Analysis of 1,25-Dihydroxyvitamin D₃ Genomic Action Reveals Calcium-Regulating and Calcium-Independent Effects in Mouse Intestine and Human Enteroids

ABSTRACT

Although vitamin D is critical for the function of the intestine, most studies have focused on the duodenum. We show that transgenic expression of the vitamin D receptor (VDR) only in the distal intestine of VDR null mice (KO/TG mice) results in the normalization of serum calcium and rescue of rickets. Although it had been suggested that calcium transport in the distal intestine involves a paracellular process, we found that the 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]-activated genes in the proximal intestine associated with active calcium transport (Trpv6, S100g, and Atp2b1) are also induced by 1,25(OH)₂D₃ in the distal intestine of KO/TG mice. In addition, Slc30a10, encoding a manganese efflux transporter, was one of the genes most induced by 1,25(OH)₂D₃ in both proximal and distal intestine. Both villus and crypt were found to express Vdr and VDR target genes. RNA sequence (RNA-seq) analysis of human enteroids indicated that the effects of 1,25(OH)₂D₃ observed in mice are conserved in humans. Using Slc30a10^−/− mice, a loss of cortical bone and a marked decrease in S100g and Trpv6 in the intestine was observed. Our findings suggest an interrelationship between vitamin D and intestinal Mn efflux and indicate the importance of distal intestinal segments to vitamin D action.

KEYWORDS:

• calcium
• manganese
• transporters
• intestine
• vitamin D
• human enteroids
• mouse
• Slc30a10
• TRPV6

ACKNOWLEDGMENTS

We thank M. Aburadi and A. Kyeremateng for assistance with certain aspects of this investigation.

S.L., S.C., S.M., N.F.S., M.P.V., and J.C.F. designed the study. S.L., J.D.L.C., S. Hutchens, Z.K.C., R.A., O.P.-C., J.H., P.D., and L.V. performed experiments. S.L., S.C., S.M., N.F.S., Z.K.C., M.P.V., J.C.F., G.C., L.V., P.D., P.S., and S. Husain provided interpretation of results. S.L. and S.C. wrote the paper with comments from all authors.

This study was supported by NIH grant DK112365 (to S.C., M.P.V., J.C.F., and N.F.S.) and NIH grant ESO24812 to S.M. as well as a grant from the FWO:G0A2416N to L.V. and G.C.

We disclose no conflicts of interest.