Celastrol ameliorates the effects of nonalcoholic fatty liver disease (NAFLD) resulting from a high-fat diet (HFD) through NAD-dependent protein deacetylase sirtuin 1 (SIRT1), according to a new study in mice. Administration of celastrol to wild-type mice fed a HFD resulted in a reduction in body weight, fat content and levels of circulating fatty acids and triglycerides compared with untreated mice, and also decreased lipid droplet formation and intracellular levels of triglycerides in the liver. Furthermore, the drug modulated the hepatic expression of crucial genes that are involved in fat metabolism, such as sterol regulatory element-binding protein 1C, and improved glucose tolerance, insulin sensitivity and the anti-inflammatory and antioxidant status of cells in the liver. Importantly, the beneficial effects of celastrol were accompanied by an increase in SIRT1 expression but were eliminated in SIRT1-deficient HFD-fed mice. These results suggest that celastrol reverses metabolic liver damage by decreasing lipid synthesis, inflammation and oxidation, and that SIRT1 has an important role in this process.