Sterol regulatory element binding protein 1 trans-activates 25-hydroxy vitamin D3 24-hydroxylase gene expression in renal proximal tubular cells
- Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, University of Tokushima, Tokushima, 770-8503 (Japan)
- Department of Nutrition and Metabolism, Institute of Biomedical Sciences, University of Tokushima, Tokushima, 770-8503 (Japan)
- Division of Functional Food Chemistry, Institute for Health Science, Tokushima Bunri University, Tokushima, 770-8514 (Japan)
Highlights: • SREBP1 activates CYP24A1 transcription in a kidney proximal tubule cell line. • SREBP1 binds to a putative SRE in mouse Cyp24a1 to activate transcription. • Mice injected with thyroid hormone T{sub 3} had reduced renal Srebp1c and Cyp24a1 levels. • SREBP1 trans-activation of CYP24A1 expression could regulate vitamin D{sub 3} levels. The physiological activity of the steroid derived hormone vitamin D is regulated by several enzymatic steps. Both 25-hydroxy vitamin D{sub 3} 1α-hydroxylase (CYP27B1) and 25-hydroxyvitamin D{sub 3} 24-hydroxylase (CYP24A1) modulate blood levels of 1,25-dihydroxyvitamin D{sub 3}, an activated form of vitamin D. We previously demonstrated that CYP27B1 expression was trans-activated by sterol regulatory element binding protein 1 (SREBP1), although whether SREBP1 also regulates CYP24A1 transcription was unclear. Here we investigated the ability of SREBP1 to affect CYP24A1 transcription. In a luciferase reporter assay, mouse and human CYP24A1 promoter activity was strongly activated by SREBP1 in opossum kidney proximal tubular cells (OK-P). Three putative SREs (pSREs) were found in the mouse Cyp24a1 gene promoter and the SREBP1 protein showed specific binding to the pSRE1 element in EMSAs. Site-directed mutagenesis of the pSRE1 element strongly decreased SREBP1-mediated Cyp24a1 gene transcription. Moreover, siRNA-mediated SREBP1 knock-down repressed CYP24A1 expression in human renal proximal tubular epithelial cells (HKC-8). In animal studies, mice given various doses of thyroid hormone (T{sub 3}) showed dose-dependent reductions in renal Srebp1c and Cyp24a1 mRNA levels. Taken together, our results suggest that SREBP1 trans-activates CYP24A1 expression through SREBP binding elements present in the promoter.
- OSTI ID:
- 23125214
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 500, Issue 2; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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