Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism

Abstract

The body has evolved effective homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. The literature documents critical contributions of PTH to this homeostatic regulation. We developed a mechanistic mathematical model documenting an important contribution from homeostatic regulation of 24-hydroxylase activity. Data on vitamin D (VitD) metabolite levels were obtained from a clinical trial conducted in healthy participants with baseline total 25-hydroxyvitamin D [25(OH)D] levels ≤20 ng/mL. The trial was designed as a crossover trial in which participants were studied before and after receiving VitD3 supplementation (≥4-6 weeks) to achieve total 25(OH)D levels >30 ng/mL. VitD3 supplementation significantly increased mean levels of 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change in response to VitD3 supplementation. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D levels ≥50 ng/mL and achieved a minimum (~90% suppression) when 25(OH)D levels were <10-20 ng/mL. Suppression of 24-hydroxylase is triggered by mild-moderate VitD deficiency and is predicted to sustain physiological levels of 1,25(OH)2D by suppressing metabolic clearance of 1,25(OH)2D. VitD metabolite ratios [e.g., 1,25(OH)2D/24,25(OH)2D] provide useful indices demonstrating that the body has triggered homeostatic regulation to compensate for limited availability of VitD. Thus, suppression of 24-hydroxylase activity provides a first line of defense protecting against VitD deficiency. In severe VitD deficiency, when this first line of defense has been maximally deployed, the body triggers secondary hyperparathyroidism, thereby providing a second line of defense.