title: Thyroid hormones decrease plasma 1α,25-dihydroxyvitamin D levels through transcriptional repression of the renal 25-hydroxyvitamin D3 1α-hydroxylase gene (CYP27B1).
abstract: The primary determinant of circulating 1α,25-dihydroxyvitamin D (1,25[OH](2)D) levels is the activity of 25-hydroxyvitamin D-1α-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 action on 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 (TRα and TRβ1) and the retinoid X receptor α (RXRα) in renal proximal tubular cells. Interestingly, we identified an everted repeat negative thyroid hormone response element (1α-nTRE) overlapping the sterol regulatory element (1α-SRE) and the TATA-box -50 to -20 base pairs from the human CYP27B1 gene transcription start site. Finally, we established that CYP27B1 gene transcription is positively regulated by SRE-binding proteins and that a T(3)-bound TRβ1/RXRα heterodimer inhibits SRE-binding protein-1c-induced transcriptional activity through the 1α-nTRE. These results suggest that transcriptional repression of the CYP27B1 gene by T(3)-bound TRs/RXRα, acting through the 1α-nTRE, results in decreased renal CYP27B1 expression and plasma 1,25(OH)(2)D levels.
authors: Department of Clinical Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors: Mina
authors: M
authors: Kozai
authors: Hironori
authors: H
authors: Yamamoto
authors: Mariko
authors: M
authors: Ishiguro
authors: Nagakatsu
authors: N
authors: Harada
authors: Masashi
authors: M
authors: Masuda
authors: Tomohiro
authors: T
authors: Kagawa
authors: Yuichiro
authors: Y
authors: Takei
authors: Ayako
authors: A
authors: Otani
authors: Otoki
authors: O
authors: Nakahashi
authors: Shoko
authors: S
authors: Ikeda
authors: Yutaka
authors: Y
authors: Taketani
authors: Ken-Ichi
authors: K
authors: Takeyama
authors: Shigeaki
authors: S
authors: Kato
authors: Eiji
authors: E
authors: Takeda
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis*; D000818:Animals; D002117:Calcitriol / Q000097:blood*; D004794:Enzyme Repression; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D013963:Thyroid Hormones / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D013963:Thyroid Hormones; D014284:Triiodothyronine; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol