University of Oulu

Aatsinki, S.-M., Elkhwanky, M.-S., Kummu, O., Karpale, M., Buler, M., Viitala, P., … Hakkola, J. (2019). Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes. Diabetes, 68(5), 918–931.

Fasting-induced transcription factors repress vitamin D bioactivation, a mechanism for vitamin D deficiency in diabetes

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Author: Aatsinki, Sanna-Mari1,2; Elkhwanky, Mahmoud-Sobhy1,2; Kummu, Outi1,2;
Organizations: 1Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland
2Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
3Admescope Ltd., Oulu, Finland
4A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
5Institute of Vegetative Physiology, Medical Faculty, University of Köln, Köln, Germany
6Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
7German Center for Diabetes Research, Neuherberg, Germany
8Department of Medicine, Washington University School of Medicine, St. Louis, MO
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 2.6 MB)
Persistent link:
Language: English
Published: American Diabetes Association, 2019
Publish Date: 2019-06-20


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.

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Series: Diabetes
ISSN: 0012-1797
ISSN-E: 1939-327X
ISSN-L: 0012-1797
Volume: 68
Issue: 5
Pages: 918 - 931
DOI: 10.2337/db18-1050
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: The study was financially supported by the Scholarship Fund of the University of Oulu (Tyyni Tani Fund) to M.-S.E., the Academy of Finland (grants 267637, 292540) and the Sigrid Juselius Foundation to P.T., the Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases and Center of Molecular Medicine Cologne of the Medical Faculty to R.J.W., National Institutes of Health grant R01-DK-104735 to B.N.F., and the Academy of Finland (grant 286743) and the Diabetes Research Foundation to J.H.
Academy of Finland Grant Number: 286743
Detailed Information: 286743 (Academy of Finland Funding decision)
Dataset Reference: This article contains Supplementary Data online at:
Copyright information: © 2019 by the American Diabetes Association. This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at