Fisetin attenuates high fat diet-triggered hepatic lipid accumulation: A mechanism involving liver inflammation overload associated TACE/TNF-α pathway

Abstract Excess fat-rich diet ingestion predisposes the liver to non-alcoholic fatty liver disease (NAFLD), but the mechanism is complicated. Fisetin (Fn) as a natural flavonoid with many bio-activities was determined in a number of diseases models. TACE (tumor necrosis factor-α-converting enzyme)-combined tumor necrosis factor-α (TACE/TNF-α) signaling played a significant role in inflammation-associated diseases. The study aimed to explore the protective mechanisms of Fn against high fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH), with particular focus on TACE/TNF-α signaling. HFD-fed C57BL/6 mice were used as the metabolic syndrome model to explore the effects of Fn on NASH and to determine whether TACE/TNF-α activation was involved in the process. Indeed, HFD increases systemic metabolic disorder, promotes circulating levels of pro-inflammatory cytokines produce, aggravates development of hepatic inflammation, resulting in inflammation overload-associated excessive activation of TACE/TNF-α, ultimately induces hepatic lipid accumulation and NASH. Fisetin protected against HFD-induced liver inflammation and lipid accumulation by decreasing metabolic disorder and inflammation overload-related TACE/TNF-α activation, inhibiting over-expression of pro-inflammatory cytokines, negatively regulating HFD-triggered abnormal lipid metabolism-related genes expression, finally restricting lipid deposition and hepatic steatosis. Fisetin suppressed HFD-induced liver inflammation and lipid accumulation by decreasing metabolic disorder and hepatic inflammation overload-related TACE/TNF-α activation.