Ischemia/reperfusion injury, induced by abnormal mitochondrial fission–related apoptosis, is a major concern in liver transplantation settings. Our previous studies have demonstrated that hepatic stimulator substance (HSS) is an antiapoptotic effector and could protect liver from ischemia/reperfusion injury. However, the underlying mechanism remains unclear. In the present study, we report that in vitro and in vivo HSS could regulate mitochondrial fission and hepatocyte apoptosis during liver ischemia/reperfusion injury by orchestrating the translocation and activation of dynamin-related protein 1 (Drp1). Using a mouse model of ischemia/reperfusion-induced liver injury, we found that HSS-haploinsufficient (HSS^+/−) mice displayed exacerbated liver damage based on their increased serum aminotransferase levels, cell structural destruction, and apoptosis levels compared to wild-type (HSS^+/+) littermates. Disruption of HSS markedly increased cyclin-dependent kinase 1 (CDK1) and Bax expression, accompanied by elevated phosphorylated Drp1 and release of cytochrome c. In parallel in vitro studies, we found that HSS could inhibit the expression of CDK1 and that HSS inhibits hepatocyte apoptosis through its suppression of CDK1/cyclin B–mediated phosphorylation at Ser-616 of Drp1, thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. On the contrary, knockdown of HSS increased CDK1 as well as Drp1 phosphorylation and aggravated hepatocellular apoptosis. Mechanistic investigation showed that HSS was able to reduce the stability and translation of CDK1 mRNA by modulating the expression of several microRNAs (miRs), including miR-410-3p, miR-490-3p, and miR-582-5p. Conclusion: Our data reveal a novel mechanism for HSS in regulating the mitochondrial fission machinery and further suggest that modulation of HSS may provide a therapeutic approach for combating liver damage. (Hepatology 2017;66:1989–2001)

中文翻译：

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肝刺激物质可通过调节Drp1的转运和激活来抵抗肝缺血/再灌注损伤

异常的线粒体裂变相关的细胞凋亡引起的缺血/再灌注损伤是肝脏移植中的主要关注点。我们以前的研究表明，肝刺激物（HSS）具有抗凋亡作用，可以保护肝脏免受缺血/再灌注损伤。但是，其潜在机制仍不清楚。在本研究中，我们报道了在体外和体内HSS可以通过编排的发动相关蛋白1（DRP1）的易位和激活肝缺血/再灌注损伤期间调节线粒体裂变和肝细胞凋亡。使用小鼠缺血/再灌注引起的肝损伤模型，我们发现HSS单倍体不足（HSS ^+/-）与野生型（HSS ^{+ / +}）同窝仔猪相比，小鼠的血清氨基转移酶水平升高，细胞结构破坏和细胞凋亡水平升高，显示出加剧的肝损伤。HSS的中断显着增加了细胞周期蛋白依赖性激酶1（CDK1）和Bax表达，并伴有磷酸化Drp1的升高和细胞色素c的释放。体外平行研究发现，HSS可以抑制CDK1的表达，并且通过抑制CDK1 / cyclin B介导的Drp1的Ser-616磷酸化来抑制肝细胞凋亡，从而减少Drp1在线粒体中的积累和Drp1介导的线粒体激活。裂变程序。相反，HSS的敲低增加了CDK1以及Drp1的磷酸化并加重了肝细胞凋亡。机理研究表明，HSS能够通过调节包括miR-410-3p，miR-490-3p和miR-582-5p在内的几种microRNA（miR）的表达来降低CDK1 mRNA的稳定性和翻译。结论：我们的数据揭示了HSS在调节线粒体裂变机制中的新机制，并进一步表明，HSS的调节可能为抗击肝损伤提供了一种治疗方法。（肝病学2017; 66：1989–2001）