TY - JOUR
T1 - Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury
AU - Liu, Yuan
AU - Lu, Tianfei
AU - Zhang, Cheng
AU - Xu, Jin
AU - Xue, Zhengze
AU - Busuttil, Ronald W.
AU - Xu, Ning
AU - Xia, Qiang
AU - Kupiec-Weglinski, Jerzy W.
AU - Ji, Haofeng
N1 - Funding Information:
NIH Grant R21 AI122155 and AI138165 (HJ). PO1 AI120944, RO1 DK107533, DK102110, and DK062357 (JWKW). Shanghai Yangfan Program 19YF1428000 (YL). The Dumont Research Foundation.
Publisher Copyright:
© 2019 European Association for the Study of the Liver
PY - 2019/10
Y1 - 2019/10
N2 - Background & 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.
AB - Background & 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.
KW - Fibrogenesis
KW - Hippo
KW - Immune response
KW - Inflammation
KW - Liver ischemia-reperfusion injury
KW - Orthotopic liver transplantation
KW - YAP
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U2 - 10.1016/j.jhep.2019.05.029
DO - 10.1016/j.jhep.2019.05.029
M3 - Article
C2 - 31201834
AN - SCOPUS:85068004207
SN - 0168-8278
VL - 71
SP - 719
EP - 730
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -