TY - JOUR T1 - Withaferin A Improves Nonalcoholic Steatohepatitis in Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 360 LP - 374 DO - 10.1124/jpet.119.256792 VL - 371 IS - 2 AU - Daxesh P. Patel AU - Tingting Yan AU - Donghwan Kim AU - Henrique B. Dias AU - Kristopher W. Krausz AU - Shioko Kimura AU - Frank J. Gonzalez Y1 - 2019/11/01 UR - http://jpet.aspetjournals.org/content/371/2/360.abstract N2 - Nonalcoholic steatohepatitis (NASH) is the progressive stage of nonalcoholic fatty liver disease 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 used, the methionine-choline-deficient 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 histologic 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 with the control vehicle–treated group. To further explore whether WA has an anti-NASH effect independent of its known action in leptin signaling associated with obesity, leptin signaling–deficient ob/ob mice maintained on an HFD were used to induce NASH. WA therapeutically reduced NASH in HFD-treated leptin-deficient ob/ob mice, thus demonstrating a leptin-independent hepatoprotective effect. This study revealed that WA treatment could be an option for NASH treatment. ER -