Affiliation:
1. Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
2. Institute of Pathology, University Hospital Essen, Essen, Germany
Abstract
Abstract
Context
3,5,3’-L-triiodothyronine (T3) is a potent inducer of hepatocyte proliferation via the Wnt/β-catenin signaling pathway. Previous studies suggested the involvement of rapid noncanonical thyroid hormone receptor (TR) β signaling, directly activating hepatic Wnt/β-catenin signaling independent from TRβ DNA binding. However, the mechanism by which T3 increases Wnt/β-catenin signaling in hepatocytes has not yet been determined.
Objective
We aimed to determine whether DNA binding of TRβ is required for stimulation of hepatocyte proliferation by T3.
Methods
Wild-type (WT) mice, TRβ knockout mice (TRβ KO), and TRβ mutant mice with either specifically abrogated DNA binding (TRβ GS) or abrogated direct phosphatidylinositol 3 kinase activation (TRβ 147F) were treated with T3 for 6 hours or 7 days. Hepatocyte proliferation was assessed by Kiel-67 (Ki67) staining and apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Activation of β-catenin signaling was measured in primary murine hepatocytes. Gene expression was analyzed by microarray, gene set enrichment analysis (GSEA), and quantitative reverse transcription polymerase chain reaction.
Results
T3 induced hepatocyte proliferation with an increased number of Ki67-positive cells in WT and TRβ 147F mice (9.2% ± 6.5% and 10.1% ± 2.9%, respectively) compared to TRβ KO and TRβ GS mice (1.2% ± 1.1% and 1.5% ± 0.9%, respectively). Microarray analysis and GSEA showed that genes of the Wnt/β-catenin pathway—among them, Fzd8 (frizzled receptor 8) and Ctnnb1 (β-catenin)—were positively enriched only in T3-treated WT and TRβ 147F mice while B-cell translocation gene anti-proliferation factor 2 was repressed. Consequently, expression of Ccnd1 (CyclinD1) was induced.
Conclusions
Instead of directly activating Wnt signaling, T3 and TRβ induce key genes of the Wnt/β-catenin pathway, ultimately stimulating hepatocyte proliferation via CyclinD1. Thus, canonical transcriptional TRβ action is necessary for T3-mediated stimulation of hepatocyte proliferation.
Funder
Deutsche Forschungsgemeinschaft
Reference60 articles.
1. Liver regeneration;Mao;Transl Res.,2014
2. Clinical implications of advances in the basic science of liver repair and regeneration;Karp;Am J Transplant.,2009
3. Thyroid hormones, thyromimetics and their metabolites in the treatment of liver disease;Kowalik;Front Endocrinol.,2018
4. Thyroid hormone metabolites and analogues;Senese;Endocrine.,2019
5. Hepatocyte proliferation and gene expression induced by triiodothyronine in vivo and in vitro;Francavilla;Hepatology.,1994
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献