The Role of 24-hydroxylase in Homeostatic Regulation of 1,25-dihydroxyvitamin D

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Background. Because of the importance of vitamin D (VitD) in calcium balance and bone health, the body has evolved effective homeostatic mechanisms to maintain 1,25-dihydroxyvitamin D [1,25(OH)2D] — the biologically active form — in a narrow physiological range. Objective and hypothesis. We developed a mathematical model to investigate homeostatic mechanisms regulating VitD metabolism with the objective of elucidating regulatory mechanisms maintaining levels of 1,25(OH)2D within a narrow physiological range despite wide variation in availability of VitD. Methods. We studied 11 otherwise healthy VitD deficient [25(OH)D<20 ng/mL] participants before and after VitD3 supplementation (50,000 IU once or twice a week depending on BMI for 4-6 weeks). We measured 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, PTH, and FGF23. We used a 2-tailed paired Student’s t-test to analyze our data; p=0.05 was selected as the criterion for statistical significance. This represents a secondary analysis of a previously published clinical trial [Shahidzadeh Yazdi et al. (2023) J Clin Endocrinol Metab, doi: 10.1210/clinem/dgad554]. Results. VitD3 supplements induced a significant 2.7-fold increase (p=0.0006) in mean 25(OH)D and a 4.3-fold increase (p=0.0002) in 24,25(OH)2D, but did not change 1,25(OH)2D, PTH, or FGF23. Our model showed that 24-hydroxylase activity was regulated over a 10-fold range — with maximal induction for 25(OH)D>50 ng/mL and maximal suppression for 25(OH)D<10-20 ng/mL). Because 24-hydroxylase catalyzes metabolic clearance of 1,25(OH)2D, high levels protect against VitD toxicity and low levels preserve 1,25(OH)2D when VitD is scarce. Thus, suppression of 24-hydroxylase activity is a homeostatic mechanism reflecting the body’s perception of VitD deficiency. Accordingly, measurements of 24,25(OH)2D levels can contribute to assessment of VitD status. However, measurements of total levels of all VitD metabolites [including 24,25(OH)2D] are confounded by the ~3-fold inter-individual variation in VitD binding protein (VDBP) levels. Fortunately, the ratio of 1,25(OH)2D /24,25(OH)2D is independent of VDBP levels. Our analysis suggests that this ratio provides a superior assessment of VitD status compared to the current recommendation to measure total 25(OH)D. For example, 24-hydroxylase activity is highly correlated with 1,25(OH)2D /24,25(OH)2D (ρ2=0.91) but less well correlated with 25(OH)D (ρ2=0.91). Conclusions. The body has two defense mechanisms to protect against VitD deficiency. The first line of defense is suppression of 24-hydroxylase, which is triggered by mild-moderate VitD deficiency and preserves VitD from degradation. However, at times of severe VitD deficiency, the first line of defense may be insuffcient to maintain 1,25(OH)2D in a physiological range. Therefore, the body triggers a second line of defense — secondary hyperparathyroidism, which in turn upregulates 1-hydroxylation and increases production of 1,25(OH)2D. By better understanding the physiology of homeostatic regulation of VitD metabolism, physicians can advance the state-of-the-art in diagnosing and treating VitD deficiency. Funding: R01DK118942; T32DK098107. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.