Withaferin A improves non-alcoholic steatohepatitis in mice.

Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease (NAFLD) that highly increases the risk of cirrhosis and liver cancer, and there are few therapeutic options available in the clinic. Withaferin A (WA), extracted from the ayurvedic medicine Withania Somnifera, has a wide range of pharmacological activities, however, little is known about its effects on NASH. To explore the role of WA in treating NASH, two well-defined NASH models were employed, the methionine-choline-deficient (MCD) diet and the 40 kcal% high-fat diet (HFD). In both NASH models, WA treatment or control vehicle was administered to evaluate its hepatoprotective effects. As assessed by biochemical and histological analyses, WA prevented and therapeutically improved liver injury in both models, as revealed by lower serum aminotransaminases, hepatic steatosis, liver inflammation and fibrosis. In the HFD-induced NASH model, both elevated serum ceramides and increased hepatic oxidative stress were decreased in the WA-treated group compared to the control vehicle-treated group. To further explore whether WA has an anti-NASH effect independent of its known action in leptin signaling during combating obesity, leptin signaling-deficient ob/ob mice maintained on HFD were employed to induce NASH. WA was also found to therapeutically reduce NASH in HFD-treated leptin-deficient ob/ob mice, thus demonstrating a leptin-independent hepatoprotective effect. This study revealed that WA treatment could be a therapeutic option for NASH treatment. SIGNIFICANCE STATEMENT: N/A.