GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids
GPR120 on Kupffer cells mediates hepatoprotective effects of ω3-fatty acids
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DOI：
10.1016/j.jhep.2013.11.006
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发表时间：
2014-03-01
影响因子：
25.7
通讯作者：
Clavien, Pierre-Alain
中科院分区：
文献类型：
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作者：
Raptis, Dimitri Aristotle;Limani, Perparim;Clavien, Pierre-Alain
背景与目的：欧米茄3脂肪酸（omega 3FAs）的许多有益作用归因于其抗炎特性。在动物模型中，omega 3FA还可以保护肝脏免受肝脏缺血再灌注损伤（IRI），这是肝脏手术后并发症的重要原因。Omegaven（R）是一种临床欧米茄3FA制剂，可能会抵消IRI下夸大的炎症反应，但相关机制尚未研究。最近，GPR 120已被鉴定为ω-3FA的第一受体，介导其抗炎作用。本研究旨在探讨Omegaven（R）是否通过GPR 120对肝脏IRI具有保护作用。方法：采用小鼠肝脏IRI模型，比较GPR 120激动剂与Omegaven（R）的作用。激动剂和Omegaven（R）提供了类似的IRI保护，通过氯膦酸盐耗尽KC或用α Gpr 120-siRNA预处理消除了IRI。在体外和体内，这两种药物抑制NF κ B B/JNK介导的炎症反应。如通过标记物表达所评估的，阻尼与M1>M2巨噬细胞极化转变相关。在有或无缺血的alpha Gpr 120-siRNA预处理小鼠中，Omegaven（R）不再能够促进M2标记物表达，表明其抗炎特性依赖于肝脏中的GPR 120.Conclusions：这些发现确立了KC-GPR 120作为Omegaven（R）作用的关键介质，并表明GPR 120作为减轻肝脏炎症应激的治疗靶点。(C)2013年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
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.