Thyroid Hormones Decrease Plasma 1α,25-Dihydroxyvitamin D Levels Through Transcriptional Repression of the Renal 25-Hydroxyvitamin D3 1α-Hydroxylase Gene (CYP27B1)
Thyroid Hormones Decrease Plasma 1α,25-Dihydroxyvitamin D Levels Through Transcriptional Repression of the Renal 25-Hydroxyvitamin D3 1α-Hydroxylase Gene (CYP27B1)
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DOI：
10.1210/en.2012-1647
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发表时间：
2013-02-01
期刊：
影响因子：
4.8
通讯作者：
Takeda, Eiji
中科院分区：
文献类型：
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作者：
Kozai, Mina;Yamamoto, Hironori;Takeda, Eiji
循环 1 α,25-二羟基维生素 D (1,25[OH](2)D) 水平的主要决定因素是肾脏中 25-羟基维生素 D-1 α-羟化酶（细胞色素 P450 27B1 [CYP27B1]）的活性。据报道，甲状腺功能亢进患者的血浆 1,25(OH)(2)D 水平较低。然而，甲状腺激素作用于维生素D代谢的详细机制仍知之甚少。本研究确定肾脏 CYP27B1 基因表达是否受到甲状腺激素的负调节。 T-3诱导的甲状腺功能亢进小鼠血浆1,25(OH)(2)D水平和CYP27B1 mRNA肾表达显着降低，但血浆钙、PTH或成纤维细胞生长因子23浓度没有变化。此外，我们观察到，T-3 给药显着降低血浆 1,25(OH)(2)D 和肾脏 CYP27B1 mRNA 水平，而低钙或低磷饮食会增加血浆 1,25(OH)(2)D 和肾 CYP27B1 mRNA 水平，并在低钙饮食喂养的小鼠中诱导低钙血症。启动子分析显示，T-3 通过肾近端肾小管细胞中的甲状腺激素受体（TR α 和 TR β 1）和类视黄醇 X 受体 α（RXR α）降低 CYP27B1 基因的基础转录活性。有趣的是，我们从人CYP27B1基因转录起始位点鉴定出与甾醇调节元件（1α-SRE）和TATA盒-50至-20个碱基对重叠的外翻重复阴性甲状腺激素反应元件（1α-nTRE）。最后，我们确定 CYP27B1 基因转录受到 SRE 结合蛋白的正向调节，并且 T-3 结合的 TR beta 1/RXR α 异二聚体通过 1 α-nTRE 抑制 SRE 结合蛋白 1c 诱导的转录活性。这些结果表明，T-3 结合的 TRs/RXR α 对 CYP27B1 基因的转录抑制通过 1 α-nTRE 起作用，导致肾 CYP27B1 表达和血浆 1,25(OH)(2)D 水平降低。 （内分泌学154：609-622，2013）
The primary determinant of circulating 1 alpha,25-dihydroxyvitamin D (1,25[OH](2)D) levels is the activity of 25-hydroxyvitamin D-1 alpha-hydroxylase (cytochrome P450 27B1 [CYP27B1]) in the kidney. Hyperthyroid patients have been reported to have low levels of plasma 1,25(OH)(2)D. However, the detailed mechanism of thyroid hormone actionon vitamin D metabolism is still poorly understood. The present study determined whether renal CYP27B1 gene expression was negatively regulated by thyroid hormones. T-3-induced hyperthyroid mice showed marked decreases in plasma 1,25(OH)(2)D levels and in renal expression of CYP27B1 mRNA but no changes in plasma concentrations of calcium, PTH, or fibroblast growth factor-23. In addition, we observed that T-3 administration significantly decreased plasma 1,25(OH)(2)D and renal CYP27B1 mRNA levels that were increased by low-calcium or low-phosphorus diets and induced hypocalcemia in mice fed a low-calcium diet. Promoter analysis revealed that T-3 decreases the basal transcriptional activity of the CYP27B1 gene through thyroid hormone receptors (TR alpha and TR beta 1) and the retinoid X receptor alpha(RXR alpha) in renal proximal tubular cells. Interestingly, we identified an everted repeat negative thyroid hormone response element (1 alpha-nTRE) overlapping the sterol regulatory element (1 alpha-SRE) and the TATA-box -50 to -20 base pairs from thehumanCYP27B1 gene transcription start site. Finally, we established that CYP27B1 gene transcription is positively regulated by SRE-binding proteins and that a T-3-bound TR beta 1/RXR alpha heterodimer inhibits SRE-binding protein-1c-induced transcriptional activity through the 1 alpha-nTRE. These results suggest that transcriptional repression of the CYP27B1 gene by T-3-bound TRs/RXR alpha, acting through the 1 alpha-nTRE, results in decreased renal CYP27B1 expression and plasma 1,25(OH)(2)D levels. (Endocrinology 154: 609-622, 2013)