Zheng Shaoping, Chen Yixiong, Zheng Shaojiang, He Zhihui, Weng Zhihong
Department of Ultrasound, Tongji Medical College, Huazhong University of Science and Technology, Union Hospital, Wuhan 430022, China.
Division of Gastroenterology, Tongji Medical College, Huazhong University of Science and Technology, Union Hospital, Wuhan 430022, China.
Exp Biol Med (Maywood). 2018 Oct;243(14):1099-1108. doi: 10.1177/1535370218810892. Epub 2018 Nov 6.
Mastermind-like 1 (MAML1) functions in critical transcriptional coactivation in Notch and Wnt/β-catenin signal pathways, which participate in hepatic fibrosis. This study is aimed to reveal the potential role of MAML1 in liver fibrosis and identify its underlying mechanism. In present research, the enhanced expression of MAML1 was found in the fibrotic liver tissues in carbon tetrachloride (CCl)-induced hepatic fibrosis in rats, and MAML1 expression increased gradually during the activation of hepatic stellate cells (HSCs) isolated from the normal rat. Further studies showed that blocking MAML1 expression efficiently decreased the expression of α-SMA and collagen I (Col1a1) in HSCs. Interestingly, MAML1 may modulate HSCs activation via interrupting both Notch and Wnt/β-catenin signal transductions, and the inhibition of MAML1 by a recombinant adeno-associated virus type 1 vector carrying shRNA targeting MAML1 alleviated CCl-induced hepatic fibrosis in rats. These findings suggest that the selective regulation of MAML1 expression may be a feasible therapeutic approach to reverse liver fibrosis.
Liver fibrosis is a common wound-healing response to all kinds of liver injuries. Hepatic stellate cells (HSCs) activation is the key event during liver fibrogenesis. Thus, the elucidation of mechanisms for regulating HSCs activation is helpful for identifying novel anti-fibrotic targets and strategies. MAML1, an important component of Notch signal, functions in critical transcriptional coactivation in the Notch and Wnt/β-catenin signal pathways. In the present study, we investigated the potential function of MAML1 during hepatic fibrogenesis in rats. Our results demonstrated that MAML1 participates in liver fibrosis through modulating HSCs activation via interrupting both the Notch and Wnt/β-catenin signal transductions. Additionally, the inhibition of MAML1 markedly attenuated CCl-induced hepatic fibrogenesis in rats. Our results shed a light for the exploitation of a new therapeutic strategy for hepatic fibrosis via targeting MAML1.
类主脑蛋白1（MAML1）在Notch和Wnt/β-连环蛋白信号通路的关键转录共激活中发挥作用，这些信号通路参与肝纤维化过程。本研究旨在揭示MAML1在肝纤维化中的潜在作用，并确定其潜在机制。在目前的研究中，发现四氯化碳（CCl）诱导的大鼠肝纤维化模型的纤维化肝组织中MAML1表达增强，并且从正常大鼠分离的肝星状细胞（HSC）激活过程中MAML1表达逐渐增加。进一步研究表明，阻断MAML1表达可有效降低HSC中α-平滑肌肌动蛋白（α-SMA）和I型胶原（Col1a1）的表达。有趣的是，MAML1可能通过中断Notch和Wnt/β-连环蛋白信号转导来调节HSC激活，携带靶向MAML1的短发夹RNA（shRNA）的重组1型腺相关病毒载体对MAML1的抑制作用减轻了CCl诱导的大鼠肝纤维化。这些发现表明，选择性调节MAML1表达可能是逆转肝纤维化的一种可行治疗方法。
肝纤维化是对各种肝损伤的常见伤口愈合反应。肝星状细胞（HSC）激活是肝纤维化发生过程中的关键事件。因此，阐明调节HSC激活的机制有助于确定新的抗纤维化靶点和策略。MAML1是Notch信号的重要组成部分，在Notch和Wnt/β-连环蛋白信号通路的关键转录共激活中发挥作用。在本研究中，我们研究了MAML1在大鼠肝纤维化发生过程中的潜在功能。我们的结果表明，MAML1通过中断Notch和Wnt/β-连环蛋白信号转导来调节HSC激活，从而参与肝纤维化过程。此外，抑制MAML1可显著减轻CCl诱导的大鼠肝纤维化。我们的结果为通过靶向MAML1开发肝纤维化新治疗策略提供了线索。
