Mechanisms of Liver Regeneration After Acetaminophen-Induced Acute Liver Failure

项目摘要 过量服用对乙酰氨基酚(APAP)是最常见的原因，对乙酰氨基酚是一种流行的止痛药和退热剂 急性肝功能衰竭(ALF)在西方世界的发病率。APAP诱发的ALF的治疗选择是极其重要的 有限的。大多数ALF患者使用N-乙酰半胱氨酸治疗，N-乙酰半胱氨酸是谷胱甘肽的前体，只有在 在APAP过量用药后数小时内交付。唯一的其他疗法是肝移植，这是 供体器官稀缺、终身使用免疫抑制剂和昂贵的费用使情况变得复杂。有一个 迫切需要为APAP诱导的ALF开发新的治疗方法。最近使用动物模型和 患者样本已经证明，及时刺激先天肝再生与更好的 结果包括APAP诱导的ALF的无移植生存。这些研究表明，如果没有适当的 肝再生、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诱导的ALF后肝再生的治疗潜力。然而， APAP过量给药后肝再生的机制尚不完全清楚。在这个的前一个周期中 Grant，我们研究了典型的Wnt--catenin信号在APAP过量用药后肝再生中的作用。 有趣的是，我们的初步研究揭示了河马激酶途径的一个新的和矛盾的作用 及其下游调节因子YAP在APAP诱导的ALF发病机制中的作用。我们的学习， 使用肝细胞特异性YAP基因敲除(YAP-KO)小鼠进行的研究表明，APAP后YAP被激活 过量用药与APAP过量后再生延迟有关。删除YAP导致增强了 APAP过量用药后肝再生恢复较快。从机械上讲，删除中的YAP 肝细胞激活-连环蛋白的速度加快，从而促进了肝再生。 行政管理。此外，我们观察到更快且增强的促再生性炎症反应。 在肝细胞-连环蛋白靶标--血清淀粉样蛋白A和CXCL1高表达的推动下，YAP- Ko老鼠。最后，我们的初步研究表明，YAP及其靶基因结缔组织生长因子 (CTGF)可作为APAP所致ALF的预后指标。这些研究将探索一种 YAP在药物诱导的急性肝功能衰竭和随后的肝再生中的非常规和新的作用。 这些研究的成功完成将对APAP过量的临床治疗产生重大影响 因为他们将YAP确定为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.