Qin Dan, Wang Rui, Ji Jinwei, Wang Duo, Lu Yuanyuan, Cao Shiyao, Chen Yaqing, Wang Liqiang, Chen Xiangmei, Zhang Lisheng
College of Veterinary Medicine/College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.
Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, 28th Fuxing Road, Beijing, 100853, China.
Cell Biosci. 2023 Aug 30;13(1):159. doi: 10.1186/s13578-023-01104-5.
Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9 hepatocytes in response to the acute liver injury and repair are poorly understood.
In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (HO) in order to induce cellular damage in an in vitro setting.
We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in HO-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription.
Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future.
Y染色体性别决定区相关高迁移率族蛋白9（Sox9）在一部分肝细胞中表达，对慢性肝损伤很重要。然而，Sox9阳性肝细胞在急性肝损伤和修复中的作用尚不清楚。
在本研究中，我们构建了成熟肝细胞特异性Sox9基因敲除小鼠品系，并应用了三种急性肝损伤模型，包括部分肝切除术（PHx）、四氯化碳（CCl）和肝脏缺血再灌注（IR）。用过氧化氢（HO）处理Huh-7细胞，以在体外诱导细胞损伤。
我们发现敲除Sox9对急性肝损伤修复有积极作用。在肝细胞特异性Sox9基因敲除小鼠肝脏中，小分子异源二聚体伴侣（SHP）的表达受到高度抑制，同时细胞死亡减少，细胞增殖增加。然而，在肝细胞特异性Sox9基因敲除并过表达SHP的小鼠中，我们观察到了相反的表型。此外，在HO处理的Huh-7细胞中过表达SOX9导致细胞质中SHP积累增加，同时细胞核中SHP减少。这导致线粒体功能受损，随后细胞死亡。值得注意的是，当使用SHP siRNA时，线粒体功能障碍和细胞损伤均得到逆转，表明SHP在介导这些效应中起关键作用。此外，我们发现Sox9作为一种重要的转录因子，直接与SHP启动子结合以调节SHP转录。
总体而言，我们的研究结果揭示了肝细胞特异性Sox9基因敲除通过抑制SHP信号传导和改善线粒体功能来减轻急性肝损伤的机制。本研究可能为未来急性肝损伤提供一种新的治疗策略。
