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

Abstract

ABSTRACTContextThe body has evolved homeostatic mechanisms to maintain free levels of Ca+2and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis.ObjectiveTo investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.DesignCrossover clinical trial studying participants before and after VitD3-supplementation.SettingCommunity.Participants11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL).InterventionsVitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL.ResultsVitD3-supplementation significantly increased mean 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≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. Suppression of 24-hydroxylase activity was triggered by mild-moderate VitD-deficiency, which sustains 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 of VitD status. When VitD availability is limited, this suppresses 24-hydroxylase activity – thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, a high 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation in response to mild-moderate VitD-deficiency.ConclusionsSuppression of 24-hydroxylase activity provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio can provide a useful index of clinical VitD status.