Maresin 1 protects the liver against ischemia/reperfusion injury via the ALXR/Akt signaling pathway

Abstract

Background Hepatic ischemia/reperfusion (I/R) injury can be a major complication following liver surgery contributing to post-operative liver dysfunction. Maresin 1 (MaR1), a pro-resolving lipid mediator, has been shown to suppress I/R injury. However, the mechanisms that account for the protective effects of MaR1 in I/R injury remain unknown. Methods WT (C57BL/6J) mice were subjected to partial hepatic warm ischemia for 60mins followed by reperfusion. Mice were treated with MaR1 (5-20 ng/mouse), Boc2 (Lipoxin A4 receptor antagonist), LY294002 (Akt inhibitor) or corresponding controls just prior to liver I/R or at the beginning of reperfusion. Blood and liver samples were collected at 6 h post-reperfusion. Serum aminotransferase, histopathologic changes, inflammatory cytokines, and oxidative stress were analyzed to evaluate liver injury. Signaling pathways were also investigated in vitro using primary mouse hepatocyte (HC) cultures to identify underlying mechanisms for MaR1 in liver I/R injury. Results MaR1 treatment significantly reduced ALT and AST levels, diminished necrotic areas, suppressed inflammatory responses, attenuated oxidative stress and decreased hepatocyte apoptosis in liver after I/R. Akt signaling was significantly increased in the MaR1-treated liver I/R group compared with controls. The protective effect of MaR1 was abrogated by pretreatment with Boc2, which together with MaR1-induced Akt activation. MaR1-mediated liver protection was reversed by inhibition of Akt. Conclusions MaR1 protects the liver against hepatic I/R injury via an ALXR/Akt signaling pathway. MaR1 may represent a novel therapeutic agent to mitigate the detrimental effects of I/R-induced liver injury.

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation

“…MaR1 increased the population of restorative macrophages, the movement of Nrf2 from the cytoplasm to the nucleus, and decreased NF-κB at nuclear levels [ 15 ]. The hepatoprotective effects of MaR1 on IR liver damage could be related to an activation of the ALXR (lipoxin A4 receptor)/Akt signaling pathway [ 16 ]. In non-alcoholic fatty liver disease (NFLD), MaR1 allows hepatocytes to return to homeostasis, reducing apoptosis and increasing phagocytic activity, which is a cardinal sign of active resolution of inflammation [ 17 , 18 ].…”

Maresin-1 and Inflammatory Disease

“…In another study, the hepatoprotective effect of maresin-1 was abrogated by pretreatment with Boc2 (lipoxin A4 receptor antagonist), and the hepatoprotective effect of maresin-1 was further reversed by inhibition of Akt. Thus, maresin-1 protected the liver from hepatic ischemia-reperfusion injury mediated by the ALXR/Akt signaling pathway [69].…”

Protective Potential of Maresins in Cardiovascular Diseases

“…Similarly, after screening hundreds of GPCRs, Serhan et al found that MaR1 is a ligand for leucine-rich repeat containing G protein-coupled receptor 6 (LGR6), whereas MaR1 stimulates efferocytosis, enhances phagocytosis, and reduces chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages in LGR6-dependent manners via coupling a Gαs protein to stimulate cAMP ( 4 ). Besides, studies have shown that MaR1 exerts its function via interacting with lipoxin A4 receptor (ALXR) in several inflammatory disease model, and the salutary effect of MaR1 could be blocked by ALXR antagonist ( 18 , 19 ), thus ALXR might be another GPCR for MaR1, although the direct binding of MaR1 to ALXR has not been explored. Furthermore, MaR1 is also considered as an endogenous ligand for nuclear receptor retinoic acid-related orphan receptor α (RORα), thus MaR1 enhances the expression and transcriptional activity of RORα and thereby increases the M2 polarity of liver macrophages ( 20 ).…”