Zhou Bisheng, Zeng Sheng, Li Luyuang, Fan Zhiwen, Tian Wenfang, Li Min, Xu Huihui, Wu Xiaoyan, Fang Mingming, Xu Yong
Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China; Department of Medicine and Nursing, Jiangsu Jiankang Vocational University, Nanjing, China.
Biochim Biophys Acta. 2016 Jun;1862(6):1203-13. doi: 10.1016/j.bbadis.2016.02.002. Epub 2016 Feb 2.
Fibrosis is a common pathophysiological process following liver injury and can lead to, if left unattended to, irreversible end-stage liver disease such as cirrhosis. Hepatic stellate cells (HSCs) are a major contributor to liver fibrosis. Here we investigated the involvement of angiogenic factor with G patch and FHA domains 1 (Aggf1) in HSC activation and the underlying mechanisms. Aggf1 expression was down-regulated in the livers in three different mouse models of liver fibrosis following injury. Aggf1 expression was also suppressed in activated HSCs when compared to quiescent HSCs. Over-expression of Aggf1 alleviated liver fibrosis in mice and in cultured HSCs. RNA-sequencing (RNA-seq) analysis performed in HSCs revealed that Aggf1-dependent transcription regulates several key fibrogenic pathways. Mechanistically, Aggf1 regulated liver fibrogenesis by forming a complex with the inhibitor SMAD protein (SMAD7) thereby leading to diminished SMAD3 binding to the pro-fibrogenic gene promoters. On the contrary, SMAD7 knockdown abrogated the effect of Aggf1 and rescued HSC activation. Aggf1 expression was silenced during HSC activation/liver fibrogenesis as a result of DNA methylation. Treatment with a DNA methyltransferase inhibitor (5-Azacytidine) restored Aggf1 expression and repressed liver fibrosis in an Aggf1-dependent manner. In conclusion, our data illustrate a previously unknown role for Aggf1 and shed light on the development of novel therapeutic solutions against liver fibrosis.
纤维化是肝损伤后常见的病理生理过程，若不加以治疗，可导致肝硬化等不可逆的终末期肝病。肝星状细胞（HSCs）是肝纤维化的主要促成因素。在此，我们研究了具有G结构域和FHA结构域的血管生成因子1（Aggf1）在肝星状细胞激活中的作用及其潜在机制。在三种不同的肝损伤小鼠肝纤维化模型中，Aggf1的表达均下调。与静止的肝星状细胞相比，激活的肝星状细胞中Aggf1的表达也受到抑制。Aggf1的过表达减轻了小鼠和培养的肝星状细胞中的肝纤维化。对肝星状细胞进行的RNA测序（RNA-seq）分析表明，Aggf1依赖的转录调节了几个关键的纤维化途径。从机制上讲，Aggf1通过与抑制性SMAD蛋白（SMAD7）形成复合物来调节肝纤维化，从而导致SMAD3与促纤维化基因启动子的结合减少。相反，SMAD7的敲低消除了Aggf1的作用并挽救了肝星状细胞的激活。由于DNA甲基化，在肝星状细胞激活/肝纤维化过程中Aggf1的表达被沉默。用DNA甲基转移酶抑制剂（5-氮杂胞苷）处理可恢复Aggf1的表达，并以Aggf1依赖的方式抑制肝纤维化。总之，我们的数据揭示了Aggf1以前未知的作用，并为开发抗肝纤维化的新型治疗方案提供了线索。
