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An ALOX12–12-HETE–GPR31 signaling axis is a key mediator of hepatic ischemia–reperfusion injury

Nature Medicine volume 24, pages 73–83 (2018)Cite this article

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Abstract

Hepatic ischemia–reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)–12-hydroxyeicosatetraenoic acid (12-HETE)–G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12–12-HETE–GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.

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Figure 1: ALOX12 is dramatically upregulated during hepatic IR injury.
Figure 2: ALOX12 directly promotes 12-HETE accumulation in hepatic IR injury.
Figure 3: Alox12 knockout inhibits IR-induced liver dysfunction, cell death and inflammation.
Figure 4: 12-HETE promotes hepatic IR injury by inducing a burst of inflammation.
Figure 5: GPR31 is responsible for 12-HETE-mediated hepatic IR injury.
Figure 6: ML355 inhibits liver damage in a monkey hepatic IR model.

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Acknowledgements

We thank Shanghai Metabolome Institute–Wuhan for their help in examining AA metabolites in the liver, serum and cell lysates. This work was supported by grants from the National Science Fund for Distinguished Young Scholars (no. 81425005; H.L.), the Key Project of the National Natural Science Foundation (no. 81330005 and 81630011; H.L.), the National Science and Technology Support Project (no. 2014BAI02B01 and 2015BAI08B01; H.L.), the National Key Research and Development Program (no. 2013YQ030923-05 (H.L.) and 2016YFF0101504 (Z.-G.S.)), the National Natural Science Foundation of China (no. 81770053; Z.-G.S.) and the Key Collaborative Project of the National Natural Science Foundation (no. 91639304; H.L. and Z.-G.S.).

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Author notes

  1. Xiao-Jing Zhang, Xu Cheng, Zhen-Zhen Yan and Jing Fang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China

    Xiao-Jing Zhang, Xiaozhan Wang, Li-Jun Shen, Pi-Xiao Wang, Song Tian, Xue-Yong Zhu, Yan Zhang, Rui-Feng Tian, Zhi-Gang She & Hongliang Li

  2. Institute of Model Animals of Wuhan University, Wuhan, China

    Xiao-Jing Zhang, Xiaozhan Wang, Zhen-Yu Liu, Li-Jun Shen, Peng Zhang, Pi-Xiao Wang, Yan-Xiao Ji, Jun-Yong Wang, Song Tian, Xue-Yong Zhu, Yan Zhang, Rui-Feng Tian, Zhi-Gang She & Hongliang Li

  3. Basic Medical School, Wuhan University, Wuhan, China

    Xiao-Jing Zhang, Peng Zhang, Pi-Xiao Wang, Yan-Xiao Ji, Zhi-Gang She & Hongliang Li

  4. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China

    Xiao-Jing Zhang, Xu Cheng, Peng Zhang, Pi-Xiao Wang, Yan-Xiao Ji, Jun-Yong Wang, Zhi-Gang She & Hongliang Li

  5. College of Life Sciences, Wuhan University, Wuhan, China

    Zhen-Zhen Yan, Zhen-Yu Liu & Zan Huang

  6. Division of Cardiothoracic and Vascular Surgery, Key Laboratory of Organ Transplantation, Ministry of Education and Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jing Fang

  7. Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Weijun Wang

  8. Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China

    Peng Zhang, Yan-Xiao Ji & Hongliang Li

  9. Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Rufang Liao

  10. Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China

    Lin Wang

  11. Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Xin-Liang Ma

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  1. Xiao-Jing Zhang
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Contributions

X.-J.Z., X.C., Z.-Z.Y. and J.F. designed and performed the experiments, analyzed the data and wrote the manuscript; X.W. performed animal experiments, analyzed data and edited the manuscript; W.W. and Z.-Y.L. performed biological experiments and analyzed data; L.-J.S. analyzed data and organized figures; P.Z., P.-X.W. and Y.-X.J. performed omics analyses and provided important advice for this study; R.L. performed perfusion CT experiments; J.-Y.W. performed ultra-high-performance liquid chromatography–mass spectrometry experiments; S.T. established the animal hepatic IR models; X.-Y.Z. performed western blot experiments; Y.Z. performed staining experiments; R.-F.T. assisted in the performance of pig and monkey surgeries; L.W. collected clinical human liver and serum samples; X.-L.M., Z.H. and Z.-G.S. helped design the project and edited the manuscript; and H.L. designed experiments, wrote the manuscript and supervised the study.

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Correspondence to Hongliang Li.

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Zhang, XJ., Cheng, X., Yan, ZZ. et al. An ALOX12–12-HETE–GPR31 signaling axis is a key mediator of hepatic ischemia–reperfusion injury. Nat Med 24, 73–83 (2018). https://doi.org/10.1038/nm.4451

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