A Novel Sox9/lncRNA H19 Axis Contributes to Hepatocyte Death and Liver Fibrosis
A Novel Sox9/lncRNA H19 Axis Contributes to Hepatocyte Death and Liver Fibrosis
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新型 Sox9/lncRNA H19 轴导致肝细胞死亡和肝纤维化
DOI：
10.1093/toxsci/kfaa097
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发表时间：
2020-09-01
影响因子：
3.8
通讯作者：
Zang, Yuhui
中科院分区：
文献类型：
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作者：
Wang, Chenqi;Deng, Jia;Zang, Yuhui
Sox 9先前已被表征为在肝纤维化期间负责细胞外基质产生的转录因子。然而，肝细胞Sox 9在肝纤维化进展中的失调和功能作用仍然是难以捉摸的。在这里，我们发现了一个显着增加的Sox 9的肝细胞分离CCl 4诱导的肝纤维化，并表明，反义寡核苷酸耗尽Sox 9是足以减弱CCl 4诱导的肝纤维化。值得注意的是，在体外和体内系统中，肝细胞中Sox 9的增加与长非编码RNA H19的上调相关。机制研究表明，Sox 9通过与H19的保守启动子区域结合来诱导H19。在体外实验中，肝细胞损伤引起Sox 9/H19轴表达增加，而H19沉默则显著减轻H2 O2诱导的肝细胞凋亡，提示H19作为Sox 9信号的下游效应子参与肝细胞凋亡。在动物实验中，H19的抑制减轻了肝星状细胞的活化，并降低了肝纤维化的程度，而H19的异位表达则消除了Sox 9耗竭对肝纤维化的抑制作用，这表明肝细胞Sox 9的促纤维化作用依赖于H19。最后，我们研究了Sox 9/H19轴与肝纤维化的临床相关性，并确定了肝硬化患者中Sox 9/H19轴的增加。总之，我们的研究结果链接Sox 9/H19轴的内在机制的肝细胞凋亡，并可能代表一个迄今为止未知的范例，肝细胞损伤与肝纤维化的进展。
Sox9 has been previously characterized as a transcription factor responsible for the extracellular matrix production during liver fibrosis. However, the deregulation and functional role of hepatocyte Sox9 in the progression of liver fibrosis remains elusive. Here, we found a significant increase of Sox9 in the hepatocytes isolated from CCl4-induced fibrotic liver and showed that antisense oligoribonucleotides depletion of Sox9 was sufficient to attenuate CCl4-induced liver fibrosis. Notably, the increase of Sox9 in hepatocyte was associated with the upregulation of long noncoding RNA H19 in both in vitro and in vivo systems. Mechanistic studies revealed that Sox9 induced H19 by binding to a conserved promoter region of H19. In vitro, hepatocyte injury triggered the increase of Sox9/H19 axis, whereas silence of H19 greatly alleviated the H2O2-induced hepatocyte apoptosis, suggesting that H19 functions as a downstream effector of Sox9 signaling and is involved in hepatocyte apoptosis. In animal experiments, inhibition of H19 alleviated the activation of hepatic stellate cells and reduced the extent of liver fibrosis, whereas ectopic expression of H19 abolished the inhibitory effects of Sox9 depletion on liver fibrosis, suggesting that the profibrotic effect of hepatocyte Sox9 depends on H19. Finally, we investigated the clinical relevance of Sox9/H19 axis to liver fibrosis and identified the increase of Sox9/H19 axis in liver cirrhosis patients. In conclusion, our findings link Sox9/H19 axis to the intrinsic mechanisms of hepatocyte apoptosis and may represent a hitherto unknown paradigm in hepatocyte injury associated with the progression of liver fibrosis.