Background & aims: Many of the beneficial effects of ω3-fatty acids (ω3FAs) are being attributed to their anti-inflammatory properties. In animal models, ω3FAs also protect from hepatic ischemia reperfusion injury (IRI), a significant cause of complications following liver surgery. Omegaven®, a clinical ω3FA-formulation, might counteract the exaggerated inflammatory response underlying IRI, but the according mechanisms are unresearched. Recently, GPR120 has been identified as a first receptor for ω3FAs, mediating their anti-inflammatory effects. Here, we sought to investigate whether Omegaven® protects from hepatic IRI through GPR120.
Methods: Using a mouse model of liver IRI, we compared the effects of a GPR120 agonist with those of Omegaven®.
Results: GPR120 in liver was located to Kupffer cells (KCs). Agonist and Omegaven® provided similar protection from IRI, which was abolished by clodronate-depletion of KCs or by pretreatment with an αGpr120-siRNA. In vitro and in vivo, both agents dampened the NFκB/JNK-mediated inflammatory response. Dampening was associated with an M1>M2 macrophage polarization shift as assessed by marker expression. In αGpr120-siRNA-pretreated mice with or without ischemia, Omegaven® was no more able to promote M2 marker expression, indicating its anti-inflammatory properties are dependent on GPR120 in liver.
Conclusions: These findings establish KC-GPR120 as a key mediator of Omegaven® effects and suggest GPR120 as a therapeutic target to mitigate inflammatory stress in liver.
Keywords: ALT; AST; Alanine transaminase; Aspartate transaminase; Fatty acids; G protein-coupled receptor 120; GPR120; IRI; KC; Kupffer cells; Liver; O3far1; Omega-3; ROS; Reperfusion injury; i.p.; i.v.; intra-peritoneal; intra-venous; ischemia reperfusion injury; omega-3 fatty acids; reactive oxygen species; ω3FAs.
Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.