Pituitary Adenylate Cyclase-activating Polypeptides Prevent Hepatocyte Damage by Promoting Yes-associated Protein in Liver Ischemia-Reperfusion Injury
Year: 2019
Type: article
Abstract: BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is a severe complication in liver transplantation, hepatectomy, and hemorrhagic shock. As neuropeptides transmit the regulatory signal between nervous and immune systems communication, our previous study documented that pituitary adenylate cyclase-activating polypeptides (PACAP) depressed hepatic Toll-like receptor 4 immune response in liver IRI. METHODS: Here, we focused on how PACAP suppressed hepatocellular damage and enhanced hepatocyte regeneration in a murine model of partial liver warm IRI. RESULTS: Yes-associated protein (YAP), a cellular modulator of tissue regeneration, was readily induced in wild type (WT) mouse IR-livers. As its induction was failed in PACAP-deficient livers, PACAP supplement enhanced YAP expression in WT mouse and promoted its nuclear translocation and downstream antioxidative/regenerative genes expression both in vivo and in vitro. Further, verteporfin, a YAP transcriptional inhibitor, abolished PACAP-mediated hepatoprotection significantly. Meanwhile, blockade of protein kinase A (PKA)-CRE-binding protein (CREB) signaling recreated liver damage in PACAP-protected liver as well as impeded stimulation on YAP and its downstream gene expressions. Consistently, inhibition of PKA-CREB decreased PACAP-promoted YAP expression in primary hepatocytes culture, and made them vulnerable to H2O2 stress in vitro. In addition, lysophosphatidic acid, another Hippo pathway inhibitor, failed to affect PACAP-mediated hepatoprotection or hepatocellular YAP induction. This implies that PACAP regulated YAP through PKA-CREB pathway at the transcriptional level rather than canonical hippo pathway. CONCLUSIONS: Our study discovered the neural modulation of PACAP-YAP axis in hepatic cytoprotection and homeostasis in liver IRI. These reveal a novel insight of neuropeptide PACAP in combating liver IRI in clinical patients.
Source: Transplantation
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: TIM-3 Negative Costimulation Signaling at the Innate-Adaptive Immune interface in Liver Transplant Ischemia-Reperfusion Injury, Tim Costimulation in Liver Transplant Ischemia Injury, Ischemia / Reperfusion Injury Mediated TIM-3+CD4+ T Cell Exhaustion In Liver Transplant, PACAP Mediated Neural Regulation of Hepatic Inflammation in Orthotopic Liver Transplantation, Innate-Adaptive Immunoregulation in Liver Transplant Ischemia/Reperfusion Injury, HuR/HIF – SIRT1 Signaling Axis in Liver Transplant Rejuvenation
OpenAlex ID: W2937952592