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 gamma coactivator 1-a (PGC-1a), induced physiologically by fasting and pathologically in diabetes, resulted in dramatic downregulation of CYP2R1 in mouse hepatocytes in an estrogen-related receptor a (ERRa)-dependent manner. However, PGC-1a 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-1a-ERRa pathway. Our study uncovers a molecular mechanism for vitamin D deficiency in diabetics and reveals a novel negative feedback mechanism controlling cross-talk between energy homeostasis and the vitamin D pathway.

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