Premium
Obesity Decreases Hepatic 25‐Hydroxylase Activity Causing Low Serum 25‐Hydroxyvitamin D
Author(s) -
Roizen Jeffrey D,
Long Caela,
Casella Alex,
O'Lear Lauren,
Caplan Ilana,
Lai Meizan,
Sasson Issac,
Singh Ravinder,
Makowski Andrew J,
Simmons Rebecca,
Levine Michael A
Publication year - 2019
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3686
Subject(s) - cholecalciferol , endocrinology , medicine , vitamin d and neurology , vitamin d deficiency , vitamin , ergocalciferol , calcifediol , obesity , homeostasis , adipose tissue , biology , chemistry
Normal vitamin D homeostasis is critical for optimal health; nevertheless, vitamin D deficiency is a worldwide public health problem. Vitamin D insufficiency is most commonly due to inadequate cutaneous synthesis of cholecalciferol and/or insufficient intake of vitamin D, but can also arise as a consequence of pathological states such as obesity. Serum concentrations of 25(OH)D (calcidiol) are low in obesity, and fail to increase appropriately after vitamin D supplementation. Although sequestration of vitamin D in adipose tissues or dilution of ingested or cutaneously synthesized vitamin D in the large fat mass of obese patients has been proposed to explain these findings, here we investigate the alternative mechanism that reduced capacity to convert parent vitamin D to 25(OH)D due to decreased expression of CYP2R1 , the principal hepatic vitamin D 25‐hydroxylase. To test this hypothesis, we isolated livers from female mice of 6 to 24 weeks of age, weaned onto either a normal chow diet or a high‐fat diet, and determined the abundance of Cyp2r1 mRNA using digital droplet‐quantitative PCR. We observed a significant ( p < 0.001) decrease in Cyp2r1 mRNA in the liver of high‐fat diet–fed mice relative to lean‐chow–fed female mice. Moreover, there was a significant ( p < 0.01) relationship between levels of Cyp2r1 mRNA and serum 25(OH)D concentrations as well as between Cyp2R1 mRNA and the ratio of circulating 25(OH)D3 to cholecalciferol ( p < 0.0001). Using linear regression we determined a curve with 25(OH)D3/cholecalciferol versus normalized Cyp2R1 mRNA abundance with an R 2 value of 0.85. Finally, we performed ex vivo activity assays of isolated livers and found that obese mice generated significantly less 25(OH)D 3 than lean mice ( p < 0.05). Our findings indicate that expression of CYP2R1 is reduced in obesity and accounts in part for the decreased circulating 25(OH)D. © 2019 American Society for Bone and Mineral Research.