Fisetin protects against hepatosteatosis in mice by inhibiting miR-378

Scope Lipid homeostasis in vertebrates is regulated at many levels including synthesis, degradation, and distribution. MicroRNAs (miRNAs) are key regulators of lipid homeostasis. The use of phytochemicals to target miRNA (miR) 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 miRs 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 miR‐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 miR‐378. Conclusion Dietary fisetin protects against hepatosteatosis in association with modulation of lipid metabolism genes and miR‐378 in mice. These observations suggest that the use of fisetin to target miRs could be an effective prevention or intervention against metabolic diseases.