Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China.
J Dig Dis. 2023 Jan;24(1):39-50. doi: 10.1111/1751-2980.13161. Epub 2023 Mar 26.
Previous studies have demonstrated the pivotal role of transforming growth factor (TGF)-β signaling in activating hepatic stellate cells during liver fibrosis. In this study we aimed to demonstrate the effects and underlying mechanism of TGF-β signaling in hepatocytes on hepatic fibrogenesis.
Hepatocyte-specific Tgfbr2-knockout (Tgfbr2 ) mice were generated by AAV8-TBG-Cre injection via the tail vein of Tgfbr2 mice. CCl was injected intraperitoneally twice a week for 4 weeks to establish the fibrotic mouse model. The expression of the fibrogenesis markers was evaluated by immunohistochemistry, western blot, and real-time polymerase chain reaction (PCR). RNA-seq analysis was used to detect the transcriptional profiles of primary hepatocytes isolated from Tgfbr2 mice and control mice.
The expression of TβR2 (Tgfbr2) was markedly upregulated in hepatocytes of the fibrotic liver. Tgfbr2 depletion in hepatocytes decreased the expressions of profibrogenic markers (Col1a1 and Acta2) in the CCl -treated fibrotic liver. RNA-seq analysis revealed that Tgfbr2 deletion in hepatocytes significantly reduced the inflammatory response and suppressed epithelial-mesenchymal transition of hepatocytes accompanied by upregulation of the metabolic pathways during liver fibrosis. Moreover, the expressions of hepatocyte nuclear factors (HNFs), including Hnf4α, Foxa1, Foxa2, and Foxa3, which are important for maintaining liver metabolism and homeostasis, were decreased in fibrotic livers and significantly increased after Tgfbr2 blockade.
Blocking the TGF-β signaling pathway in hepatocytes reduces hepatic fibrosis and improves hepatic function in fibrotic livers.
先前的研究表明转化生长因子 (TGF)-β 信号在肝纤维化过程中激活肝星状细胞中起着关键作用。在这项研究中，我们旨在证明 TGF-β 信号在肝实质细胞中对肝纤维化的作用及其潜在机制。
通过尾静脉注射 AAV8-TBG-Cre 在 Tgfbr2 小鼠中生成肝实质细胞特异性 Tgfbr2 敲除 (Tgfbr2 ) 小鼠。用 CCl 经腹腔内注射，每周两次，共 4 周，建立纤维化小鼠模型。通过免疫组织化学、western blot 和实时聚合酶链反应 (PCR) 评估纤维化标志物的表达。使用 RNA-seq 分析检测从 Tgfbr2 小鼠和对照小鼠分离的原代肝细胞的转录谱。
纤维化肝脏中 TβR2 (Tgfbr2) 的表达明显上调。肝实质细胞中 Tgfbr2 的缺失减少了 CCl 处理的纤维化肝脏中促纤维化标志物 (Col1a1 和 Acta2) 的表达。RNA-seq 分析表明，肝实质细胞中 Tgfbr2 的缺失显著降低了肝纤维化过程中的炎症反应，并抑制了肝实质细胞的上皮-间充质转化，同时伴随着代谢途径的上调。此外，在纤维化肝脏中，维持肝脏代谢和内稳态的重要的肝细胞核因子 (HNFs)，包括 Hnf4α、Foxa1、Foxa2 和 Foxa3 的表达降低，而在 Tgfbr2 阻断后显著增加。
阻断肝实质细胞中的 TGF-β 信号通路可减少肝纤维化并改善纤维化肝脏的肝功能。
