Evidence for in vivo upregulation of the intestinal vitamin D receptor during dietary calcium restriction in the rat

1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃] increases intestinal calcium absorption through events that include binding of 1,25(OH)₂D₃ to the intracellular vitamin D receptor. In vitro studies using mammalian cell cultures reveal an increase in vitamin D receptor content after exposure to 1,25(OH)₂D₃. To test the hypothesis that 1,25(OH)₂D₃ increases enterocyte vitamin D receptor content in vivo, male rats were fed either a normal calcium diet (NCD, 1.2% Ca) or low calcium diet (LCD, 0.002% Ca). After 21 d LCD increased serum 1,25(OH)₂D₃ levels (27 ± 3 vs. 181 ± 17 pg/ml, P < 0.001) and increased transepithelial mucosal to serosal calcium fluxes (J(ms)) across duodenum (65 ± 21 vs. 204 ± 47 nmol/cm²·h, NCD vs. LCD, P < 0.01) and jejunum (23 ± 3 vs. 46 ± 4, P < 0.007). No change in serosal to mucosal calcium fluxes (J(sm)) were observed. LCD increased 1,25(OH)₂D₃ receptor number threefold in duodenum (32.9 ± 6.7 vs. 98.7 ± 13.7 fmol 1,25(OH)₂D₃/mg protein) and jejunum (34.1 ± 9.5 vs. 84.9 ± 7.7) without a change in the receptor affinity for 1,25(OH)₂D₃ (K(d)) is 0.17 ± 0.06 vs. 0.21 ± 0.02 nM for NCD and LCD duodenum, respectively). Duodenal polyadenylated vitamin D receptor mRNA determined by Northern blot analysis did not increase appreciably during LCD, suggesting that upregulation in vivo may not be due primarily to increased receptor synthesis. The results of this study indicate that under physiologic conditions as during chronic dietary calcium restriction, increased intestinal vitamin D receptor content accompanies increased calcium active transport. Upregulation of the vitamin D receptor by 1,25(OH)₂D₃ may result primarily from post-translational processes that decrease degradation of the receptor with increased receptor synthesis responsible for a negligible portion of the accumulation.