低温氧合灌注通过TFPI2抑制CLIP1介导的TIRAP泛素化，以减少脂肪肝的缺血再灌注损伤-动脉网

Hypothermic oxygenated perfusion inhibits CLIP1-mediated TIRAP ubiquitination via TFPI2 to reduce ischemia‒reperfusion injury of the fatty liver

Nature 等信源发布 2024-12-02 09:27

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AbstractThe use of fatty livers in liver transplantation has emerged as a crucial strategy to expand the pool of donor livers; however, fatty livers are more sensitive to ischemia‒reperfusion injury (IRI). Excessive congenital inflammatory responses are crucial in IRI. Hypothermic oxygenated perfusion (HOPE) is a novel organ preservation technique that may improve marginal donor liver quality by reducing the inflammatory response.

摘要脂肪肝在肝移植中的应用已成为扩大供体肝脏库的关键策略；然而，脂肪肝对缺血再灌注损伤（IRI）更敏感。过度的先天性炎症反应在IRI中至关重要。低温氧合灌注（HOPE）是一种新型的器官保存技术，可以通过减少炎症反应来改善边缘供体肝脏的质量。

Tissue factor pathway inhibitor-2 (TFPI2) and CAP-Gly domain-containing linker protein 1 (CLIP1) exhibit modulatory effects on the inflammatory response. However, the underlying mechanisms of HOPE in fatty liver and the effects of TFPI2 and CLIP1 in fatty liver IRI remain unclear. Here, we aimed to explore the impact of HOPE on the inflammatory response in a rat model of fatty liver IRI and the mechanisms of action of TFPI2 and CLIP1.

组织因子途径抑制剂-2（TFPI2）和含帽甘氨酸结构域的接头蛋白1（CLIP1）对炎症反应具有调节作用。然而，脂肪肝中HOPE的潜在机制以及TFPI2和CLIP1在脂肪肝IRI中的作用仍不清楚。在这里，我们旨在探讨HOPE对脂肪肝IRI大鼠模型炎症反应的影响以及TFPI2和CLIP1的作用机制。

HOPE significantly reduces liver injury, especially the inflammatory response, and alleviates damage to hepatocytes and endothelial cells. Mechanistically, HOPE exerts its effects by inhibiting TFPI2, and CLIP1 can rescue the damaging effects of TFPI2. Moreover, HOPE promoted the ubiquitination and subsequent degradation of Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP) by regulating the binding of R24 of the KD1 domain of TFPI2 with CLIP1, thereby negatively regulating the TLR4/NF-κB-mediated inflammatory response and reducing IRI.

HOPE可显着减少肝损伤，尤其是炎症反应，并减轻对肝细胞和内皮细胞的损伤。从机制上讲，HOPE通过抑制TFPI2发挥作用，而CLIP1可以挽救TFPI2的破坏作用。此外，HOPE通过调节TFPI2 KD1结构域的R24与CLIP1的结合，从而负调节TLR4/NF-κB介导的炎症反应，促进了含Toll/白细胞介素-1受体结构域的衔接蛋白（TIRAP）的泛素化和随后的降解。减少IRI。

Furthermore, TFPI2 expression increased and CLIP1 expression decreased following cold ischemia in human fatty livers. Overall, our results suggest that targeting the inflammatory response by modulating the TFPI2/CLIP1/TIRAP signaling pathway via HOPE represents a potential therapeutic approach to ameliorate IRI during fatty liver transplantation..

此外，人脂肪肝冷缺血后TFPI2表达增加，CLIP1表达降低。总体而言，我们的研究结果表明，通过HOPE调节TFPI2/CLIP1/TIRAP信号通路来靶向炎症反应是改善脂肪肝移植过程中IRI的潜在治疗方法。。

IntroductionLiver transplantation is the sole efficacious therapy for terminal liver disease. Nevertheless, the insufficiency of donor organs constrains the advancement of liver transplantation technologies1. The quality of donor livers has become a focus of attention in the field of organ transplantation because of the increasing number of organ donations each year.

简介肝移植是治疗终末期肝病的唯一有效方法。然而，供体器官的不足限制了肝移植技术的进步1。由于每年器官捐赠的数量不断增加，供体肝脏的质量已成为器官移植领域关注的焦点。

Among the donated organs, fatty liver is a substantial concern for poor liver quality, with an incidence rate of 15–30%2. The accumulation of fatty acids and neutral fats in liver cells leads to a specific change in the liver parenchyma known as steatosis. Steatosis is associated with liver damage caused by proapoptotic activity and inflammatory stimulation by free fatty acids3.

在捐赠的器官中，脂肪肝是肝脏质量差的主要原因，发病率为15-30%2。脂肪酸和中性脂肪在肝细胞中的积累导致肝实质的特定变化，称为脂肪变性。脂肪变性与促凋亡活性和游离脂肪酸的炎症刺激引起的肝损伤有关3。

Fatty livers are more susceptible to cold ischemia‒reperfusion injury (IRI) than normal livers. First, the liver cell volume increases, inhibiting the liver sinusoids during liver cell steatosis, causing a relatively ischemic environment within the fatty liver. Second, insufficient mitochondrial beta-oxidation in fatty livers reduces ATP generation in liver cells, thereby decreasing energy in the liver during IRI and increasing reactive oxygen species (ROS) production.

脂肪肝比正常肝脏更容易发生冷缺血再灌注损伤（IRI）。首先，肝细胞体积增加，在肝细胞脂肪变性期间抑制肝窦，导致脂肪肝内相对缺血的环境。其次，脂肪肝中线粒体β-氧化不足会减少肝细胞中ATP的产生，从而降低IRI期间肝脏的能量并增加活性氧（ROS）的产生。

Third, abnormal regulation of Kupffer cells in fatty livers decreases the regulation of liver sinusoidal blood flow4,5.During IRI, endothelial cells (ECs) are more susceptible to damage because of the leakage of damage-associated molecular patterns (DAMPs), such as endogenous DNA or high mobility group box 1 (HMGB1), from damaged steatotic hepatocytes, which activate the TLR inflammatory pathway in ECs, leading to the release of inflammatory cytokines6,7.

第三，脂肪肝中库普弗细胞的异常调节降低了肝窦血流的调节4,5。在IRI期间，内皮细胞（EC）更容易受到损伤，因为损伤相关分子模式（DAMP）的泄漏，例如内源性DNA或高迁移率族蛋白1（HMGB1）来自受损的脂肪肝细胞，其激活EC中的TLR炎症途径，导致炎性细胞因子的释放6,7。

Extracellular vesicles secreted by steatotic hepatocytes contain proteins, lipids, and nucleic acids that further .

脂肪变性肝细胞分泌的细胞外囊泡含有蛋白质，脂质和核酸。

Data availability

数据可用性

The data of this study are available from the corresponding authors upon reasonable request.

本研究的数据可根据合理要求从通讯作者处获得。

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Download referencesAcknowledgementsThis work was supported by the National Natural Science Foundation of China (grant number 82370671), the Medical Talent Climbing Program of Zhongnan Hospital of Wuhan University (grant number PDJH202315), and the Platform Support Key Project of Zhongnan Hospital of Wuhan University (grant number PTXM2023003).Author informationAuthors and AffiliationsZhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-based Medical Materials, 430071, Wuhan, ChinaPengpeng Yue, Hankun Cao, Jian You, Jun Luo, Zhongshan Lu, Hao Chen, Zhongzhong Liu, Zibiao Zhong, Yan Xiong, Xiaoli Fan & Qifa YeDepartment of Hematology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, ChinaXiaoyan LvDepartment of Hepatobiliary Surgery, Department of Organ Transplantation, Guizhou Provincial People’s Hospital, 550002, Guiyang, ChinaYongkang ZouThe Third Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, 410013, Changsha, ChinaQifa YeAuthorsPengpeng YueView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了国家自然科学基金（批准号82370671），武汉大学中南医院医学人才攀登计划（批准号PDJH202315）和武汉大学中南医院平台支持重点项目（批准号PTXM2023003）的支持。作者信息作者和附属机构武汉大学中南医院，武汉大学肝胆疾病研究所，武汉大学移植中心，国家捐赠器官采购质量控制中心，湖北省移植医学技术重点实验室，湖北省天然聚合物生物肝临床研究中心，湖北省天然聚合物基医用材料工程中心，430071，武汉，中国彭彭鹏岳，曹汉坤，建友，罗军，吕中山，陈浩，刘忠忠，钟子标，熊燕，范晓丽，叶奇发武汉大学中南医院血液科，430071，中国小燕吕贵州省人民医院肝胆外科，器官移植科s医院，550002，中国贵阳市中南大学永康区湘雅三医院，国家卫生部移植医学工程技术研究中心，410013，长沙，ChinaQifa YeAuthorsPengpeng YueView作者出版物您也可以在中搜索此作者。

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PubMed Google ScholarContributionsX.L.F. and Q.F.Y. developed the study concept and design, reviewed and revised the paper, and provided funding support; P.P.Y. developed the study concept and design, performed the experiments and data analysis, developed the methodology, and wrote and revised the paper; X.Y.L., H.K.C., Y.K.Z., J.L., Z.S.L., and J.Y.

PubMed谷歌学术贡献x。五十、 F.和Q.F.Y.制定了研究概念和设计，审查和修订了论文，并提供了资金支持；P、 P.Y.开发了研究概念和设计，进行了实验和数据分析，开发了方法，撰写并修订了论文；十、 Y.L.，H.K.C.，Y.K.Z.，J.L.，Z.S.L。和J.Y。

performed the clinical sample collection and analysis. P.P.Y., H.C., Z.Z.L., Y.X., and Z.B.Z. analyzed the data. All of the authors have read and approved the final manuscript.Corresponding authorsCorrespondence to.

。P、 P.Y.，H.C.，Z.Z.L.，Y.X。和Z.B.Z.分析了数据。所有作者都阅读并批准了最终稿件。通讯作者通讯。

Xiaoli Fan or Qifa Ye.Ethics declarations

Competing interests

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The authors declare no competing interests.

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Ethical approval

道德认可

The animal experimental protocol was approved by the Experimental Animal Welfare Ethics Committee at Zhongnan Hospital of Wuhan University (approval no. ZN2022202). Human liver samples were obtained from Wuhan University Zhongnan Hospital. Approval for the study was obtained from the Medical Ethics Committee of the hospital (approval no.

动物实验方案经武汉大学中南医院实验动物福利伦理委员会批准（批准号ZN2022202）。人肝脏样品获自武汉大学中南医院。该研究获得了医院医学伦理委员会的批准（批准号：。

2020122), and we obtained informed consent from all participants..

2020122），我们获得了所有参与者的知情同意。。

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Reprints and permissionsAbout this articleCite this articleYue, P., Lv, X., Cao, H. et al. Hypothermic oxygenated perfusion inhibits CLIP1-mediated TIRAP ubiquitination via TFPI2 to reduce ischemia‒reperfusion injury of the fatty liver.

转载和许可本文引用本文Yue，P.，Lv，X.，Cao，H。等人。低温氧合灌注通过TFPI2抑制CLIP1介导的TIRAP泛素化，以减少脂肪肝的缺血再灌注损伤。

Exp Mol Med (2024). https://doi.org/10.1038/s12276-024-01350-8Download citationReceived: 03 May 2024Revised: 03 September 2024Accepted: 04 September 2024Published: 02 December 2024DOI: https://doi.org/10.1038/s12276-024-01350-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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