Mechanisms of Liver Regeneration After Acetaminophen-Induced Acute Liver Failure

项目摘要 过量的对乙酰氨基酚（APAP），流行的镇痛和解热剂，是最常见的原因 急性肝功能衰竭（ALF）在西方世界。APAP诱导的ALF的治疗选择非常 有限公司大多数ALF患者使用N-乙酰半胱氨酸治疗，这是谷胱甘肽的前体，只有当 在过量服用APAP后数小时内被送到唯一的其他疗法是肝移植， 由于缺乏捐赠器官、终身使用免疫抑制剂和高昂的费用，使情况更加复杂。有一个 迫切需要开发APAP诱导的ALF的新疗法。最近的研究使用动物模型和 患者样本已经证明，及时刺激先天性肝再生与更好的 结果包括APAP诱导的ALF的无移植存活率。这些研究表明，如果没有适当的 APAP诱导的急性肝损伤可发展为ALF并导致死亡。这些研究 强调APAP诱导ALF后肝再生的治疗潜力。但 APAP过量后肝再生的机制尚不完全清楚。在上一个周期中， 格兰特，我们研究了经典Wnt-β-连环蛋白信号在APAP过量后肝再生中的作用。 有趣的是，我们的初步研究发现了Hippo激酶通路的一个新的和矛盾的作用， 及其下游调节因子是相关蛋白（雅普）在APAP诱导ALF发病机制中的作用。我们的研究， 使用肝细胞特异性雅普敲除（Yap-KO）小鼠进行，表明APAP后雅普活化 过量与APAP过量后的延迟再生有关。删除雅普导致增强 肝脏再生导致APAP过量后更快恢复。从机制上讲，删除雅普， 肝细胞导致β-连环蛋白的更快活化，从而刺激APAP后更快的肝再生 局此外，我们观察到更快和增强的促再生炎症反应， 在雅普细胞中，由于血清淀粉样蛋白A和CXCL 1（两者都是肝细胞中β-连环蛋白的靶点）的高表达， KO小鼠。最后，我们的初步研究表明，雅普及其靶基因结缔组织生长因子 CTGF可作为APAP诱导ALF的预后指标。这些研究将探索一种 雅普在药物诱导的急性肝衰竭和随后的肝再生中的非常规和新颖的作用。 这些研究的成功完成将对APAP过量的临床管理产生重大影响 因为他们将把雅普作为APAP诱导的ALF患者再生治疗的新靶点。

Project Summary Overdose of acetaminophen (APAP), the popular analgesic and antipyretic agent, is the most common cause of acute liver failure (ALF) in the Western world. Treatment options for APAP-induced ALF are extremely limited. Most ALF patients are treated with N-acetyl cystein, a precursor of glutathione, which works only if delivered within hours after APAP overdose. The only other therapy is liver transplantation, which is complicated by scarcity of donor organs, life long immunosuppressant use and exorbitant cost. There is a critical need to develop novel therapies for APAP-induced ALF. Recent studies using animal models and patient samples have demonstrated that timely stimulation of innate liver regeneration is associated with better outcomes including transplant free survival in APAP-induced ALF. These studies indicate that without proper liver regeneration, APAP-induced acute liver injury can develop into ALF and result in death. These studies underscore the therapeutic potential of liver regeneration following APAP-induced ALF. However, the mechanisms of liver regeneration after APAP overdose are not completely known. In the previous cycle of this grant, we investigated the role of canonical Wnt--catenin signaling in liver regeneration after APAP overdose. Interestingly, our preliminary studies have uncovered a novel and paradoxical role for Hippo Kinase pathway and its downstream regulator yes associated protein (Yap) in pathogenesis of APAP-induced ALF. Our studies, performed using hepatocyte specific Yap knockout (Yap-KO) mice, indicate that Yap activation after APAP overdose is associated with delayed regeneration after APAP overdose. Deletion of Yap resulted in enhanced liver regeneration leading to faster recovery after APAP overdose. Mechanistically, deletion of Yap in hepatocytes resulted in faster activation of -catenin, which stimulated the faster liver regeneration after APAP administration. Furthermore, we observed a faster and augmented pro-regenerative inflammatory response driven by higher expression of serum amyloid A and CXCL1, both -catenin targets in hepatocytes, in the Yap- KO mice. Finally, our preliminary studies indicate that Yap and its target gene connective tissue growth factor (CTGF) could be used as prognostic markers in APAP-induced ALF. These studies will explore an unconventional and novel role of Yap in drug induced acute liver failure and subsequent liver regeneration. Successful completion of these studies will have substantial impact on clinical management of APAP overdose because they will identify Yap as a new target for regenerative therapies for APAP-induced ALF patients.