Objective: Fibroblast growth factor 21 (FGF21) is an atypical member of the FGF family that functions as an endocrine hormone. FGF21 is predominantly produced by the liver, and is also expressed in adipocytes, muscle and the pancreas. In mice, FGF21 stimulates gluconeogenesis, fatty acid oxidation, and ketogenesis in the liver, as an adaptive response to fasting and starvation, and confers multiple metabolic benefits on insulin sensitivity, blood glucose and lipid profiles. Lipopolysaccharide (LPS) is the toxic moiety of the endotoxin, and LPS-induced liver injury is a frequently used model that represents liver injury in human sepsis. Interestingly, LPS significantly decreased the expression of FGF21 in the liver, whereas it increased FGF21 expression in adipose tissue and muscle. However, the molecular mechanism by which LPS decreases FGF21 expression in the liver is presently unknown Methods: Seven-week-old C57BL/6J mice were divided into 3 groups, and given LPS (15 mg/kg) with or without FGF21 (1 mg/kg) by intraperitoneal injection. Results: LPS acts as a ‘pathogen-associated molecular patterns’ (PAMPs), which is recognized by the innate immune system. NLRP3 inflammasome is activated by the PAMPs to prudence IL-1β. LPS administration significantly suppressed hepatic expression of FGF21. However, LPS treatment in cultured hepatocytes did not change FGF21 expression. On the other hand, LPS treatment activated NLRP3 inflammasome in macrophages, and conditioned media from these cells or IL-1β significantly decreased FGF21 expression in primary hepatocytes. Similarly, LPS administration to NLRP3 knockout mice did not decrease hepatic FGF21 expression. Conclusion: These results suggest that NLRP3 activation in macrophages and its product IL-1β are responsible for LPS-induced suppression of hepatic FGF21 production.