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Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
Vise andre og tillknytning
2016 (engelsk)Inngår i: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 158, s. 178-188Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2016. Vol. 158, s. 178-188
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-271604DOI: 10.1016/j.jsbmb.2015.12.010ISI: 000372690200018PubMedID: 26704532OAI: oai:DiVA.org:uu-271604DiVA, id: diva2:892719
Forskningsfinansiär
Swedish Research Council, 621-2008-3562, 621-2011-4423Tilgjengelig fra: 2016-01-11 Laget: 2016-01-11 Sist oppdatert: 2017-12-01bibliografisk kontrollert
Inngår i avhandling
1. Expression and regulation of steroid metabolizing enzymes in cells of the nervous and skeletal systems: Special focus on vitamin D metabolism
Åpne denne publikasjonen i ny fane eller vindu >>Expression and regulation of steroid metabolizing enzymes in cells of the nervous and skeletal systems: Special focus on vitamin D metabolism
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Little is known about the mechanisms of vitamin D actions in the brain and bone. In this study, the metabolism of vitamin D and its regulation in various cell cultures of the nervous and skeletal systems were examined.

Human osteosarcoma Saos-2 cells, human primary osteoblasts (hOB) and murine motor neuron-like NSC-34 cells were found to express mRNA for all enzymes required in vitamin D3 metabolism as well as the vitamin D receptor (VDR) that mediates vitamin D actions. Also, production of 24,25-dihydroxyvitamin D3 was found in these cells. Studies on vitamin D metabolism in NSC-34 cells and in primary neuron-enriched cells from rat cerebral cortex indicate formation of a previously unknown major metabolite formed from 25-hydroxyvitamin D3. Evaluation of the NSC-34 cells suggests that this cell line could be a novel model for studies of neuronal vitamin D metabolism and its regulation by endogenous and exogenous compounds.

Treatment with glucocorticoids down regulated mRNA expression for the CYP24A1 gene in Saos-2 and hOB cells. Additionally, the glucocorticoid prednisolone showed suppression of CYP24A1-mediated metabolism and CYP24A1 promoter activity in Saos-2 cells. In NSC-34 cells, CYP24A1 mRNA levels were up-regulated by prednisolone, 1α,25-dihydroxyvitamin D3 and its synthetic analogues, EB1089 and tacalcitol. Formation of an endogenous glucocorticoid, 11-deoxycortisol, was observed in Saos-2 cells. Effects of glucocorticoids on the vitamin D system in bone cells may contribute to the adverse side effects in long-term treatment with glucocorticoids. Also, there may be a correlation between the administration of corticosteroids and adverse effects in the CNS.

Expression and effects of vitamin D on steroidogenic enzymes were studied in primary neuron-enriched rat cortex cells, primary rat astrocytes and human neuroblastoma SH-SY5Y cells. These different cell cultures all expressed CYP17A1, whereas only astrocytes expressed 3β-hydroxysteroid dehydrogenase (3β-HSD). 1α,25-Dihydroxyvitamin D3 suppressed mRNA levels and enzyme activity of CYP17A1 in SH-SY5Y cells and astrocytes. 1α,25-Dihydroxyvitamin D3 suppressed enzyme activity and mRNA levels of 3β-HSD in astrocytes. The results suggest that vitamin D-mediated regulation of CYP17A1 and 3β-HSD may play a role in the nervous system.

The results presented here contribute to our understanding of vitamin D metabolism and effects of glucocorticoids in the brain and bone.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 58
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 242
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-333920 (URN)978-91-513-0154-9 (ISBN)
Disputas
2018-01-18, B7:101a, BMC, Husargatan 3, Uppsala, 13:15 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2017-12-21 Laget: 2017-11-19 Sist oppdatert: 2018-03-08

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