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

Nat Med. 2018 Jan;24(1):73-83. doi: 10.1038/nm.4451. Epub 2017 Dec 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / antagonists & inhibitors
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / biosynthesis
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / metabolism*
  • Animals
  • Arachidonate 12-Lipoxygenase / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Lipid Metabolism
  • Liver / blood supply*
  • Mice
  • Receptors, G-Protein-Coupled / metabolism*
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / parasitology
  • Signal Transduction*
  • Swine

Substances

  • GPR31 protein, human
  • Receptors, G-Protein-Coupled
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • Arachidonate 12-Lipoxygenase
  • ALOX12 protein, human