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ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver ischemia/reperfusion injury
Ran Liu, … , Daichao Xu, Jinyang Gu
Ran Liu, … , Daichao Xu, Jinyang Gu
Published May 14, 2024
Citation Information: J Clin Invest. 2024;134(13):e180451. https://doi.org/10.1172/JCI180451.
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Research Article

ZBP1-mediated apoptosis and inflammation exacerbate steatotic liver ischemia/reperfusion injury

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Abstract

Steatotic donor livers are becoming more and more common in liver transplantation. However, the current use of steatotic grafts is less acceptable than normal grafts due to their higher susceptibility to ischemia/reperfusion (I/R) injury. To investigate the mechanism underlying the susceptibility of steatotic liver to I/R injury, we detected cell death markers and inflammation in clinical donor livers and animal models. We found that caspase-8–mediated hepatic apoptosis is activated in steatotic liver I/R injury. However, ablation of caspase-8 only slightly mitigated steatotic liver I/R injury without affecting inflammation. We further demonstrated that RIPK1 kinase induces both caspase-8–mediated apoptosis and cell death–independent inflammation. Inhibition of RIPK1 kinase significantly protects against steatotic liver I/R injury by alleviating both hepatic apoptosis and inflammation. Additionally, we found that RIPK1 activation is induced by Z-DNA binding protein 1 (ZBP1) but not the canonical TNF-α pathway during steatotic liver I/R injury. Deletion of ZBP1 substantially decreases the steatotic liver I/R injury. Mechanistically, ZBP1 is amplified by palmitic acid–activated JNK pathway in steatotic livers. Upon I/R injury, excessive reactive oxygen species trigger ZBP1 activation by inducing its aggregation independent of the Z-nucleic acids sensing action in steatotic livers, leading to the kinase activation of RIPK1 and the subsequent aggravation of liver injury. Thus, ZBP1-mediated RIPK1-driven apoptosis and inflammation exacerbate steatotic liver I/R injury, which could be targeted to protect steatotic donor livers during transplantation.

Authors

Ran Liu, Huan Cao, Shuhua Zhang, Mao Cai, Tianhao Zou, Guoliang Wang, Di Zhang, Xueling Wang, Jianjun Xu, Shenghe Deng, Tongxi Li, Daichao Xu, Jinyang Gu

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Figure 7

ROS triggers ZBP1 aggregation and activation in liver I/R injury.

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ROS triggers ZBP1 aggregation and activation in liver I/R injury.
(A) Fl...
(A) Flag immunostaining was performed in I/R-challenged ND-fed mouse livers overexpressing Zbp1-Flag (n = 8). (B) ZBP1 aggregation was detected with immunoblot under nonreducing or reducing conditions in I/R-challenged mouse livers or transplantation-challenged donor livers (n = 3). (C) hZBP1-GFP plasmids were transfected into HEK293T cells. After 1 mM H2O2 treatment for 4 hours or H/R challenge after pretreatment with 10 mM NAC, ZBP1 oligomers were detected from green fluorescence (n = 8). (D–H) After AAV8-mediated Zbp1-Flag overexpression in ND-fed mice and pretreatment with NAC, I/R operation was performed (n = 8). Flag immunostaining (D), ZBP1 aggregation and ZBP1-RIPK1 interaction (E), serum ALT/AST levels (F), H&E and TUNEL staining (G), and detection of serum levels of the proinflammatory cytokines (H) were detected. All data are presented as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. Unpaired, 2-tailed Student’s t test (A and D). 2-way ANOVA, post hoc Bonferroni’s test (C, G, and H). Scale bars (A, C, and D): 10 μm, (G) 200 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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