Fisetin protects against hepatosteatosis in mice by inhibiting mi R ‐378

Scope Lipid homeostasis in vertebrates is regulated at many levels including synthesis, degradation, and distribution. M icro RNA s (mi RNA s) are key regulators of lipid homeostasis. The use of phytochemicals to target mi RNA (mi R ) could provide new therapeutic approaches to human diseases. Thus, we investigated the regulation of lipid metabolism by the flavonoid fisetin during experimental analysis of hepatic mi R s in mice. Methods and results Mice were separated into three groups. One group was maintained on the normal diet and the other two groups were fed either a high‐fat ( HF ) diet or HF supplemented with fisetin. We found that fisetin lowered hepatic fat accumulation in HF mice and reversed abnormal expressions of lipid metabolism genes. The co‐expression of mi R ‐378 and its host gene PGC ‐1β was significantly induced by HF , whereas fisetin prevented the induction of both genes. We also identified nuclear respiratory factor‐1 (NRF‐1), a critical regulator of the mitochondrial function, as a direct target of mi R ‐378. Conclusion Dietary fisetin protects against hepatosteatosis in association with modulation of lipid metabolism genes and mi R ‐378 in mice. These observations suggest that the use of fisetin to target mi R s could be an effective prevention or intervention against metabolic diseases.