Ma, JingCao, HaixiaRodrigues, Robim M.Xu, MingjiangRen, TianyiHe, YongHwang, SeonghwanFeng, DechunRen, RuixueYang, PeixinLiangpunsakul, SuthatSun, JianGao, Bin2021-05-282021-05-282020-06-16Ma, J., Cao, H., Rodrigues, R. M., Xu, M., Ren, T., He, Y., Hwang, S., Feng, D., Ren, R., Yang, P., Liangpunsakul, S., Sun, J., & Gao, B. (2020). Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanisms. JCI Insight, 5(14). https://doi.org/10.1172/jci.insight.1364960021-9738https://hdl.handle.net/1805/26047Alcohol-associated liver disease is a spectrum of liver disorders with histopathological changes ranging from simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Recent data suggest that chronic-plus-binge ethanol intake induces steatohepatitis by promoting release by hepatocytes of proinflammatory mitochondrial DNA–enriched (mtDNA-enriched) extracellular vesicles (EVs). The aim of the present study was to investigate the role of the stress kinase apoptosis signal–regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38) in chronic-plus-binge ethanol–induced steatohepatitis and mtDNA-enriched EV release. Microarray analysis revealed the greatest hepatic upregulation of metallothionein 1 and 2 (Mt1/2), which encode 2 of the most potent antioxidant proteins. Genetic deletion of the Mt1 and Mt2 genes aggravated ethanol-induced liver injury, as evidenced by elevation of serum ALT, neutrophil infiltration, oxidative stress, and ASK1/p38 activation in the liver. Inhibition or genetic deletion of Ask1 or p38 ameliorated ethanol-induced liver injury, inflammation, ROS levels, and expression of phagocytic oxidase and ER stress markers in the liver. In addition, inhibition of ASK1 or p38 also attenuated ethanol-induced mtDNA-enriched EV secretion from hepatocytes. Taken together, these findings indicate that induction of hepatic mtDNA-enriched EVs by ethanol is dependent on ASK1 and p38, thereby promoting alcoholic steatohepatitis.AlcoholismFatty liverBinge DrinkingExtracellular VesiclesMAP Kinase Kinase Kinase 5HepatologyToxicologyArticle