Hepatic Stimulator Substance Resists Hepatic Ischemia/Reperfusion Injury by Regulating Drp1 Translocation and Activation
Hepatic Stimulator Substance Resists Hepatic Ischemia/Reperfusion Injury by Regulating Drp1 Translocation and Activation
复制标题
肝刺激物质通过调节Drp1易位和激活来抵抗肝缺血再灌注损伤。
DOI：
10.1002/hep.29326
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发表时间：
2017-12-01
期刊：
影响因子：
13.5
通讯作者：
An, Wei
中科院分区：
文献类型：
--
作者：
Zhang, Chao;Huang, Jing;An, Wei
异常线粒体分裂相关细胞凋亡引起的缺血/再灌注损伤是肝移植中的一个主要问题。我们的前期研究表明，肝刺激物质（HSS）是一种抗凋亡效应物质，可以保护肝脏免受缺血/再灌注损伤。然而，其潜在机制尚不清楚。在本研究中，我们报道了体外和体内HSS可以通过协调动力蛋白相关蛋白1 （Drp1）的易位和激活来调节肝脏缺血/再灌注损伤时的线粒体分裂和肝细胞凋亡。通过小鼠缺血/再灌注诱导的肝损伤模型，我们发现与野生型（HSS+/+）相比，HSS-单倍体不足（HSS+/-）小鼠的血清转氨酶水平、细胞结构破坏和细胞凋亡水平均有所增加，从而加剧了肝损伤。破坏HSS可显著增加细胞周期蛋白依赖性激酶1 （CDK1）和Bax的表达，并伴有Drp1磷酸化升高和细胞色素c的释放。在平行的体外研究中，我们发现HSS可以抑制CDK1的表达，HSS通过抑制CDK1/cyclin b介导的Drp1 Ser-616位点的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介导的线粒体裂变程序的激活。相反，敲低HSS可增加CDK1和Drp1磷酸化，加重肝细胞凋亡。机制研究表明，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 （miRs）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调节线粒体分裂机制的新机制，并进一步表明HSS的调节可能为对抗肝损伤提供一种治疗方法。
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.