Background: Previously we have demonstrated that neuropeptide pituitary adenylate cyclase-activating polypeptides (PACAP) suppressed local inflammation, and protected liver against IRI by innervating the liver and immune cells. Recently, we focused on Yes-associated protein (YAP), a regulator of cellular anti-oxidation and regeneration, which drives cell proliferation and promotes survival. The current work studied how PACAP prevented hepatocellular damage and promoted hepatocyte homeostasis/regeneration by promoting YAP function. Methods&Results: Exogenous PACAP therapy protected liver against IR stress mediated damage, while PACAP KO mice showed increased susceptibility to hepatic IRI. Interestingly, unlike in WT mates, IR stress failed to mediate YAP gene induction 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 function. VP treatment alone could exacerbate the IR-induced liver injury in WT mice, as evidenced by elevated serum alanine aminotransferase (sALT) level and damaged hepatic architecture. In addition, 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 (p<0.001). In parallel, PACAP treatment diminished otherwise abundant hepatocellular necrosis/apoptosis after IR insult, as evidenced by decreased frequency of TUNEL⁺ cells and caspase-3 activity. However, VP supplement significantly aggravated liver damage by elevated frequency of TUNEL⁺ cells and increased caspase-3 activity. Consistently, PACAP-induced YAP ameliorated hydrogen peroxide (H₂O₂)-triggered necrosis in primary hepatocyte cultures in vitro. 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: Xue Z., Liu Y., Zhang C., Busuttil R., Kupiec-Weglinski J., Ji H. Neuropeptide PACAP Protects Hepatocyte against Liver Ischemia/Reperfusion Injury by Promoting Yes-Associated Protein (YAP) Function Am J Transplant. 2017;17 (suppl 3).

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