Disturbed function of TBL1X has a differential effect on T3-regulated gene expression in two human liver cell models.

IF 3.5 2区医学 Q2 ENDOCRINOLOGY & METABOLISM European Thyroid Journal Pub Date : 2024-10-14 Print Date: 2024-10-01 DOI:10.1530/ETJ-24-0162

Yalan Hu, Lorraine Soares De Oliveira, Kim Falize, A S Paul van Trotsenburg, Eric Fliers, Joseph E Kaserman, Andrew A Wilson, Anthony N Hollenberg, Eveline Bruinstroop, Anita Boelen

{"title":"Disturbed function of TBL1X has a differential effect on T3-regulated gene expression in two human liver cell models.","authors":"Yalan Hu, Lorraine Soares De Oliveira, Kim Falize, A S Paul van Trotsenburg, Eric Fliers, Joseph E Kaserman, Andrew A Wilson, Anthony N Hollenberg, Eveline Bruinstroop, Anita Boelen","doi":"10.1530/ETJ-24-0162","DOIUrl":null,"url":null,"abstract":"Background: Mutations in TBL1X, part of the NCOR1/SMRT corepressor complex, were identified in patients with hereditary X-linked central congenital hypothyroidism and associated hearing loss. The role of TBL1X in thyroid hormone (TH) action, however, is incompletely understood. The aim of the present study was to investigate the role of TBL1X on T3-regulated gene expression in two human liver cell models.Methods: A human hepatoma cell line (HepG2) wherein TBL1X was downregulated using siRNAs, and human-induced pluripotent stem cell-derived hepatocytes (iHeps) generated from individuals with a TBL1X N365Y mutation. Both cell types were treated with increasing concentrations of T3. The expression of T3-regulated genes was measured by qPCR.Results: KLF9, CPT1A, and PCK1 mRNA expression were higher upon T3 stimulation in the HepG2 cells with decreased TBL1X expression compared to controls, while DIO1 mRNA expression was lower. Hemizygous TBL1X N365Y iHeps exhibited decreased expression of CPT1A, G6PC1, PCK1, FBP1, and ELOVL2 compared to cells with the heterozygous TBL1X N365Y allele, but KLF9 and HMGCS2 expression was unaltered.Conclusion: Downregulation of TBL1X in HepG2 cells and the TBL1X N365Y variant in iHeps have differential effects on T3-regulated gene expression. This suggests that TBL1X may play a gene context role in TH action.","PeriodicalId":12159,"journal":{"name":"European Thyroid Journal","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558919/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Thyroid Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1530/ETJ-24-0162","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/1 0:00:00","PubModel":"Print","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Mutations in TBL1X, part of the NCOR1/SMRT corepressor complex, were identified in patients with hereditary X-linked central congenital hypothyroidism and associated hearing loss. The role of TBL1X in thyroid hormone (TH) action, however, is incompletely understood. The aim of the present study was to investigate the role of TBL1X on T3-regulated gene expression in two human liver cell models.

Methods: A human hepatoma cell line (HepG2) wherein TBL1X was downregulated using siRNAs, and human-induced pluripotent stem cell-derived hepatocytes (iHeps) generated from individuals with a TBL1X N365Y mutation. Both cell types were treated with increasing concentrations of T3. The expression of T3-regulated genes was measured by qPCR.

Results: KLF9, CPT1A, and PCK1 mRNA expression were higher upon T3 stimulation in the HepG2 cells with decreased TBL1X expression compared to controls, while DIO1 mRNA expression was lower. Hemizygous TBL1X N365Y iHeps exhibited decreased expression of CPT1A, G6PC1, PCK1, FBP1, and ELOVL2 compared to cells with the heterozygous TBL1X N365Y allele, but KLF9 and HMGCS2 expression was unaltered.

Conclusion: Downregulation of TBL1X in HepG2 cells and the TBL1X N365Y variant in iHeps have differential effects on T3-regulated gene expression. This suggests that TBL1X may play a gene context role in TH action.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

在两种人类肝细胞模型中，TBL1X 的功能紊乱对 T3 调控基因的表达有不同影响。

背景：在患有遗传性X连锁中枢性先天性甲状腺功能减退症和相关听力损失的患者中发现了TBL1X的突变，TBL1X是NCoR1/SMRT corepressor复合体的一部分。然而，人们对TBL1X在甲状腺激素（TH）作用中的作用尚不完全清楚。本研究的目的是调查两种人类肝细胞模型中 TBL1X 对 T3 调控基因表达的作用：方法：使用 siRNAs 下调 TBL1X 的人肝癌细胞系（HepG2），以及由 TBL1X N365Y 突变个体生成的人诱导多能干细胞衍生肝细胞（iHeps）。这两种细胞都接受了浓度不断增加的 T3 处理。通过 qPCR 测量 T3 调控基因的表达：结果：与对照组相比，TBL1X 表达减少的 HepG2 细胞在 T3 刺激下 KLF9、CPT1A 和 PCK1 mRNA 表达较高，而 DIO1 mRNA 表达较低。与杂合子 TBL1X N365Y 细胞相比，半杂合子 TBL1X N365Y iHeps 细胞中 CPT1A、G6PC1、PCK1、FBP1 和 ELOVL2 的表达量减少，但 KLF9 和 HMGCS2 的表达量没有变化：结论：下调HepG2细胞中的TBL1X和iHeps中的TBL1X N365Y变体对T3调控基因的表达有不同的影响。这表明TBL1X可能在甲状腺激素TH作用中发挥基因背景作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

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.