GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids

Background & Aims: Many of the beneficial effects of omega 3-fatty acids (omega 3FAs) are being attributed to their anti-inflammatory properties. In animal models, omega 3FAs also protect from hepatic ischemia reperfusion injury (IRI), a significant cause of complications following liver surgery. Omegaven(R), a clinical omega 3FA-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 omega 3FAs, mediating their anti-inflammatory effects. Here, we sought to investigate whether Omegaven(R) 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(R). Results: GPR120 in liver was located to Kupffer cells (KCs). Agonist and Omegaven(R) provided similar protection from IRI, which was abolished by clodronate-depletion of KCs or by pretreatment with an alpha Gpr120-siRNA. In vitro and in vivo, both agents dampened the NF kappa B/JNK-mediated inflammatory response. Dampening was associated with an M1>M2 macrophage polarization shift as assessed by marker expression. In alpha Gpr120-siRNA-pretreated mice with or without ischemia, Omegaven(R) 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(R) effects and suggest GPR120 as a therapeutic target to mitigate inflammatory stress in liver. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.