Slide Session : OS-GAS-04 ; Gastroenterology : Uric Acid Regulates Hepatic Steatosis and Insulin Sig-naling Through the NLRP3 Infl ammasome Dependent Mechanism = Slide Session : OS-GAS-04 ; Gastroenterology : Uric Acid Regulates Hepatic Steatosis and Insulin Sig-naling Through the NLRP3 Infl ammasome Dependent Mechanism

다국어 초록 (Multilingual Abstract)

Background: Serum uric acid is strongly associated with nonalcoholic fatty liver disease (NAFLD) and insulin resistance in patients. However, whether this association is causally or coincidentally with NAFLD and insulin resistance remains uncertain, neither the mechanisms behind this association are unclear so far. Methods: We first analyzed the impact of uric acid on development of hepatic steatosis in mice and two cell models (HepG2 and HL7702), and then explored the effect of uric acid on insulin signaling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt in HepG2 and HL7702 cells. Further, we studied the role of NLRP3 inflammasome in regulation of hepatic steatosis and insulin signaling. Results: Uric acid directly induced hepatocyte fat accumulation both in vivo and in vitro. Further, uric acid treatment decreased insulin-induced phospho-Akt (ser437) and enhanced the phospho-IRS1(ser307) in HepG2 and HL7702 cells. Then, we found significant increases of NLRP3 inflammasome-related molecules, both mRNA and protein levels, including NLPR3, caspase-1, IL-1ß, and IL-18, in HepG2 and HL7702 cells stimulated with uric acid. We also found that uric acid induced significant elevations of IL-1ß and IL-18 levels in culture supernatants of HepG2 and HL7702 cells. Consistent with in vitro results, mice fed 8 weeks of hyperuricemia-inducing diet resulted in significant up-regulation of hepatic mRNA and protein expressions of NLPR3, caspase-1, IL-1ß and IL-18, and elevation of serum IL-1ß and IL-18 levels. Further experiments indicated that silencing NLRP3 expression significantly alleviated uric acid-induced fat accumulation in vitro. Moreover, inhibition of NLRP3 expression ameliorated uric acid induced insulin signaling impairing, confirmed by increased insulin- induced phospho-Akt (ser437) and reduced the phospho-IRS1(ser307) in vitro. Conclusions: Our results suggest that uric acid contributes to hepatic steatosis and impairs insulin signaling through the NLRP3 inflammasome dependent mechanism.