Highlights
- •High graft YAP expression was correlated with well-preserved histology and improved hepatocellular function in human OLT.
- •YAP activation promoted downstream regenerative/anti-oxidative gene induction.
- •YAP activation diminished oxidative stress, necrosis/apoptosis, and suppressed the innate inflammatory response.
- •YAP activation suppressed extracellular matrix synthesis and hepatic stellate cell activation, and stopped fibrogenesis.
- •YAP activation failed to protect Nrf2-deficient mouse livers against IR-mediated tissue damage.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: June 12, 2019
Accepted:
May 20,
2019
Received in revised form:
May 7,
2019
Received:
January 31,
2019
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
