Obesity Represses CYP2R1, the Vitamin D 25‐Hydroxylase, in the Liver and Extrahepatic Tissues

Abstract

Low plasma level of 25-hydroxyvitamin D (25-OH-D), namely vitamin D deficiency, is associated with obesity and weight loss improves 25-OH-D status. However, the mechanism behind obesity-induced vitamin D deficiency remains unclear. Here, we report that obesity suppresses the expression of cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase, in both mice and humans. In humans, weight loss induced by gastric bypass surgery increased the expression of CYP2R1 in the s.c. adipose tissue suggesting recovery after the obesity-induced suppression. At the same time, CYP27B1, the vitamin D 1α-hydroxylase, was repressed by the weight loss. In a mouse (C57BL/6N) model of diet-induced obesity, the plasma 25-OH-D was decreased. In accordance, the CYP2R1 expression was strongly repressed in the liver. Moreover, obesity repressed the expression of CYP2R1 in several extrahepatic tissues, the kidney, brown adipose tissue, and testis, but not in the white adipose tissue. Obesity had a similar effect in both male and female mice. In mice, obesity repressed expression of the vitamin D receptor in brown adipose tissue. Obesity also upregulated the expression of the vitamin D receptor and CYP24A1 in the s.c. adipose tissue of a subset of mice; however, no effect was observed in the human s.c. adipose tissue. In summary, we show that obesity affects CYP2R1 expression both in the mouse and human tissues. We suggest that in mouse the CYP2R1 repression in the liver plays an important role in obesity-induced vitamin D deficiency. Currently, it is unclear whether the CYP2R1 downregulation in extrahepatic tissues could contribute to the obesity-induced low plasma 25-OH-D, however, this phenomenon may affect at least the local 25-OH-D concentrations.

Insulin Resistance and Vitamin D Deficiency: A Link Beyond the Appearances

“…In particular, it has been demonstrated that high fat diet-induced obesity decreased the hepatic gene expression of 25-hydroxylases in mice ( 140 , 141 ). Similar data were found in obese subjects, in whom the overweight determined a decreased expression of cytochrome P450 (CYP) 2R1, the main vitamin D 25-hydroxylase, while the weight loss, induced by gastric bypass, increased the expression of CYP 2R1 ( 142 ).…”

Vitamin D and Obesity/Adiposity—A Brief Overview of Recent Studies

“…Although the 25-hydroxylation is classically thought to be poorly regulated, Bell et al reported that hepatic 25-hydroxylation was inhibited by 1,25(OH) 2 D and parathyroid hormone (PTH) in humans [ 26 ]. Furthermore, several recent studies have described the inhibition of Cyp2r1 mRNA levels and/or 25-hydroxylation activity in the liver of obese/diabetic mice [ 27 , 28 , 29 , 30 , 31 ] via mechanisms involving several transcription factors including PGC1α and GR [ 31 ]. The 25(OH)D thus produced is the major circulating form of VD, with a half-life of about 15 days, and is classically used as a biomarker of VD status [ 32 ].…”

Streptozotocin-induced Diabetes Represses Hepatic CYP2R1 Expression but Induces Vitamin D 25-Hydroxylation in Male Mice

“…The liver is the major site expressing Cyp2r1 ; however, our previous studies have shown that Cyp2r1 is expressed also in extrahepatic tissues ( 11 ). Therefore, we analyzed Cyp2r1 expression in some extrahepatic tissues [ie, kidney, brown adipose tissue (BAT), and testis] of the nondiabetic and diabetic mice from the 13-week experiment.…”

“…We previously demonstrated that CYP2R1 expression was suppressed in the mouse liver by fasting, high-fat diet (HFD)-induced obesity and streptozotocin (STZ)-induced diabetes ( 10 ). Furthermore, in the obese mice, the plasma 25-OH-D level was reduced, and in the livers of fasting mice, the vitamin D 25-hydroxylase activity was strongly reduced ( 10 , 11 ) Moreover, Roizen et al reported that livers of the HFD-fed, obese mice had reduced vitamin D 25-hydroxylase activity ( 12 ). These data thus support the notion that downregulation of CYP2R1 expression associates with reduced vitamin D 25-hydroxylase activity and could at least partially explain why the vitamin D deficiency is commonly associated with obesity and diabetes.…”