title: GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland.
authors.forename: Dimitri Aristotle
authors.initials: DA
authors.lastname: Raptis
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland.
authors.forename: Perparim
authors.initials: P
authors.lastname: Limani
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland.
authors.forename: Jae Hwi
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland.
authors.forename: Udo
authors.initials: U
authors.lastname: Ungethüm
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Tschuor
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Graf
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Humar
authors.affiliation: Department of Surgery, Laboratory of the Swiss HPB Center, University Hospital of Zurich, Switzerland. Electronic address: clavien@access.uzh.ch.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D016764:Cell Polarity; D005395:Fish Oils / Q000494:pharmacology*; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000187:drug effects*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D014280:Triglycerides
chemical_list: C498007:FFAR4 protein, mouse; D005395:Fish Oils; D043562:Receptors, G-Protein-Coupled; D014280:Triglycerides; C568345:fish oil triglycerides
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