Canonical Thyroid Hormone Receptor ß Action Stimulates Hepatocyte Proliferation in Male Mice.
Endocrinology
; 163(3)2022 03 01.
Article
em En
| MEDLINE
| ID: mdl-35038735
ABSTRACT
CONTEXT 3,5,3'-L-triiodothyronine (T3) is a potent inducer of hepatocyte proliferation via the Wnt/ß-catenin signaling pathway. Previous studies suggested the involvement of rapid noncanonical thyroid hormone receptor (TR) ß signaling, directly activating hepatic Wnt/ß-catenin signaling independent from TRß DNA binding. However, the mechanism by which T3 increases Wnt/ß-catenin signaling in hepatocytes has not yet been determined. OBJECTIVE:
We aimed to determine whether DNA binding of TRß is required for stimulation of hepatocyte proliferation by T3.METHODS:
Wild-type (WT) mice, TRß knockout mice (TRßâKO), and TRß mutant mice with either specifically abrogated DNA binding (TRßâGS) or abrogated direct phosphatidylinositol 3 kinase activation (TRßâ147F) 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 ß-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 TRßâ147F mice (9.2%â ±â 6.5% and 10.1%â ±â 2.9%, respectively) compared to TRßâKO and TRßâGS mice (1.2%â ±â 1.1% and 1.5%â ±â 0.9%, respectively). Microarray analysis and GSEA showed that genes of the Wnt/ß-catenin pathway-among them, Fzd8 (frizzled receptor 8) and Ctnnb1 (ß-catenin)-were positively enriched only in T3-treated WT and TRßâ147F 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 TRß induce key genes of the Wnt/ß-catenin pathway, ultimately stimulating hepatocyte proliferation via CyclinD1. Thus, canonical transcriptional TRß action is necessary for T3-mediated stimulation of hepatocyte proliferation.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tri-Iodotironina
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Hepatócitos
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Receptores beta dos Hormônios Tireóideos
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Proliferação de Células
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article