Hepatology：开发出治疗急性肝功能衰竭的新方法

急性肝功能衰竭是一种威胁生命的疾病，其常常伴随着突然间大量的干细胞死亡；目前并没有好的治疗方法，尤其是对于肝衰竭晚期，肝移植或许是唯一的可行性治疗选择。如何研究者基于小鼠模型开发出了一种新的治疗肝衰竭方法。

相关研究成果刊登在了国际杂志Hepatology上，研究中小鼠的肝衰竭可以逆转而且完全恢复，研究者希望这种方法可以应用于临床治疗中。研究者利用最近发现的蛋白质ARC（携带半胱天冬酶募集结构域的细胞凋亡抑制物），其可以充当机体存活开关的作用。ARC可以在心脏、骨骼肌细胞以及大脑中表达，但是不能在肝脏中表达。

细胞凋亡可以保护机体远离疾病或者细胞缺陷，肿瘤细胞的凋亡失活了，因此使得癌细胞无限制地生长。研究者Donath和其同事重点研究了ARC，将其融合进了人类HIV的无感染性的片段中，简称TAT；研究者使用TAT作为一个穿梭工具来向肝脏中转移存活开关。当融合工具TAT-ARC到达肝脏中时，其就可以立马发挥效应。

研究中，研究者同样发现了ARC的一种新的激活机制，其在肝脏中可以发挥重要的保护作用。其可以抑制分子JNK（JNK分子是在肝脏细胞的免疫细胞中被激活的），并且引发异常的过程，ARC同样可以保护肝脏细胞免受破坏。最后，研究者希望能够在临床试验中检测他们开发的新技术。

编译自：New Approach to Treat Acute Liver Failure

doi:10.1002/hep.25697
PMC:
PMID:

TAT-apoptosis repressor with caspase recruitment domain protein transduction rescues mice from fulminant liver failure†

Junfeng An1, Christoph Harms2,3, Gisela Lättig-Tünnemann2,3, Gernot Sellge4, Ana D. Mandić4, Yann Malato4, Arnd Heuser5, Matthias Endres2,3, Christian Trautwein4, Stefan Donath1,3,5,‡,*

Acute liver failure (ALF) is associated with massive hepatocyte cell death and high mortality rates. Therapeutic approaches targeting hepatocyte injury in ALF are hampered by the activation of distinct stimulus-dependent pathways, mechanism of cell death, and a limited therapeutic window. The apoptosis repressor with caspase recruitment domain (ARC) is a recently discovered death repressor that inhibits both death receptor and mitochondrial apoptotic signaling. Here, we investigated the in vivo effects of ARC fused with the transduction domain of human immunodeficiency virus 1 (HIV-1) (TAT-ARC) on Fas- and tumor necrosis factor (TNF)-mediated murine models of fulminant liver failure. Treatment with TAT-ARC protein completely abrogated otherwise lethal liver failure induced by Fas-agonistic antibody (Jo2), concanavalin A (ConA), or D-galactosamine/lipopolysaccharide (GalN/LPS) administration. Importantly, survival of mice was even preserved when TAT-ARC therapy was initiated in a delayed manner after stimulation with Jo2, ConA, or GalN/LPS. ARC blocked hepatocyte apoptosis by directly interacting with members of the death-inducing signaling complex. TNF-mediated liver damage was inhibited by two independent mechanisms: inhibition of jun kinase (JNK)-mediated TNF-α expression and prevention of hepatocyte apoptosis by inhibition of both death receptor and mitochondrial death signaling. We identified JNK as a novel target of ARC. ARC's caspase recruitment domain (CARD) directly interacts with JNK1 and JNK2, which correlates with decreased JNK activation and JNK-dependent TNF-α production. Conclusion: This work suggests that ARC confers hepatoprotection upstream and at the hepatocyte level. The efficacy of TAT-ARC protein transduction in multiple murine models of ALF demonstrates its therapeutic potential for reversing liver failure. (Hepatology 2012)