PACAP neuropeptide promotes Hepatocellular Protection via CREB-KLF4 dependent autophagy in mouse liver Ischemia Reperfusion Injury
PACAP neuropeptide promotes Hepatocellular Protection via CREB-KLF4 dependent autophagy in mouse liver Ischemia Reperfusion Injury
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DOI：
10.7150/thno.42354
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发表时间：
2020-03
期刊：
影响因子：
12.4
通讯作者：
Zhengze Xue;Yu Zhang;Yuan Liu;Cheng Zhang;Xiu‐da Shen;F. Gao;R. Busuttil;Shusen Zheng;J. Kup
中科院分区：
文献类型：
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作者：
Zhengze Xue;Yu Zhang;Yuan Liu;Cheng Zhang;Xiu‐da Shen;F. Gao;R. Busuttil;Shusen Zheng;J. Kup
器官缺血再灌注损伤（IRI）是肝移植术后肝细胞急性死亡的重要原因。自噬是一种细胞内的自我消化过程，负责恢复应激后稳态所需的细胞重编程。研究方法：在这里，我们在临床相关的延长肝脏冷藏（4 °C UW溶液20小时）然后进行同基因原位肝奥尔特的小鼠模型中分析了垂体腺苷酸环化酶激活多肽（PACAP）促进肝细胞自噬的细胞保护机制。结果如下：与对照组移植后第7天41.7%的肝移植失败相比，PACAP治疗显著提高了移植物存活率（第14天为91.7%），并促进了奥尔特中自噬相关的再生程序。在平行的体外研究中，PACAP增强的自噬改善了细胞损伤（LDH/ALT水平），并减少了H2 O2应激原代肝细胞的坏死。有趣的是，PACAP不仅诱导核cAMP反应元件结合蛋白（CREB），但也触发重编程因子Kruppel样因子4（KLF 4）的表达在IR应激奥尔特。事实上，CREB抑制减弱了肝脏自噬，并在其他PACAP保护的肝脏中重建了肝细胞损伤。此外，CREB抑制抑制PACAP诱导的KLF 4表达，而KLF 4阻断废除PACAP促进的自噬和中和PACAP介导的肝保护在体内和体外。结论：目前的研究证明了PACAP促进的自噬在奥尔特肝细胞稳态中的重要神经调节作用，这为对抗奥尔特中肝脏IRI提供了新的治疗原则。
Organ ischemia reperfusion injury (IRI), associated with acute hepatocyte death, remains an unresolved problem in clinical orthotopic liver transplantation (OLT). Autophagy, an intracellular self-digesting progress, is responsible for cell reprograming required to regain post-stress homeostasis. Methods: Here, we analyzed the cytoprotective mechanism of pituitary adenylate cyclase-activating polypeptide (PACAP)-promoted hepatocellular autophagy in a clinically relevant mouse model of extended hepatic cold storage (4 °C UW solution for 20 h) followed by syngeneic OLT. Results: In contrast to 41.7% of liver graft failure by day 7 post-transplant in control group, PACAP treatment significantly improved graft survival (91.7% by day 14), and promoted autophagy-associated regeneration programs in OLT. In parallel in vitro studies, PACAP-enhanced autophagy ameliorated cellular damage (LDH/ALT levels), and diminished necrosis in H2O2-stressed primary hepatocytes. Interestingly, PACAP not only induced nuclear cAMP response element-binding protein (CREB), but also triggered reprogramming factor Kruppel-like factor 4 (KLF4) expression in IR-stressed OLT. Indeed, CREB inhibition attenuated hepatic autophagy and recreated hepatocellular injury in otherwise PACAP-protected livers. Furthermore, CREB inhibition suppressed PACAP-induced KLF4 expression, whereas KLF4 blockade abolished PACAP-promoted autophagy and neutralized PACAP-mediated hepatoprotection both in vivo and in vitro. Conclusion: Current study documents the essential neural regulation of PACAP-promoted autophagy in hepatocellular homeostasis in OLT, which provides the emerging therapeutic principle to combat hepatic IRI in OLT.