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Nogo-B is a key mediator of hepatic ischemia and reperfusion injury.

ABSTRACT: Nogo-B is an endoplasmic reticulum-residential protein with distinctive functions in different diseases. However, it remains unclear the role of Nogo-B in liver sterile inflammatory injury. This study aims to elucidate the functions and mechanisms in liver ischemia and reperfusion injury (IRI). The Nogo-B expression and liver function were analyzed in biopsy/serum specimens from 36 patients undergoing ischemia-related hepatectomy and in a mouse model of liver IRI. Human specimens were harvested prior to ischemia and post-reperfusion. The Nogo-B knockout (Nogo-BKO) and myeloid-specific Nogo-B knockout (Nogo-BMKO) mice were used to analyze the function and mechanism of Nogo-B in a mouse model of liver IRI. In human specimens, the Nogo-B expression was positively correlated with higher levels of serum transaminase (sALT) and severe histopathological injury at one day post-hepatectomy. Moreover, Nogo-B is mainly expressed on macrophages in normal and ischemic liver tissues from human and mice. Unlike in controls, the Nogo-BKO or Nogo-BMKO livers was protected against IRI, with reduced reactive oxygen species (ROS) production and liver inflammation in ischemic livers. In parallel in vitro studies, Nogo-B deficiency reduced M1 macrophage polarization and inhibited proinflammatory cytokines (TNF-?, IL-6, MCP-1 and iNOS) in response to LPS or HMGB-1 stimulation. Mechanistic studies showed that Nogo-B bound to MST1/2, increased MST1/2, LAST1, and YAP phosphorylation, leading to reduced YAP activity. Interestingly, disruption of macrophage YAP abolished Nogo-B deficiency-mediated cytoprotective effects in vitro and in vivo. Thus, YAP is crucial for the regulation of macrophage Nogo-B-triggered liver inflammation. Nogo-B promotes macrophage-related innate inflammation and contributes to IR-induced liver injury by activating the MST-mediated Hippo/YAP pathway, which provides a potential therapeutic target for clinical management in liver IRI.

SUBMITTER: Rao J

PROVIDER: S-EPMC7582106 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Nogo-B is a key mediator of hepatic ischemia and reperfusion injury.

Rao Jianhua J Cheng Feng F Zhou Haoming H Yang Wenjie W Qiu Jiannan J Yang Chao C Ni Xuehao X Yang Shikun S Xia Yongxiang Y Pan Xiongxiong X Zhang Feng F Lu Ling L Wang Xuehao X

Redox biology 20201008

Nogo-B is an endoplasmic reticulum-residential protein with distinctive functions in different diseases. However, it remains unclear the role of Nogo-B in liver sterile inflammatory injury. This study aims to elucidate the functions and mechanisms in liver ischemia and reperfusion injury (IRI). The Nogo-B expression and liver function were analyzed in biopsy/serum specimens from 36 patients undergoing ischemia-related hepatectomy and in a mouse model of liver IRI. Human specimens were harvested ...[more]

PMID: 33099216

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Project description:Background & aimsIschemia-reperfusion (I/R) is a major mechanism of liver injury following hepatic surgery or transplantation. Despite numerous reports on the role of oxidative/nitrosative stress and mitochondrial dysfunction in hepatic I/R injury, the proteins that are oxidatively modified during I/R damage are poorly characterized. This study was aimed at investigating the oxidatively modified proteins underlying the mechanism for mitochondrial dysfunction in hepatic I/R injury. We also studied the effects of a superoxide dismutase mimetic/peroxynitrite scavenger metalloporphyrin (MnTMPyP) on oxidatively modified proteins and their functions.MethodsThe oxidized and/or S-nitrosylated mitochondrial proteins from I/R-injured mouse livers with or without MnTMPyP pretreatment were labeled with biotin-N-maleimide, purified with streptavidin-agarose, and resolved by 2-dimensional gel electrophoresis. The identities of the oxidatively modified proteins were determined using mass spectrometric analysis. Liver histopathology, serum transaminase levels, nitrosative stress markers, and activities of oxidatively modified mitochondrial proteins were measured.ResultsComparative 2-dimensional gel analysis revealed markedly increased numbers of oxidized and S-nitrosylated mitochondrial proteins following hepatic I/R injury. Many key mitochondrial enzymes involved in cellular defense, fat metabolism, energy supply, and chaperones were identified as being oxidatively modified proteins. Pretreatment with MnTMPyP attenuated the I/R-induced increased serum transaminase levels, histologic damage, increased inducible nitric oxide synthase expression, and S-nitrosylation and/or nitration of various key mitochondrial proteins. MnTMPyP pretreatment also restored I/R-induced suppressed activities of mitochondrial aldehyde dehydrogenase, 3-ketoacyl-CoA thiolases, and adenosine triphosphate synthase.ConclusionsThese results suggest that increased nitrosative stress is critically important in promoting S-nitrosylation and nitration of various mitochondrial proteins, leading to mitochondrial dysfunction with decreased energy supply and increased hepatic injury.

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Nogo-B is a key mediator of hepatic ischemia and reperfusion injury.

Publications

Nogo-B is a key mediator of hepatic ischemia and reperfusion injury.

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