GAS5抑制的肝细胞焦亡通过微小RNA-684和芳烃受体促进肝星状细胞失活。
GAS5-inhibited hepatocyte pyroptosis contributes to hepatic stellate cell inactivation via microRNA-684 and AHR.
作者信息
Lang Zhichao, Zhang Rongrong, Li Xinmiao, Jin Yan, Hu Yuhang, Lin Xinyi, Tang Yunzhi, Zhang Jingnan, Zheng Lei, Yu Zhixian, Zheng Jianjian
机构信息
Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo 315300, China.
出版信息
iScience. 2023 Jul 13;26(8):107326. doi: 10.1016/j.isci.2023.107326. eCollection 2023 Aug 18.
Hepatocyte pyroptosis has been shown to be involved in liver damage progression. Previously, we found that growth arrest-specific 5 (GAS5) is a regulator of hepatic stellate cell (HSC) activation. However, whether GAS5 plays a role in hepatocyte pyroptosis remains unclear. In this study, reduced GAS5 was shown in CCl-treated mice and restoration of GAS5-inhibited liver fibrosis . Hepatocyte pyroptosis participated in the effects of GAS5-inhibited liver fibrosis, associated with reduced caspase-1, NLRP3, and IL-1β (hepatocyte pyroptosis markers). Notably, AHR expression, a suppressor of NLRP3, was enhanced by GAS5. Silencing AHR inhibited GAS5-mediated hepatocyte pyroptosis. GAS5 and AHR were targets of microRNA-684 (miR-684). In addition, the effects of GAS5 on hepatocyte pyroptosis could be inhibited by miR-684. Interestingly, GAS5-mediated hepatocyte pyroptosis contributed to HSC inactivation. In conclusion, we demonstrate that GAS5 inhibits hepatocyte pyroptosis and HSC activation, at least in part, via regulation of miR-684 and AHR.
肝细胞焦亡已被证明参与肝脏损伤的进展。此前，我们发现生长停滞特异性蛋白5（GAS5）是肝星状细胞（HSC）激活的调节因子。然而，GAS5是否在肝细胞焦亡中发挥作用仍不清楚。在本研究中，CCl4处理的小鼠中GAS5表达降低，恢复GAS5可抑制肝纤维化。肝细胞焦亡参与了GAS5抑制肝纤维化的作用，这与半胱天冬酶-1、NLRP3和白细胞介素-1β（肝细胞焦亡标志物）的减少有关。值得注意的是，作为NLRP3抑制剂的芳烃受体（AHR）表达被GAS5增强。沉默AHR可抑制GAS5介导的肝细胞焦亡。GAS5和AHR是微小RNA-684（miR-684）的靶点。此外，miR-684可抑制GAS5对肝细胞焦亡的影响。有趣的是，GAS5介导的肝细胞焦亡有助于HSC失活。总之，我们证明GAS5至少部分通过调节miR-684和AHR来抑制肝细胞焦亡和HSC激活。
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