1489-P: iPLA2gamma as a Mediator of Lipid-Induced Metabolic Inflammation and Insulin Resistance

Abstract

We have reported that bromenol lactone (BEL) improves metabolic profile. Here, we studied effect of BEL and its target iPLA2 in inflammasome which is a crucial in insulin resistance and metabolic inflammation. BEL inhibited inflammasome by LPS+palmitic acid (PA). BEL also ameliorated mitochondrial ROS and mitochondrial potential loss by LPS+PA, explaining reduced inflammasome. BEL administration in vivo also reduced metabolic inflammation and inflammasome. iPLA2gamma-KO but not iPLA2beta-KO macrophages showed reduced inflammasome by LPS+PA. Mitochondrial ROS and mitochondrial potential loss by LPS+PA were markedly reduced by iPLA2gamma KO. Cardiolipin content in macrophages was reduced by LPS+PA, which was recovered by BEL or myxothiazol, an inhibitor of mitochondrial complex bc1. Cardiolipin loss by LPS+PA was also ameliorated by iPLA2gamma KO. Cardiolipin liposome or expression of CRLS1, a gene for rate-limiting step of cardiolipin biosynthesis, reduced inflammasome by LPS+PA, while CRLS1 siRNA aggravated, suggesting that reduced cardiolipin content is critical in inflammasome by LPS+PA. iPLA2gamma-KO mice were protected from diet-induced insulin resistance, associated with reduced inflammasome and metabolic inflammation. These results suggest that initial reduction of cardiolipin content by PA-induced ROS probably due to removal of oxidized cardiolipin by iPLA2gamma might induce further mitochondrial ROS accumulation likely due to compromised mitochondrial complex activity, which would eventually lead to massive mitochondrial ROS production, marked loss of mitochondrial cardiolipin, profound mitochondrial dysfunction, and finally metabolic inflammation with lipid-induced insulin resistance, through a feed-forward mechanism. Replenishment of cardiolipin could a novel modality for treatment of diet-induced insulin resistance through recovery of mitochondrial function and amelioration of lipid-mediated inflammasome or metabolic inflammation. Disclosure M.Lee: None. H.Kang: None. Funding National Research Foundation of Korea (2019R1A2C3002924)