Zhinous Shahidzadeh Yazdi, Elizabeth A Streeten, Hilary B Whitlatch, May E Montasser, Amber L Beitelshees, Simeon I Taylor
{"title":"24-羟基化在维生素D代谢稳态调节中的关键作用。","authors":"Zhinous Shahidzadeh Yazdi, Elizabeth A Streeten, Hilary B Whitlatch, May E Montasser, Amber L Beitelshees, Simeon I Taylor","doi":"10.1101/2023.06.27.23291942","DOIUrl":null,"url":null,"abstract":"<p><strong>Context: </strong>The body has evolved homeostatic mechanisms to maintain free levels of Ca<sup>+2</sup> and 1,25-dihydroxyvitamin D [1,25(OH)<sub>2</sub>D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis.</p><p><strong>Objective: </strong>To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.</p><p><strong>Design: </strong>Crossover clinical trial studying participants before and after VitD3-supplementation.</p><p><strong>Setting: </strong>Community.</p><p><strong>Participants: </strong>11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL).</p><p><strong>Interventions: </strong>VitD3-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.</p><p><strong>Results: </strong>VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)<sub>2</sub>D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)<sub>2</sub>D did not change. 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. The 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio better predicted modeled 24-hydroxylase activity (<i>h</i>) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)<sub>2</sub>D/25(OH)D ratio (ρ=0.37; p=0.3).</p><p><strong>Conclusions: </strong>Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)<sub>2</sub>D. The 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio provides a useful index of VitD status since it incorporates 24,25(OH)<sub>2</sub>D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)<sub>2</sub>D and increasing the 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio. Thus, an increased 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.</p>","PeriodicalId":18659,"journal":{"name":"medRxiv : the preprint server for health sciences","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f4/c6/nihpp-2023.06.27.23291942v1.PMC10327282.pdf","citationCount":"0","resultStr":"{\"title\":\"Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism.\",\"authors\":\"Zhinous Shahidzadeh Yazdi, Elizabeth A Streeten, Hilary B Whitlatch, May E Montasser, Amber L Beitelshees, Simeon I Taylor\",\"doi\":\"10.1101/2023.06.27.23291942\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Context: </strong>The body has evolved homeostatic mechanisms to maintain free levels of Ca<sup>+2</sup> and 1,25-dihydroxyvitamin D [1,25(OH)<sub>2</sub>D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis.</p><p><strong>Objective: </strong>To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.</p><p><strong>Design: </strong>Crossover clinical trial studying participants before and after VitD3-supplementation.</p><p><strong>Setting: </strong>Community.</p><p><strong>Participants: </strong>11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL).</p><p><strong>Interventions: </strong>VitD3-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.</p><p><strong>Results: </strong>VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)<sub>2</sub>D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)<sub>2</sub>D did not change. 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. The 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio better predicted modeled 24-hydroxylase activity (<i>h</i>) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)<sub>2</sub>D/25(OH)D ratio (ρ=0.37; p=0.3).</p><p><strong>Conclusions: </strong>Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)<sub>2</sub>D. The 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio provides a useful index of VitD status since it incorporates 24,25(OH)<sub>2</sub>D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)<sub>2</sub>D and increasing the 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio. Thus, an increased 1,25(OH)<sub>2</sub>D/24,25(OH)<sub>2</sub>D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.</p>\",\"PeriodicalId\":18659,\"journal\":{\"name\":\"medRxiv : the preprint server for health sciences\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-03-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f4/c6/nihpp-2023.06.27.23291942v1.PMC10327282.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"medRxiv : the preprint server for health sciences\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1101/2023.06.27.23291942\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv : the preprint server for health sciences","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2023.06.27.23291942","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism.
Context: The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis.
Objective: To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.
Design: Crossover clinical trial studying participants before and after VitD3-supplementation.
Setting: Community.
Participants: 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL).
Interventions: VitD3-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.
Results: VitD3-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. 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. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio (ρ=0.37; p=0.3).
Conclusions: Suppression of 24-hydroxylase 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 provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. 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, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.
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