Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.
Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Liver Int. 2024 Jan;44(1):125-138. doi: 10.1111/liv.15759. Epub 2023 Oct 23.
Progressive hepatic fibrosis can be considered the final stage of chronic liver disease. Hepatic stellate cells (HSC) play a central role in liver fibrogenesis. Thyroid hormones (TH, e.g. thyroxine; T4 and triiodothyronine; T3) significantly affect development, growth, cell differentiation and metabolism through activation of TH receptor α and/or β (TRα/β). Here, we evaluated the influence of TH in hepatic fibrogenesis.
Human liver tissue was obtained from explanted livers following transplantation. TRα-deficient (TRα-KO) and wild-type (WT) mice were fed a control or a profibrogenic methionine-choline deficient (MCD) diet. Liver tissue was assessed by qRT-PCR for fibrogenic gene expression. In vitro, HSC were treated with TGFβ in the presence or absence of T3. HSC with stable TRα knockdown and TRα deficient mouse embryonic fibroblasts (MEF) were used to determine receptor-specific function. Activation of HSC and MEF was assessed using the wound healing assay, Western blotting, and qRT-PCR.
TRα and TRβ expression is downregulated in the liver during hepatic fibrogenesis in humans and mice. TRα represents the dominant isoform in HSC. In vitro, T3 blunted TGFβ-induced expression of fibrogenic genes in HSC and abrogated wound healing by modulating TGFβ signalling, which depended on TRα presence. In vivo, TRα-KO enhanced MCD diet-induced liver fibrogenesis.
These observations indicate that TH action in non-parenchymal cells is highly relevant. The interaction of TRα with TH regulates the phenotype of HSC via the TGFβ signalling pathway. Thus, the TH-TR axis may be a valuable target for future therapy of liver fibrosis.
进行性肝纤维化可被视为慢性肝病的终末期。肝星状细胞（HSC）在肝纤维化发生中起核心作用。甲状腺激素（TH，如甲状腺素；T4 和三碘甲状腺原氨酸；T3）通过激活 TH 受体 α 和/或 β（TRα/β），对发育、生长、细胞分化和代谢产生显著影响。在这里，我们评估了 TH 对肝纤维化的影响。
肝组织取自肝移植后切除的肝脏。TRα 缺陷（TRα-KO）和野生型（WT）小鼠分别给予对照或致纤维化蛋氨酸-胆碱缺乏（MCD）饮食。采用 qRT-PCR 检测纤维化基因表达，评估肝组织。体外，用 TGFβ 处理 HSC，同时或不添加 T3。使用稳定敲低 TRα 和缺乏 TRα 的小鼠胚胎成纤维细胞（MEF），确定受体特异性功能。通过划痕愈合试验、Western blot 和 qRT-PCR 评估 HSC 和 MEF 的激活。
在人类和小鼠肝纤维化过程中，TRα 和 TRβ 在肝组织中的表达下调。TRα 是 HSC 中的主要异构体。体外，T3 减弱了 TGFβ 诱导的 HSC 纤维化基因表达，并通过调节 TGFβ 信号通路，阻断了划痕愈合，这取决于 TRα 的存在。在体内，TRα-KO 增强了 MCD 饮食诱导的肝纤维化。
这些观察结果表明，非实质细胞中的 TH 作用非常重要。TRα 与 TH 的相互作用通过 TGFβ 信号通路调节 HSC 的表型。因此，TH-TR 轴可能是肝纤维化未来治疗的一个有价值的靶点。
