Abstract：
Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-β1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of β-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-β1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
摘要：
肝星状细胞(HSC)活化是肝纤维化(LF)的重要病理进程。调节HSC活化和LF的分子机制尚不完全清楚。这里,我们探讨了转录因子SRY相关的高迁移率族蛋白7（SOX7）对HSC激活和LF的影响，以及潜在的分子机制。我们发现SOX7在人和小鼠纤维化肝脏中的表达水平降低,特别是在纤维化病灶。SOX7在原代活化的HSC和TGF-β1刺激的LX-2细胞中也下调。SOX7敲低可促进LX-2细胞的活化和增殖，同时抑制其凋亡。另一方面,SOX7的过表达抑制了HSC的活化和增殖。机械上,SOX7通过降低TGF-β1诱导的β-连环蛋白的表达和Smad2和Smad3的磷酸化来减弱HSC活化和LF。此外，使用AAV8-SOX7小鼠模型的SOX7的过表达改善了在体内响应于CCl4处理的LF的程度。总的来说，SOX7抑制HSC激活和LF。因此，以SOX7为目标，可能是一种潜在的新策略，以防止LF。
