The role of transducin β-like 1 X-linked receptor 1 (TBL1XR1) in thyroid hormone metabolism and action in mice.

IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM European Thyroid Journal Pub Date : 2023-08-14 Print Date: 2023-10-01 DOI:10.1530/ETJ-23-0077
Yalan Hu, Kim Falize, A S Paul van Trotsenburg, Raoul Hennekam, Eric Fliers, Eveline Bruinstroop, Anita Boelen
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Abstract

Transducin β-like 1 X-linked receptor 1 (TBL1XR1) is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor (TR). We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C ) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in the liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while the mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants, resulting in (subtle) changes in T3-regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular TH metabolism and action. TH transport via MCT8 might be affected as the expression is increased in WAT and kidney. The mechanisms involved need to be clarified.

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转导蛋白β样1 X连接受体1(TBL1XR1)在小鼠甲状腺激素代谢和作用中的作用。
转导素β样1 X连接受体1(TBL1XR1)是一种含有WD40重复序列的蛋白质,也是与甲状腺激素受体(TR)结合的辅压复合物SMRT/NCoR的一部分。我们最近描述了Pierpont综合征患者的TBL1XR1突变。携带该Tb1xr1突变的小鼠模型(Tb1xr1Y446C/Y446C)显示了Pierpont表型的几个方面。尽管这些小鼠的血清甲状腺激素(TH)浓度不显著,但由于TBL1XR1在SMRT/NCoR辅压复合物中的作用,组织TH作用可能受到影响。本研究的目的是评估Tbl1xr1Y446C/Y446C小鼠在各种组织中的组织TH代谢和作用。我们研究了参与TH代谢和作用的基因在幼稚Tbl1xr1Y446C/Y446C小鼠和野生型(WT)小鼠组织中的表达。此外,我们测量了肝脏(Dio1和Dio3)、肾脏(Dio3和Dio1)和BAT(Dio2)中的脱碘酶活性。Tbl1xr1Y446C/Y446C和WT小鼠在肝脏、下丘脑、肌肉和BAT方面没有观察到显著差异。与WT相比,Tbl1xr1Y446C/Y446C小鼠的垂体TRα1 mRNA表达较低,而突变小鼠的Tshβ和T3正调控基因Nmb的mRNA表达显著增加。有趣的是,突变体的WAT和肾脏中Mct8的表达明显更高,导致WAT和肾中T3调节基因表达的(微妙)变化。总之,携带TBL1XR1突变的小鼠在细胞TH代谢和作用方面表现出微小的变化。TH通过MCT8的转运可能受到影响,因为其在WAT和肾脏中的表达增加。需要澄清所涉及的机制。
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来源期刊
European Thyroid Journal
European Thyroid Journal Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
6.70
自引率
2.10%
发文量
156
期刊介绍: The ''European Thyroid Journal'' publishes papers reporting original research in basic, translational and clinical thyroidology. Original contributions cover all aspects of the field, from molecular and cellular biology to immunology and biochemistry, from physiology to pathology, and from pediatric to adult thyroid diseases with a special focus on thyroid cancer. Readers also benefit from reviews by noted experts, which highlight especially active areas of current research. The journal will further publish formal guidelines in the field, produced and endorsed by the European Thyroid Association.
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