Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting about 25% of world population, while there are still no approved targeted therapies. Although platensimycin (PTM) was first discovered to be a broad-spectrum antibiotic, it was also effective against type II diabetes in animal models due to its ability to inhibit both bacterial and mammalian fatty acid synthases (FASN). Herein, we report the pharmacological effect and potential mode of action of PTM against NAFLD in a Western diet/CCI4-induced mouse model and a free fatty acids (FFAs)-induced HepG2 cell model. The proper dose of PTM and its liposome-based nano-formulations not only significantly attenuated theWestern diet-induced weight gain and the levels of plasma total triglycerides and glucose, but reduced liver steatosis in mice according to histological analyses. Western blotting analysis showed a reduced protein level of FASN in the mouse liver, suggesting that PTM intervened in the development of NAFLD through FASN inhibition. PTM reduced both the protein and mRNA levels of FASN in FFAs-induced HepG2 cells, as well as the expression of several key proteins in lipogenesis, including sterol regulatory element binding protein-1, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. The expression of lipid oxidation-related genes, including peroxisome proliferator activated receptor and acyl-CoA oxidase 1, was significantly elevated. In conclusion, our study supports the reposition of PTM to intervene in NAFLD progression, since it could effectively inhibit de novo lipogenesis.
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