Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, |
+ | |||
+ | ===== References =====</ | ||
- | ===== References ===== |
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