Obesity Decreases Hepatic 25-Hydroxylase Activity Causing Low Serum 25-Hydroxyvitamin D

Jeffrey D. Roizen, Caela Long, Alex Casella, Lauren O'Lear, Ilana Caplan, Meizan Lai, Issac Sasson, Ravinder Singh, Andrew J. Makowski, Rebecca Simmons, Michael A. Levine

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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 R2 value of 0.85. Finally, we performed ex vivo activity assays of isolated livers and found that obese mice generated significantly less 25(OH)D3 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.

Original languageEnglish (US)
Pages (from-to)1068-1073
Number of pages6
JournalJournal of Bone and Mineral Research
Volume34
Issue number6
DOIs
StatePublished - Jun 2019

Keywords

  • CYP2R1
  • OBESITY
  • P450
  • VITAMIN D

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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    Roizen, J. D., Long, C., Casella, A., O'Lear, L., Caplan, I., Lai, M., Sasson, I., Singh, R., Makowski, A. J., Simmons, R., & Levine, M. A. (2019). Obesity Decreases Hepatic 25-Hydroxylase Activity Causing Low Serum 25-Hydroxyvitamin D. Journal of Bone and Mineral Research, 34(6), 1068-1073. https://doi.org/10.1002/jbmr.3686