Background: Yes-associated protein (YAP), a regulator of cellular anti-oxidation and regeneration, drives cell proliferation and promotes survival. We have previously demonstrated that neuropeptide pituitary adenylate cyclase-activating polypeptides (PACAP) suppressed local inflammation, and protected liver against IRI by innervating the liver and immune cells. The current study focused on how PACAP prevented hepatocellular damage and promoted hepatocyte homeostasis/regeneration. Methods&Results: In a mouse model of liver warm ischemia (90min) followed by reperfusion (0-24h), YAP was readily triggered in WT mice after the ischemia insult. Interestingly, unlike in WT mates, IR stress failed to trigger YAP expression in PACAP deficient livers, whereas PACAP monotherapy promoted YAP significantly in WT IR-stressed livers. To test whether PACAP induced YAP is essential for ameliorating liver damage during IR, we employed verteporfin (VP), an inhibitor that blocked YAP from binding TEAD. VP treatment alone could exacerbate the IR-induced liver injury, as evidenced by elevated serum alanine aminotransferase (sALT) level and damaged hepatic architecture. Meanwhile, VP restored liver IR damage in PACAP-pretreated mice, as evidenced by increased sALT level, accumulated hepatic ROS, and deteriorated liver pathology (more severe lobular edema, widespread hemorrhage, and congestion/hepatocellular necrosis), compared with PACAP monotherapy group. In parallel, neuropeptide PACAP-induced YAP ameliorated hydrogen peroxide (H₂O₂)-triggered necrosis in primary hepatocyte cultures. The regulatory function of PACAP on hepatocytes was confirmed by enhanced YAP expression and visualized endogenous nuclear translocation, decreased ALT/LDH releasing, and abundant YAP downstream anti-oxidative/regenerative gene inductions. Conclusion: Our novel findings document the neural immunomodulation of PACAP-mediated YAP signaling in hepatic homeostasis and cytoprotection in liver IRI. Because the enhancement of neural modulation differentially regulates local innate inflammation and hepatocyte survival, these results provide the rationale for novel neuropeptide-based approaches to manage liver IRI in transplant patients.

CITATION INFORMATION: Liu Y, Zhang C, Busuttil R, Kupiec-Weglinski J, Xia Q, Ji H. Neuropeptide PACAP Prevents Hepatocyte Damage by Promoting Yes-Associated Protein (YAP) in Mouse Liver Ischemia/Reperfusion Injury. Am J Transplant. 2017;17 (suppl 3).

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