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


Raptis, Dimitri Aristotle; Limani, Perparim; Jang, Jae Hwi; Ungethuem, Udo; Tschuor, Christoph; Graf, Rolf; Humar, Bostjan; Clavien, Pierre-Alain (2014). GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids. Journal of Hepatology, 60(3):625-632.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Visceral and Transplantation Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2014
Deposited On:21 Jan 2015 16:09
Last Modified:14 Feb 2018 22:28
Publisher:Elsevier
ISSN:0168-8278
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.jhep.2013.11.006
PubMed ID:24262133

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