Activation of YAP Attenuates Hepatic Damage and Fibrosis in Liver Ischemia-Reperfusion Injury

Abstract Background & Aims Hepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, the effector of Hippo pathway, is essential in determining cell fate and maintaining homeostasis in the liver. Methods This study systemically evaluated putative role of YAP/Hippo signaling in human orthotopic liver transplantation (OLT) and in a murine model of liver warm IRI. Results Hepatic biopsy specimens from OLT patients (n=60) were collected after 2-10h of cold storage (pre-OLT) and 3h post-reperfusion (post-OLT) under an institutional research broad protocol, and screened by Western blots. High post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at post-operative day 1-7 (POD 1-7). In mice, the ischemia insult (90min) triggered intrinsic hepatic YAP expression, peaking at 1-6h of reperfusion. Activating YAP protected liver against IR-stress, promoted downstream regenerative/anti-oxidative gene induction, diminished oxidative stress and necrosis/apoptosis, and suppressed innate inflammation response. In contrast, inhibiting YAP aggravated hepatic IRI and suppressed repair/anti-oxidative genes. In parallel in vitro studies, activating YAP prevented hypoxia-reoxygenation induced stress in mouse hepatocyte cultures. Although sALT levels were progressively decreased from 6h to 7d post-reperfusion in IR-stressed mouse livers, hepatic fibrogenesis was steadily developing. Interestingly, YAP activation suppressed extracellular matrix synthesis and diminished hepatic stellate cells (HSCs) activation, whereas YAP inhibition significantly delayed hepatic repair, potentiated HSCs activation, and enhanced liver fibrosis at 7d post-IRI. However, YAP activation failed to protect Nrf2-deficient livers against IR-mediated damage, leading to extensive fibrosis. Conclusion Our novel findings document the crucial role of YAP in IR-mediated hepatocellular damage and liver fibrogenesis, and imply the therapeutic potential for the management of sterile liver inflammation in transplant recipients. Lay summary In the clinical arm, graft YAP expression negatively correlated with liver function and tissue damage in human OLT. We then demonstrated that YAP activation attenuated hepatocellular oxidative stress and diminished innate immune response in mouse liver IRI. YAP inhibited HSCs activation, and abolished IR-mediated mouse liver fibrogenesis during 7d post-IRI. However, YAP activation failed to prevent IR-injury in Nrf2-deficient livers damage, leading to extensive fibrosis.