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.
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.
Authors: Lorenzo Anez-Bustillos; Duy T Dao; Gillian L Fell; Meredith A Baker; Kathleen M Gura; Bruce R Bistrian; Mark Puder Journal: Clin Nutr Date: 2017-07-08 Impact factor: 7.324
Authors: Gillian L Fell; Bennet S Cho; Duy T Dao; Lorenzo Anez-Bustillos; Meredith A Baker; Prathima Nandivada; Amy Pan; Alison A O'Loughlin; Paul D Mitchell; Vania Nose; Kathleen M Gura; Mark Puder Journal: Prostaglandins Leukot Essent Fatty Acids Date: 2019-03-05 Impact factor: 4.006
Authors: Shi Yue; Haoming Zhou; Xuehao Wang; Ronald W Busuttil; Jerzy W Kupiec-Weglinski; Yuan Zhai Journal: J Immunol Date: 2017-03-13 Impact factor: 5.422
Authors: Meredith A Baker; Prathima Nandivada; Paul D Mitchell; Gillian L Fell; Amy Pan; Bennet S Cho; Denis J De La Flor; Lorenzo Anez-Bustillos; Duy T Dao; Vania Nosé; Mark Puder Journal: J Pediatr Surg Date: 2019-04-12 Impact factor: 2.545
Authors: Lorenzo Anez-Bustillos; Duy T Dao; Meredith A Baker; Gillian L Fell; Mark Puder; Kathleen M Gura Journal: Nutr Clin Pract Date: 2016-08-16 Impact factor: 3.080
Authors: Meredith A Baker; Prathima Nandivada; Paul D Mitchell; Gillian L Fell; Amy Pan; Lorenzo Anez-Bustillos; Duy T Dao; Kathleen M Gura; Vania Nosé; Mark Puder Journal: Surgery Date: 2018-01-19 Impact factor: 3.982