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24-羟化在维生素D代谢稳态调节中的关键作用

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

作者信息

Yazdi Zhinous Shahidzadeh, Streeten Elizabeth A, Whitlatch Hilary B, Montasser May E, Beitelshees Amber L, Taylor Simeon I

机构信息

Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.

出版信息

medRxiv. 2024 Mar 7:2023.06.27.23291942. doi: 10.1101/2023.06.27.23291942.

DOI:10.1101/2023.06.27.23291942
PMID:37425945
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10327282/
Abstract

CONTEXT

The body has evolved homeostatic mechanisms to maintain free levels of Ca and 1,25-dihydroxyvitamin D [1,25(OH)D] 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)D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)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)D/24,25(OH)D ratio better predicted modeled 24-hydroxylase activity () (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)D/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)D. The 1,25(OH)D/24,25(OH)D ratio provides a useful index of VitD status since it incorporates 24,25(OH)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)D and increasing the 1,25(OH)D/24,25(OH)D ratio. Thus, an increased 1,25(OH)D/24,25(OH)D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.

摘要

背景

人体已进化出稳态机制，以将钙和1,25 - 二羟基维生素D [1,25(OH)D]的游离水平维持在狭窄的生理范围内。临床指南强调了甲状旁腺激素（PTH）在维持这种稳态中的重要作用。

目的

研究维生素D（VitD）代谢的稳态调节机制，并将机制性见解应用于改善VitD状态的临床评估。

设计

对补充维生素D3前后的参与者进行交叉临床试验。

地点

社区。

参与者

11名其他方面健康但维生素D缺乏（25 - 羟基维生素D [25(OH)D]≤20 ng/mL）的个体。

干预措施

给予维生素D3补充剂（根据体重指数每周一次或两次，每次50,000 IU，持续4 - 6周），以使25(OH)D≥30 ng/mL。

结果

补充维生素D3后，平均25(OH)D显著增加2.7倍，24,25 - 二羟基维生素D [24,25(OH)D]增加4.3倍。相比之下，PTH、成纤维细胞生长因子23（FGF23）和1,25(OH)D的平均水平没有变化。数学模型表明，对于25(OH)D≥50 ng/mL，24 - 羟化酶活性最高，而当25(OH)D<10 - 20 ng/mL时，活性达到最低水平（约90%抑制）。与总血浆25(OH)D（ρ = 0.51；p = 0.01）和24,25(OH)D/25(OH)D比值（ρ = 0.37；p = 0.3）相比，1,25(OH)D/24,25(OH)D比值能更好地预测模型中的24 - 羟化酶活性（ρ = -0.85；p = 0.001）。

结论

抑制24 - 羟化酶通过降低1,25(OH)D的代谢清除率，为预防有症状的维生素D缺乏提供了第一道防线。1,25(OH)D/24,25(OH)D比值提供了一个有用的维生素D状态指标，因为它纳入了24,25(OH)D水平，因此能深入了解24 - 羟化酶活性。当维生素D供应有限时，这会抑制24 - 羟化酶活性，从而降低24,25(OH)D水平并增加1,25(OH)D/24,25(OH)D比值。因此

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/a62edabb702a/nihpp-2023.06.27.23291942v4-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/ff0738fcead5/nihpp-2023.06.27.23291942v4-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/074a0d16a6b7/nihpp-2023.06.27.23291942v4-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/428becb7de6c/nihpp-2023.06.27.23291942v4-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/e6002b53c9de/nihpp-2023.06.27.23291942v4-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/104a893667e1/nihpp-2023.06.27.23291942v4-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/d844379241e0/nihpp-2023.06.27.23291942v4-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/a62edabb702a/nihpp-2023.06.27.23291942v4-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/ff0738fcead5/nihpp-2023.06.27.23291942v4-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/074a0d16a6b7/nihpp-2023.06.27.23291942v4-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/428becb7de6c/nihpp-2023.06.27.23291942v4-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/e6002b53c9de/nihpp-2023.06.27.23291942v4-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/104a893667e1/nihpp-2023.06.27.23291942v4-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/d844379241e0/nihpp-2023.06.27.23291942v4-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c77c/10945692/a62edabb702a/nihpp-2023.06.27.23291942v4-f0007.jpg

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2
Rickets, Vitamin D, and Ca/P Metabolism.佝偻病、维生素 D 和钙磷代谢。
Horm Res Paediatr. 2022;95(6):579-592. doi: 10.1159/000527011. Epub 2022 Nov 29.
3
Vitamin D-Mediated Regulation of Intestinal Calcium Absorption.维生素 D 介导的肠道钙吸收调节。
Nutrients. 2022 Aug 16;14(16):3351. doi: 10.3390/nu14163351.
4
VITAL Findings - A Decisive Verdict on Vitamin D Supplementation.重要发现——关于维生素D补充剂的决定性判定
N Engl J Med. 2022 Jul 28;387(4):368-370. doi: 10.1056/NEJMe2205993.
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Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults.补充维生素 D 与中年和老年人的骨折事件。
N Engl J Med. 2022 Jul 28;387(4):299-309. doi: 10.1056/NEJMoa2202106.
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Analytical methods for 25-hydroxyvitamin D: advantages and limitations of the existing assays.25-羟维生素 D 的分析方法：现有检测方法的优缺点。
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