Biochemical and Biophysical Research Communications, Vol.534, 734-739, 2021
NLRP3 inflammasome inhibitor CY-09 reduces hepatic steatosis in experimental NAFLD mice
Aims: Non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases. The NOD-like receptor protein 3 (NLRP3) inflammasome was suggested to be involved in the pathogenesis of NAFLD. A small-molecule named CY-09 is a new selective and direct inhibitor of the NLRP3 inflammasome. We aimed to investigate whether CY-09 is effective for the treatment of NAFLD in a high-fat diet (HFD)-induced mouse model. Methods: Twenty mice were fed by HFD for 14 weeks, and then were randomly assigned into two groups: (1) control group receiving dimethylsulfoxide (DMSO) solution; (2) CY-09 group receiving CY-09 injection. In an 8-week follow-up, oral glucose tolerance test (OGTT) and homeostasis model assessment of insulin resistance (HOMA-IR) were used to measure glucose metabolism. Liver steatosis was evaluated by the NAFLD activity score (NAS) and deemed as the primary outcome. Results: The body weight in CY-09 group was significantly lower than the DMSO control group on 27 weeks (41.0 +/- 3.5 g vs. 49.7 +/- 5.2 g, P = 0.014). The area under the curve (AUC) of OGTT was less in CY-09 group than that in DMSO group (35.81 +/- 6.79 vs. 22.91 +/- 2.58 mmol/L.hr, P = 0.004), as well as HOMA-IR (14.36 +/- 3.89 vs. 8.82 +/- 2.04 mmol.mlU.L-2, P = 0.023). Microscopically, liver lipid droplets dramatically improved and significantly lower NAS was observed in CY-09 group (8.25 +/- 1.26 vs. 3.20 +/- 0.45, P < 0.001). Conclusion: CY-09 reduces hepatic steatosis in experimental NAFLD mice and CY-09 may be a potential therapeutic drug of NAFLD in clinical practice. (C) 2020 Elsevier Inc. All rights reserved.