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Regulation of type 1 iodothyronine deiodinase by LXR?.

ABSTRACT: The iodothyronine deiodinases are selenoenzymes that regulate the activity of thyroid hormone via specific inner- or outer-ring deiodination. In humans, type 1 deiodinase (D1) is highly expressed in the liver, but the mechanism by which its gene expression is regulated remains to be elucidated. Liver X receptor ? (LXR?), a transcription factor of the nuclear receptor superfamily, is highly expressed in the liver, where it functions as a sensor for excess intracellular oxysterols. LXR? interacts with other nuclear receptors on promoters of genes that contain a binding core sequence for nuclear receptors. In addition, it is reported that the promoter of the gene encoding human D1 (hDIO1) contains the core sequence for one of nuclear receptors, thyroid hormone receptor (TR). We investigated the involvement of LXR? in the regulation of hDIO1, in the liver. We performed hDIO1 promoter-reporter assays using a synthetic LXR agonist, T0901317, and compared promoter activity between a human liver carcinoma cell line, HepG2, and a clone of human embryonic kidney cells, TSA201. We defined the region between nucleotides -131 and -114, especially nucleotides -126 and -125, of the hDIO1 promoter as critical for basal and LXR?-mediated specific transcriptional activation in HepG2 cells. An increase in hDIO1 expression was observed in LXR?-stimulated cells, but absent in cycloheximide-treated cells, indicating that new protein synthesis is required for LXR?-mediated regulation of hDIO1. On the other hand, electrophoretic mobility shift assays revealed that LXR? and RXR? bound to the hDIO1 promoter. We also demonstrated that LXR? and TR? compete with each other on this specific region of the promoter. In conclusion, our results indicated that LXR? plays a specific and important role in activation of TH by regulating D1, and that LXR? binds to and regulates the hDIO1 promoter, competing with TR? on specific sequences within the promoter.

SUBMITTER: Sakane Y

PROVIDER: S-EPMC5472309 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Regulation of type 1 iodothyronine deiodinase by LXRα.

Sakane Yoriko Y Kanamoto Naotetsu N Yamauchi Ichiro I Tagami Tetsuya T Morita Yusuke Y Miura Masako M Sone Masakatsu M Yasoda Akihiro A Kimura Takeshi T Nakao Kazuwa K Inagaki Nobuya N

PloS one 20170615 6

The iodothyronine deiodinases are selenoenzymes that regulate the activity of thyroid hormone via specific inner- or outer-ring deiodination. In humans, type 1 deiodinase (D1) is highly expressed in the liver, but the mechanism by which its gene expression is regulated remains to be elucidated. Liver X receptor α (LXRα), a transcription factor of the nuclear receptor superfamily, is highly expressed in the liver, where it functions as a sensor for excess intracellular oxysterols. LXRα interacts ...[more]

PMID: 28617824

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Project description:PurposeThe development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non-small-cell lung cancer (NSCLC) who had a functional thyroid.Materials and methodsThyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases.ResultsUpon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels.ConclusionAn off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.

Dataset Information

Regulation of type 1 iodothyronine deiodinase by LXR?.

Publications

Regulation of type 1 iodothyronine deiodinase by LXRα.

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