Hippo (YAP)–autophagy axis protects against hepatic ischemia-reperfusion injury through JNK signaling

May 26, 2023Chinese medical journal

The Hippo (YAP) pathway and cell recycling protect the liver from blood flow injury through JNK signaling

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Abstract

was activated in post-perfusion liver grafts during liver transplantation, with a significant positive correlation to Yes-associated protein (YAP) levels.

YAP expression positively correlates with autophagy activation in hepatocytes during liver transplantation.
Knockdown of YAP in liver-specific models inhibited autophagy during ischemia-reperfusion injury.
YAP deficiency aggravated liver ischemia-reperfusion injury by increasing hepatocyte apoptosis.
Overexpression of YAP reduced ischemia-reperfusion injury effects, but this was negated when autophagy was inhibited.
YAP's regulation of autophagy is linked to through its interaction with the TEAD domain.

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BACKGROUND: (HIRI) remains a common complication during liver transplantation (LT) in patients. As a key downstream effector of the Hippo pathway, Yes-associated protein (YAP) has been reported to be involved in various physiological and pathological processes. However, it remains elusive whether and how YAP may control activation during ischemia-reperfusion.

METHODS: Human liver tissues from patients who had undergone LT were obtained to evaluate the correlation between YAP and autophagy activation. Both an in vitro hepatocyte cell line and in vivo liver-specific YAP knockdown mice were used to establish the hepatic ischemia-reperfusion models to determine the role of YAP in the activation of autophagy and the mechanism of regulation.

RESULTS: Autophagy was activated in the post-perfusion liver grafts during LT in patients, and the expression of YAP positively correlated with the autophagic level of hepatocytes. Liver-specific knockdown of YAP inhibited hepatocytes autophagy upon hypoxia-reoxygenation and HIRI ( P <0.05). YAP deficiency aggravated HIRI by promoting the apoptosis of hepatocytes both in the in vitro and in vivo models ( P <0.05). Attenuated HIRI by overexpression of YAP was diminished after the inhibition of autophagy with 3-methyladenine. In addition, inhibiting autophagy activation by YAP knockdown exacerbated mitochondrial damage through increasing reactive oxygen species ( P <0.05). Moreover, the regulation of autophagy by YAP during HIRI was mediated by AP1 (c-Jun) N-terminal kinase (JNK) signaling through binding to the transcriptional enhanced associate domain (TEAD).

CONCLUSIONS: YAP protects against HIRI by inducing autophagy via that suppresses the apoptosis of hepatocytes. Targeting Hippo (YAP)-JNK-autophagy axis may provide a novel strategy for the prevention and treatment of HIRI.

Key numbers

100 of 100

Correlation of YAP and levels

Patient liver graft samples collected during transplantation.

42.9%

Increased apoptosis in YAP-LKD mice

Percentage of early liver dysfunction due to .

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Hippo (YAP)–autophagy axis protects against hepatic ischemia-reperfusion injury through JNK signaling

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