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

Zhang, XJ; Cheng, X; Yan, ZZ; Fang, J; Wang, XZ; Wang, WJ; Liu, ZY; Shen, LJ; Zhang, P; Wang, PX; Liao, RF; Ji, YX; Wang, JY; Tian, S; Zhu, XY; Zhang, Y; Tian, RF; Wang, L; Ma, XL; Huang, Z; She, ZG; Li, HL

Li, HL (reprint author), Wuhan Univ, Dept Cardiol, Renmin Hosp, Wuhan, Hubei, Peoples R China.; Li, HL (reprint author), Wuhan Univ, Inst Model Anim, Wuhan, Hubei, Peoples R China.; Li, HL (reprint author), Wuhan Univ, Basic Med Sch, Wuhan, Hubei, Peoples

NATURE MEDICINE, 2018; 24 (1): 73

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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