THE EFFECT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-DELTA AGONIST ON ACTIVATED INFLAMMASOME IN MODELS OF NONALCOHOLIC FATTY LIVER DISEASE

초록

Background and Aims: The inflammasome has been recently shown to be activated in the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the expression of inflmammasome in vivo and in vitro models of NAFLD, and the effect of peroxisome-proliferator activated receptor (PPAR)-delta agonist on activated inflammasome. Methods: Male C57BL/6J mice were classified according to high fat diet (HFD), lipopolysaccharide (LPS) injection, and treatment with PPAR-delta agonist (GW501516 3 mg/kg/day for 3 weeks) over period of 12 weeks: group I (control), group II (HFD), group III (HFD+LPS), and group IV (HFD+LPS+GW501516). HepG2 cells were exposed to palmitic acid (PA) (0.2 mM) and/or LPS in the absence or presence of GW501516 (1 and 10 mM). Results: In vivo, HFD caused glucose intolerance and hepatic steatosis. In the mice fed HFD with LPS injection, hepatic gene expression of caspase-1 and IL-1beta were increased significantly. Treatment with GW501516 ameliorated the steatosis and production of pro-inflammatory cytokines. In vitro, incubation with HepG2 cells with PA and LPS markedly induced gene expression of NLRP3, NLRP6, and NLRP10, and increased gene and protein levels of caspase-1 and IL-1beta. PA and LPS also exaggerated reactive oxygen species production and suppressed phosphorylation of AMP-activated protein kinase alpha (AMPKalpha). All of the above effects of PA and LPS were attenuated by GW501516. Conclusions: These results demonstrate that PPAR-delta agonist attenuates fatty acid-induced inflammation and steatosis through suppressing inflammasome activation. The targeting of inflammasome by PPAR-delta agonist may have therapeutic implications for the treatment of NAFLD.