Compared with free RAPA, NP-RAPA significantly reduced lipid accumulation in HepG2 cells, and obviously ameliorated hepatic steatosis and liver injury in mice though enhancing the therapeutic efficacy of RAPA through reducing SREBP-1c-dependent de novo lipogenesis (DNL) and promoting PPARα-mediated fatty acid oxidation. This evidence concerns the gene SREBF1 and fatty liver disease.