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Norlin, M. & Wikvall, K. (2023). Enzymatic activation in vitamin D signaling: Past, present and future. Archives of Biochemistry and Biophysics, 742, Article ID 109639.
Open this publication in new window or tab >>Enzymatic activation in vitamin D signaling: Past, present and future
2023 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 742, article id 109639Article, review/survey (Refereed) Published
Abstract [en]

Vitamin D signaling is important in regulating calcium homeostasis essential for bone health but also displays other functions in cells of several tissues. Disturbed vitamin D signaling is linked to a large number of diseases. The multiple cytochrome P450 (CYP) enzymes catalyzing the different hydroxylations in bioactivation of vitamin D3 are crucial for vitamin D signaling and function. This review is focused on the progress achieved in identification of the bioactivating enzymes and their genes in production of 1α,25-dihydroxyvitamin D3 and other active metabolites. Results obtained on species- and tissue-specific expression, catalytic reactions, substrate specificity, enzyme kinetics, and consequences of gene mutations are evaluated. Matters of incomplete understanding regarding the physiological roles of some vitamin D hydroxylases are critically discussed and the authors will give their view of the importance of each enzyme for vitamin D signaling. Roles of different vitamin D receptors and an alternative bioactivation pathway, leading to 20-hydroxylated vitamin D3 metabolites, are also discussed. Considerable progress has been achieved in knowledge of the vitamin D3 bioactivating enzymes. Nevertheless, several intriguing areas deserve further attention to understand the pleiotropic and diverse activities elicited by vitamin D signaling and the mechanisms of enzymatic activation necessary for vitamin D-induced responses.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Vitamin D bioactivation, Vitamin D hydroxylase, Cytochrome P450, CYP2R1, CYP27A1, CYP27B1
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-506600 (URN)10.1016/j.abb.2023.109639 (DOI)001002546600001 ()37196753 (PubMedID)
Available from: 2023-06-28 Created: 2023-06-28 Last updated: 2023-06-28Bibliographically approved
Raykova, D., Kermpatsou, D., Malmqvist, T., Harrison, P. J., Rubin Sander, M., Stiller, C., . . . Söderberg, O. (2022). A method for Boolean analysis of protein interactions at a molecular level. Nature Communications, 13(1), Article ID 4755.
Open this publication in new window or tab >>A method for Boolean analysis of protein interactions at a molecular level
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2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 4755Article in journal (Refereed) Published
Abstract [en]

Determination of interactions between native proteins in cells is important for understanding function. Here the authors report MolBoolean as a method to detect interactions between endogenous proteins in subcellular compartments, using antibody-DNA conjugates for identification and signal amplification. Determining the levels of protein-protein interactions is essential for the analysis of signaling within the cell, characterization of mutation effects, protein function and activation in health and disease, among others. Herein, we describe MolBoolean - a method to detect interactions between endogenous proteins in various subcellular compartments, utilizing antibody-DNA conjugates for identification and signal amplification. In contrast to proximity ligation assays, MolBoolean simultaneously indicates the relative abundances of protein A and B not interacting with each other, as well as the pool of A and B proteins that are proximal enough to be considered an AB complex. MolBoolean is applicable both in fixed cells and tissue sections. The specific and quantifiable data that the method generates provide opportunities for both diagnostic use and medical research.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-482674 (URN)10.1038/s41467-022-32395-w (DOI)000840338100011 ()35963857 (PubMedID)
Funder
Swedish Foundation for Strategic ResearchSwedish Cancer SocietySwedish Research Council
Note

Correction in: Nature Communications volume 14, Article number: 5450 (2023)

DOI: 10.1038/s41467-023-41325-3

Available from: 2022-09-20 Created: 2022-09-20 Last updated: 2023-10-24Bibliographically approved
Olsson, F., Sarri, N., Papadopoulos, N., Lennartsson, J. & Norlin, M. (2022). Effects of 1a,25-dihydroxyvitamin D-3 and tacalcitol on cell signaling and anchorage-independent growth in T98G and U251 glioblastoma cells. Biochemistry and Biophysics Reports, 31, Article ID 101313.
Open this publication in new window or tab >>Effects of 1a,25-dihydroxyvitamin D-3 and tacalcitol on cell signaling and anchorage-independent growth in T98G and U251 glioblastoma cells
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2022 (English)In: Biochemistry and Biophysics Reports, ISSN 2405-5808, Vol. 31, article id 101313Article in journal (Refereed) Published
Abstract [en]

The active hormonal form of vitamin D, 1 alpha,25-dihydroxyvitamin D-3, is reported to have 1000s of biological targets. The growth-suppressive properties of 1 alpha,25-dihydroxyvitamin D-3 and its synthetic analogs have attracted interest for the development of treatment and/or prevention of cancer. We examined effects of 1 alpha,25-dihydroxyvitamin D-3 and the vitamin D analog tacalcitol on signaling pathways and anchorage-independent growth in T98G and U251 glioblastoma cells. Assay of signaling proteins important for cellular growth indi-cated suppression of p70-S6 kinase levels by 1 alpha,25-dihydroxyvitamin D-3 and tacalcitol in T98G cells, whereas the levels of PLC gamma, a target for phospholipid signaling, was slightly increased. Activation of STAT3, an important regulator of malignancy, was suppressed by 1 alpha,25-dihydroxyvitamin D-3 and tacalcitol in T98G and U251 cells. However, despite the close structural similarity of these compounds, suppression was stronger by tacalcitol (1 alpha,24-dihydroxyvitamin D-3), indicating that even minor modifications of a vitamin D analog can impact its effects on signaling. Experiments using soft agar colony formation assay in T98G and U251 cells revealed significant suppression by 1 alpha,25-dihydroxyvitamin D-3 and tacalcitol on anchorage-independent growth, a property for cancer invasion and metastasis known to correlate with tumor-igenicity. These findings indicate that vitamin D and its analogs may be able to counteract the oncogenic transformation, invasion and metastatic potential of glioblastoma and prompt further study of these compounds in the development of improved therapy for brain cancer.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
1, 25-Dihydroxyvitamin D, Tacalcitol, Vitamin D analog, Glioblastoma, Cell signaling, Tumorigenicity
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-482668 (URN)10.1016/j.bbrep.2022.101313 (DOI)000838049200004 ()35935021 (PubMedID)
Funder
Swedish Cancer Society, 21 1427 Pj 01H
Available from: 2022-09-22 Created: 2022-09-22 Last updated: 2024-01-15Bibliographically approved
Rosén, J., Norlin, M., Stattin, K., Lipcsey, M., Frithiof, R., Malinovschi, A. & Hultström, M. (2021). ECG pathology and its association with death in critically ill COVID-19 patients, a cohort study.. PLOS ONE, 16(12), Article ID e0261315.
Open this publication in new window or tab >>ECG pathology and its association with death in critically ill COVID-19 patients, a cohort study.
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2021 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 12, article id e0261315Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We investigated the prevalence of ECG abnormalities and their association with mortality, organ dysfunction and cardiac biomarkers in a cohort of COVID-19 patients admitted to the intensive care unit (ICU).

METHODS: This cohort study included patients with COVID-19 admitted to the ICU of a tertiary hospital in Sweden. ECG, clinical data and laboratory findings during ICU stay were extracted from medical records and ECGs obtained near ICU admission were reviewed by two independent physicians.

RESULTS: Eighty patients had an acceptable ECG near ICU-admission. In the entire cohort 30-day mortality was 28%. Compared to patients with normal ECG, among whom 30-day mortality was 16%, patients with ECG fulfilling criteria for prior myocardial infarction had higher mortality, 63%, odds ratio (OR) 9.61 (95% confidence interval (CI) 2.02-55.6) adjusted for Simplified Acute Physiology Score 3 and patients with ST-T abnormalities had 50% mortality and OR 6.05 (95% CI 1.82-21.3) in univariable analysis. Both prior myocardial infarction pattern and ST-T pathology were associated with need for vasoactive treatment and higher peak plasma levels of troponin-I, NT-pro-BNP (N-terminal pro-Brain Natriuretic Peptide), and lactate during ICU stay compared to patients with normal ECG.

CONCLUSION: ECG with prior myocardial infarction pattern or acute ST-T pathology at ICU admission is associated with death, need for vasoactive treatment and higher levels of biomarkers of cardiac damage and strain in severely ill COVID-19 patients, and should alert clinicians to a poor prognosis.

Place, publisher, year, edition, pages
Public Library of Science (PLoS)Public Library of Science (PLoS), 2021
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:uu:diva-465663 (URN)10.1371/journal.pone.0261315 (DOI)000754615500034 ()34905575 (PubMedID)
Available from: 2022-01-19 Created: 2022-01-19 Last updated: 2024-01-15Bibliographically approved
Norlin, M. (2020). Effects of vitamin D in the nervous system: Special focus on interaction with steroid hormone signalling and a possible role in the treatment of brain cancer. Journal of neuroendocrinology, 32(1), Article ID e12799.
Open this publication in new window or tab >>Effects of vitamin D in the nervous system: Special focus on interaction with steroid hormone signalling and a possible role in the treatment of brain cancer
2020 (English)In: Journal of neuroendocrinology, ISSN 0953-8194, E-ISSN 1365-2826, Vol. 32, no 1, article id e12799Article, review/survey (Refereed) Published
Abstract [en]

The active vitamin D hormone, 1,25-dihydroxyvitamin D-3, exerts many physiological actions in the body, including effects on the nervous system. Studies of steroidogenesis in cells of the nervous system and elsewhere not only indicate that 1,25-dihydroxyvitamin D-3 affects steroidogenic pathways but also suggest varying responses in different cell types. For example, 1,25-dihydroxyvitamin D-3 stimulates the expression of aromatase in human glioma but not in human neuroblastoma cells or rat astrocytes. However, in astrocytes, 1,25-dihydroxyvitamin D-3 suppresses 3 beta-hydroxysteroid dehydrogenase and steroid 17-hydroxylase/lyase. Other studies indicate cross-talk between vitamin D signalling and signalling of oestrogens, progesterone or glucocorticoids. Reported data indicate synergistic effects of combinations of 1,25-dihydroxyvitamin D-3 and other steroid hormones on neuroinflammation, neurite outgrowth and neuroprotection. Also, dysregulation of steroid pathways affecting brain cells is found in vitamin D deficiency. Thus, several studies suggest that active vitamin D may affect steroid hormone synthesis and/or signalling in the nervous system, although the potential mechanisms for these responses remain unclear. 1,25-Dihydroxyvitamin D-3 suppresses proliferation in several cell types and is therefore of interest in cancer treatment. Also, epidemiological studies associate vitamin D levels with cancer risk or outcomes. Reported data on tumours of the nervous system are mainly on glioma, a common type of brain cancer. Expression of the vitamin D receptor in glioma tumours is associated with improved survival. Several studies show that 1,25-dihydroxyvitamin D-3 and vitamin D analogues (synthetic vitamin D-like compounds) suppress proliferation and migration in human vitamin D receptor-expressing glioma cell lines. Studies on mechanisms for actions of 1,25-dihydroxyvitamin D-3 or its analogues indicate regulation of cell cycle proteins and senescence markers. These compounds also show synergism in combination with other cancer therapies treating glioma. From the data available, vitamin D analogues emerge as interesting candidates for the future improved treatment of human glioma and possibly also other cancers of the nervous system.

Keywords
glioblastoma, growth, steroid hormone, steroidogenesis, vitamin D
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-409041 (URN)10.1111/jne.12799 (DOI)000491866400001 ()31593305 (PubMedID)
Available from: 2020-04-21 Created: 2020-04-21 Last updated: 2022-09-30Bibliographically approved
Zayny, A., Almokhtar, M., Wikvall, K., Ljunggren, Ö., Ubhayasekera, K., Bergquist, J., . . . Norlin, M. (2019). Effects of glucocorticoids on vitamin D3-metabolizing 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblasts. Molecular and Cellular Endocrinology, 496, Article ID 110525.
Open this publication in new window or tab >>Effects of glucocorticoids on vitamin D3-metabolizing 24-hydroxylase (CYP24A1) in Saos-2 cells and primary human osteoblasts
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2019 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 496, article id 110525Article in journal (Refereed) Published
Abstract [en]

Vitamin D is essential for bone function and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D-3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation which is essential for deactivation of the active vitamin form. However, bioactivating vitamin D-3 hydroxylase activities could not be detected in either of these cells. Several glucocorticoids, including prednisolone, down regulated CYP24A1 mRNA and CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts. Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. As part of this study we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our data showing suppression by glucocorticoids on CYP24A1 expression in human osteoblasts suggest a previously unknown mechanism for effects of glucocorticoids in human bone, where these compounds may interfere with regulation of active vitamin D levels.

Keywords
Vitamin D, Bone, Metabolism, Osteoblast, Osteosarcoma, Steroid
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-395784 (URN)10.1016/j.mce.2019.110525 (DOI)000487328200005 ()31352041 (PubMedID)
Funder
Swedish Research Council, 2015-4870
Available from: 2019-10-28 Created: 2019-10-28 Last updated: 2019-10-28Bibliographically approved
Emanuelsson, I., Almokhtar, M., Wikvall, K., Gröndbladh, A., Nylander, E., Svensson, A.-L., . . . Norlin, M. (2018). Expression and regulation of CYP17A1 and 3β-hydroxysteroid dehydrogenase in cells of the nervous system: potential effects of vitamin D on brain steroidogenesis. Neurochemistry International, 113, 46-55
Open this publication in new window or tab >>Expression and regulation of CYP17A1 and 3β-hydroxysteroid dehydrogenase in cells of the nervous system: potential effects of vitamin D on brain steroidogenesis
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2018 (English)In: Neurochemistry International, ISSN 0197-0186, E-ISSN 1872-9754, Vol. 113, p. 46-55Article in journal (Refereed) Published
Abstract [en]

Steroids are reported to have diverse functions in the nervous system. Enzymatic production of steroid hormones has been reported in different cell types, including astrocytes and neurons. However, the information on some of the steroidogenic enzymes involved is insufficient in many respects. Contradictory results have been reported concerning the relative importance of different cell types in the nervous system for expression of CYP17A1 and 3b-hydroxysteroid dehydrogenase (3b-HSD). 3b-HSD is important in all basic steroidogenic pathways and CYP17A1 is required to form sex hormones. In the current investigation we studied the expression of these enzymes in cultured primary rat astrocytes, in neuron-enriched cells from rat cerebral cortex and in human neuroblastoma SH-SY5Y cells, a cell line often used as an in vitro model of neuronal function and differentiation. As part of this study we also examined potential effects on CYP17A1 and 3b-HSD by vitamin D, a compound previously shown to have regulatory effects in steroid hormone-producing cells outside the brain. The results of our study indicate that astrocytes are a major site for expression of 3b-HSD whereas expression of CYP17A1 is found in both astrocytes and neurons. The current data suggest that neurons, contrary to some previous reports, are not involved in 3b-HSD reactions. Previous studies have shown that vitamin D can influence gene expression and hormone production by steroidogenic enzymes in some cells. We found that vitamin D suppressed CYP17A1-mediated activity by 20% in SH-SY5Ycells and astrocytes. Suppression of CYP17A1 mRNA levels was considerably stronger, about 50% in SH-SY5Y cells and 75% in astrocytes. In astrocytes 3b-HSD was also suppressed by vitamin D, about 20% at the enzyme activity level and 60% at the mRNA level. These data suggest that vitamin D-mediated regulation of CYP17A1 and 3b-HSD, particularly on the transcriptional level, may play a role in the nervous system.

Keywords
vitamin D, brain, metabolism, neurons, astrocytes, neurosteroids
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-333916 (URN)10.1016/j.neuint.2017.11.007 (DOI)000428495900005 ()29162485 (PubMedID)
Available from: 2017-11-18 Created: 2017-11-18 Last updated: 2020-02-17Bibliographically approved
Emanuelsson, I., Wikvall, K., Friman, T. & Norlin, M. (2018). Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells. Neuroscience
Open this publication in new window or tab >>Vitamin D Analogues Tacalcitol and Calcipotriol Inhibit Proliferation and Migration of T98G Human Glioblastoma Cells
2018 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544Article in journal (Refereed) Published
Abstract [en]

The active form of vitamin D (1,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. This receptor is expressed in most cell types including cells in the central nervous system (CNS). Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G. Glioblastoma is the most lethal type of primary tumours in the CNS. Both analogues decreased cell viability and/or growth, dose-dependently, in concentrations between 1 nM and 10 M. Manual counting indicated suppressive effects by the vitamin D analogues on proliferation. Treatment with tacalcitol strongly suppressed thymidine incorporation, indicating that the vitamin D analogues mainly inhibit proliferation. Also, effects on cell migration were measured with wound-healing assay. Both calcipotriol and tacalcitol reduced the migration rate of T98G cells compared to vehicle-treated cells. However, they had no effect on caspase-3 and -7 activities, suggesting that their mechanism of action does not involve induction of apoptosis. The current results indicate that the vitamin D analogues tacalcitol and calcipotriol strongly reduce proliferation and migration of human glioblastoma T98G cells, suggesting a potential role for this type of compounds in treatment of brain cancer.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-328769 (URN)10.1111/bcpt.13007 (DOI)000438196400004 ()29575677 (PubMedID)
Available from: 2017-08-31 Created: 2017-08-31 Last updated: 2023-11-01Bibliographically approved
Norlin, M., Lundqvist, J., Ellfolk, M., Hellström Pigg, M., Gustafsson, J. & Wikvall, K. (2017). Drug-mediated gene regulation of vitamin D3 metabolism in primary human dermal fibroblasts. Basic & Clinical Pharmacology & Toxicology, 120(1), 59-63
Open this publication in new window or tab >>Drug-mediated gene regulation of vitamin D3 metabolism in primary human dermal fibroblasts
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2017 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 120, no 1, p. 59-63Article in journal (Refereed) Published
Abstract [en]

Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug-mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25-hydroxyvitamin D3 and 1a,25-dihydroxyvitamin D3. The results demonstrate that primary dermal fibroblasts have an active vitamin D3 metabolising system. High incidence of low bone mineral density is a concern for HIV-infected patients treated with antiretroviral drugs. Osteomalacia and severe vitamin D deficiency have been reported. We investigated whether drug-mediated gene regulation could be a possible mechanism behind these adverse drug effects. Fibroblasts were treated with different drugs used in HIV therapy and the 1a,25-dihydroxyvitamin D3 levels and relative mRNA-levels for crucial enzymes were determined. Efavirenz, stavudine and ritonavir significantly downregulated the bioactivating CYP2R1 and upregulated the catabolic CYP24A1. The drugs reduced bioactivating enzyme activities and cellular levels of 1a,25-dihydroxyvitamin D3. The current results indicate that effects on gene expression may lead to disturbed vitamin D-metabolism and decreased cellular levels of active vitamin D3. The data are consistent with the impaired bone health in patients treated with certain antiretroviral drugs.

National Category
Basic Medicine
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-319044 (URN)10.1111/bcpt.12641 (DOI)000394527200009 ()27404500 (PubMedID)
Available from: 2017-03-30 Created: 2017-03-30 Last updated: 2018-01-13Bibliographically approved
Almokhtar, M., Wikvall, K., Ubhayasekera, S. J., Bergquist, J. & Norlin, M. (2016). Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.. Journal of Steroid Biochemistry and Molecular Biology, 158, 178-188
Open this publication in new window or tab >>Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.
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2016 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 158, p. 178-188Article in journal (Refereed) Published
Abstract [en]

Vitamin D-3 is a pro-hormone, which is sequentially activated by 25- and 1 alpha-hydroxylation to form 25-hydroxyvitamin D-3 [25(OH)D-3] and 1 alpha,25-dihydroxyvitamin D-3 [1 alpha,25(OH)2D(3)], respectively. Subsequent inactivation is performed by 24-hydroxylation. These reactions are carried out by a series of CYP450 enzymes. The 25-hydroxylation involves mainly CYP2R1 and CYP27A1, whereas 1 alpha-hydroxylation and 24-hydroxylation are catalyzed by CYP27B1 and CYP24A1, respectively, and are tightly regulated to maintain adequate levels of the active vitamin D hormone, 1 alpha,25(OH)(2)D-3. Altered circulating vitamin D levels, in particular 25(OH)D-3, have been linked to several disorders of the nervous system, e.g., schizophrenia and Parkinson disease. However, little is known about the mechanisms of vitamin D actions in the neurons. In this study, we examined vitamin D metabolism and its regulation in a murine motor neuron-like hybrid cell line, NSC-34. We found that these cells express mRNAs for the four major CYP450 enzymes involved in vitamin D activation and inactivation, and vitamin D receptor (VDR) that mediates vitamin D actions. We also found high levels of CYP24A1-dependent 24,25-dihydroxyvitamin D-3 [24,25(OH)(2)D-3] production, that was inhibited by the well-known CYP enzyme inhibitor ketoconazole and by several inhibitors that are more specific for CYP24A1. Furthermore, CYP24A1 mRNA levels in NSC-34 cells were up-regulated by 1 alpha,25(OH)(2)D-3 and its synthetic analogs, EB1089 and tacalcitol. Our results suggest that NSC-34 cells could be a novel model for the studies of neuronal vitamin D metabolism and its mechanism of actions.

National Category
Chemical Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-271604 (URN)10.1016/j.jsbmb.2015.12.010 (DOI)000372690200018 ()26704532 (PubMedID)
Funder
Swedish Research Council, 621-2008-3562, 621-2011-4423
Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2017-12-01Bibliographically approved
Projects
CYP7B1, a multifunctional enzyme that affects cellular steroid levels: physiological roles in endocrine signalling, cellular growth and neurosteroid metabolism [2008-02661_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4348-6269

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