期刊
NATURE MEDICINE
卷 24, 期 1, 页码 73-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4451
关键词
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资金
- National Science Fund for Distinguished Young Scholars [81425005]
- Key Project of the National Natural Science Foundation [81330005, 81630011]
- National Science and Technology Support Project [2014BAI02B01, 2015BAI08B01]
- National Key Research and Development Program [2013YQ030923-05, 2016YFF0101504]
- National Natural Science Foundation of China [81770053]
- Key Collaborative Project of the National Natural Science Foundation [91639304]
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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