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Mechanisms by Which Gamma Tocotrienol Suppresses NLRP3 Inflammasome and Nonalcoholic Fatty Liver Disease
Gamma tocotrienol (γT3) is an unsaturated isomer of vitamin E that can be found in palm, rice bran, and coconut. It has been reported that nod-like receptor protein 3 (NLRP3) inflammasome, which is an immune sensory multicomplex against danger stimuli, plays a critical role in metabolic diseases. However, little is known about the effect of γT3 on NLRP3 inflammasome and metabolic diseases. Herein, we investigated three studies; i) attenuation of type 2 diabetes through suppression of NLRP3 inflammasome activation by γT3; ii) the suppression of lipid mediators by γT3 through the alteration of lipidomic analysis in NLRP3 inflammasome activation; iii) the hepatoprotective effect of γT3 in diet-induced NAFLD in C57BL/6 mice. First of all, we demonstrated that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. The one µM of γT3 repressed NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDM). Furthermore, supplementation of γT3 in leptin-receptor KO mice attenuated immune cell infiltration into adipose tissue, preserved pancreatic β-cells, and improved insulin sensitivity. Second, we identified the effect of γT3 in attenuation of lipid mediator production in NLRP3 inflammasome activation through the distinct modification of the macrophage lipidome. In NLRP3 inflammasome-activated macrophages, γT3 resulted in a substantial decrease of lysophospholipids, diacylglycerol, and arachidonic acid (AA, C20:4), the precursor for eicosanoids. γT3 suppressed the free AA by diminishing the activity of cytosolic phospholipase A2, prostaglandin E2 by inhibition of cyclooxygenase 2. Lastly, we demonstrated the hepatoprotective effect of γT3 in C57BL/6 mice against high fat, cholesterol, and sucrose (HFCS) diet or methionine choline deficient (MCD) diet through suppression of ER stress and NFκB. The inclusion of γT3 reduced the HFCS diet-induced systemic insulin resistance, hepatic ER stress and inflammation leading to a substantial decrease in hepatic steatosis and fibrosis. Moreover, supplementation of γT3 significantly reduced MCD diet-induced hepatic ER stress, inflammation, and fibrosis compared to the MCD diet alone. In conclusion, γT3 provides a beneficial effect on inflammation and metabolic dysfunction. This three studies collectively provide an insight into the novel therapeutic values of γT3 for treating inflammation-mediated chronic diseases.
Kim, Yongeun, "Mechanisms by Which Gamma Tocotrienol Suppresses NLRP3 Inflammasome and Nonalcoholic Fatty Liver Disease" (2018). ETD collection for University of Nebraska - Lincoln. AAI10843802.