Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes
| Autor: | Mahmoud-Sobhy Elkhwanky, Valtteri Rinne, Pirkko Viitala, Kari T. Chambers, Mikko Karpale, Maija Mutikainen, Jukka Hakkola, Marcin Buler, Rudolf J. Wiesner, Brian N. Finck, Sanna-Mari Aatsinki, Pasi Tavi, Outi Kummu, Andras Franko |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty fasting Endocrinology Diabetes and Metabolism PGC-1α 030209 endocrinology & metabolism vitamin D deficiency 03 medical and health sciences Mice 0302 clinical medicine Glucocorticoid receptor Receptors Glucocorticoid CYP24A1 Downregulation and upregulation vitamin D metabolism Internal medicine Coactivator Internal Medicine medicine Vitamin D and neurology Diabetes Mellitus Animals Vitamin D Receptor Psychological repression diabetes Chemistry Fasting medicine.disease Vitamin D Deficiency 25-hydroxyvitamin D Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mifepristone 030104 developmental biology Endocrinology Metabolism Liver Receptors Estrogen CYP2R1 Cholestanetriol 26-Monooxygenase Transcription Factors |
| Zdroj: | Diabetes |
| Popis: | Low 25-hydroxyvitamin D levels correlate with the prevalence of diabetes; however, the mechanisms remain uncertain. Here, we show that nutritional deprivation–responsive mechanisms regulate vitamin D metabolism. Both fasting and diabetes suppressed hepatic cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase responsible for the first bioactivation step. Overexpression of coactivator peroxisome proliferator–activated receptor γ coactivator 1-α (PGC-1α), induced physiologically by fasting and pathologically in diabetes, resulted in dramatic downregulation of CYP2R1 in mouse hepatocytes in an estrogen-related receptor α (ERRα)–dependent manner. However, PGC-1α knockout did not prevent fasting-induced suppression of CYP2R1 in the liver, indicating that additional factors contribute to the CYP2R1 repression. Furthermore, glucocorticoid receptor (GR) activation repressed the liver CYP2R1, suggesting GR involvement in the regulation of CYP2R1. GR antagonist mifepristone partially prevented CYP2R1 repression during fasting, suggesting that glucocorticoids and GR contribute to the CYP2R1 repression during fasting. Moreover, fasting upregulated the vitamin D catabolizing CYP24A1 in the kidney through the PGC-1α-ERRα pathway. Our study uncovers a molecular mechanism for vitamin D deficiency in diabetes and reveals a novel negative feedback mechanism that controls crosstalk between energy homeostasis and the vitamin D pathway. |
| Databáze: | OpenAIRE |
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