Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury
Authors: Qiang Xia
Haofeng Ji
Cheng Zhang
Ning Xu
Yuan Liu
Jin Xu
Ronald W Busuttil
Tianfei Lu
Jerzy W Kupiec-Weglinski
Zhengze Xue
Journal: Journal of Hepatology (2019)
Discipline: CLINICAL MEDICINE
Keywords: Fibrogenesis; Hippo; Immune response; Inflammation; Liver ischemia-reperfusion injury
Affiliations: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA; Department of Liver Surgery, Ren Ji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China., Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA; Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China., Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA; Department of Pancreatic Surgery, Shengjing Hospital, China Medical University, Shenyang, China., Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA., Department of Liver Surgery, Ren Ji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: ., Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA, USA. Electronic address: .

Abstract:  Background &amp; aims: Hepatic ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver resection and transplantation. YAP, a key downstream effector of the Hippo pathway, is essential for determining cell fate and maintaining homeostasis in the liver. We aimed to elucidate its role in IRI. Methods: The role of YAP/Hippo signaling was systematically studied in biopsy specimens from 60 patients after orthotopic liver transplantation (OLT), and in a mouse model of liver warm IRI. Human biopsy specimens were collected after 2-10 h of cold storage and 3 h post-reperfusion, before being screened by western blot. In the mouse model, the role of YAP was probed by activating or inhibiting YAP prior to ischemia-reperfusion. Results: In human biopsies, high post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at postoperative day 1-7. In mice, the ischemia insult (90 min) triggered intrinsic hepatic YAP expression, which peaked at 1-6 h of reperfusion. Activation of YAP protected the liver against IR-stress, by promoting regenerative and anti-oxidative gene induction, while diminishing oxidative stress, necrosis/apoptosis and the innate inflammatory response. Inhibition of YAP aggravated hepatic IRI and suppressed repair/anti-oxidative genes. In mouse hepatocyte cultures, activating YAP prevented hypoxia-reoxygenation induced stress. Interestingly, YAP activation suppressed extracellular matrix synthesis and diminished hepatic stellate cell (HSC) activation, whereas YAP inhibition significantly delayed hepatic repair, potentiated HSC activation, and enhanced liver fibrosis at 7 days post-IRI. Notably, 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, providing evidence of a potential therapeutic target 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 after human liver transplantation. YAP activation attenuated hepatocellular oxidative stress and diminished the innate immune response in mouse livers following ischemia-reperfusion injury. In the mouse model, YAP inhibited hepatic stellate cell activation, and abolished injury-mediated fibrogenesis up to 7 days after the ischemic insult. 

Retracted: No

PubPeer comments:
 There are many paradoxical results in Figure2.  Please see the Fig2, there is no any difference in YAP protein expression between IR-Ctrl and sham in Figure 2E, however, there are obvious difference in YAP mRNA expression in Fig2A and Fig2B. As we known , the protein is the function effector. The YAP protein expression did not change in the IR process. In addition, the phosphorylation of YAP increased between IR-Ctrl and sham, that is to say, the YAP activity was inhibited during IR, however, why the transcription of YAP target genes increased during IR in Figure2F??? It is too strange. I think the authors did not recognized that the activity of YAP is regulated by the phosphorylation, that is very important . ,