Fasting-Induced Transcription Factors Repress Vitamin D Bioactivation, a Mechanism for Vitamin D Deficiency in Diabetes

Abstract

Low 25-hydroxyvitamin D levels correlate with the prevalence of diabetes; however, the mechanisms remain uncertain. Here, we show that nutritional deprivationresponsive 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 g 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 diabetes and reveals a novel negative feedback mechanism that controls crosstalk between energy homeostasis and the vitamin D pathway.

Vitamin D Metabolism Revised: Fall of Dogmas

“…This hormonal system functions as most steroid and thyroid hormones and regulates a very large number of genes involved in calcium and phosphate transport but also regulates a very large number of genes (up to 10% of all genes of the some organisms such as the zebrafish) not involved in ion transport or bone metabolism (reviewed in Bouillon and colleagues(1)).However, a few recent publications have challenged some aspects of our understanding of vitamin D metabolism including the concept of stable expression of the hepatic 25-hydroxylases. (2,3) We review these new data regarding CYP2R1, discuss their potential implications, and extend this review to examine the overall metabolism of vitamin D to explore whether old dogmas still hold today.Obesity and the metabolic syndrome are associated with low vitamin D status. (1) Prospective studies suggest that low nonepimeric 25OHD or increased 3-epi-25OHD concentrations are associated with higher risk for type 2 diabetes.…”

“…They also used the ratio of serum 25OHD to serum vitamin D concentrations as a marker of 25-hydroxylase activity and found a strong positive correlation between this ratio and liver mRNA expression of CYP2R1.Aatsinki and colleagues addressed a similar question about the origin of fairly systematic low serum 25OHD concentrations in diabetic subjects compared with their euglycemic controls, by studying high-fat-diet-induced obesity and type 2 diabetes in mice. (3) In addition, they also studied the effect of 24-hour fasting and of streptozotocin-induced type 1 diabetes. All these…”

“…However, a few recent publications have challenged some aspects of our understanding of vitamin D metabolism including the concept of stable expression of the hepatic 25-hydroxylases. (2,3) We review these new data regarding CYP2R1, discuss their potential implications, and extend this review to examine the overall metabolism of vitamin D to explore whether old dogmas still hold today.…”

“…Aatsinki and colleagues addressed a similar question about the origin of fairly systematic low serum 25OHD concentrations in diabetic subjects compared with their euglycemic controls, by studying high-fat-diet-induced obesity and type 2 diabetes in mice. (3) In addition, they also studied the effect of 24-hour fasting and of streptozotocin-induced type 1 diabetes. All these metabolic situations decreased the hepatic mRNA and protein concentration of CYP2R1.…”

ERRα/VDR Axis Promotes Calcitriol Degradation and Estrogen Signaling Activation and Correlates with Poor Prognosis in Basal-like Breast Cancer Patients.

“…High levels of ERRα expression are associated with a poor prognosis in breast cancer [21] while several reports have described ERRα as a predictive biomarker of response to endocrine therapy in the same setting [22][23][24]. Recent studies have described a novel cross-talk between ERRα and the vitamin D pathway in diabetes [25]. Astninski et al, indeed, demonstrated that the induction of CYP24A1 by fasting was regulated through a peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-ERRα-dependent mechanism, showing, for the rst time, a role for ERRα in the suppression of vitamin D signaling.…”