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

J Hepatol. 2014 Mar;60(3):625-32. doi: 10.1016/j.jhep.2013.11.006. Epub 2013 Nov 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Polarity
  • Fish Oils / pharmacology*
  • Kupffer Cells / physiology*
  • Liver / drug effects*
  • Macrophages / physiology
  • Mice
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction
  • Triglycerides

Substances

  • FFAR4 protein, mouse
  • Fish Oils
  • Receptors, G-Protein-Coupled
  • Triglycerides
  • fish oil triglycerides