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

1. Nat Med. 2018 Jan;24(1):73-83. doi: 10.1038/nm.4451. Epub 2017 Dec 11. An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury. Zhang XJ(1)(2)(3)(4), Cheng X(4), Yan ZZ(5), Fang J(6), Wang X(1)(2), Wang W(7), Liu ZY(2)(5), Shen LJ(1)(2), Zhang P(2)(3)(4)(8), Wang PX(1)(2)(3)(4), Liao R(9), Ji YX(2)(3)(4)(8), Wang JY(2)(4), Tian S(1)(2), Zhu XY(1)(2), Zhang Y(1)(2), Tian RF(1)(2), Wang L(10), Ma XL(11), Huang Z(5), She ZG(1)(2)(3)(4), Li H(1)(2)(3)(4)(8). Author information: (1)Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China. (2)Institute of Model Animals of Wuhan University, Wuhan, China. (3)Basic Medical School, Wuhan University, Wuhan, China. (4)Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China. (5)College of Life Sciences, Wuhan University, Wuhan, China. (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. (7)Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (8)Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China. (9)Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China. (10)Department of Hepatic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China. (11)Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Comment in Hepatology. 2018 Oct;68(4):1642-1643. doi: 10.1002/hep.29870. Transplantation. 2018 Jun;102(6):887-889. doi: 10.1097/TP.0000000000002206. 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. DOI: 10.1038/nm.4451 PMID: 29227475 [Indexed for MEDLINE]