{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:47:13Z","timestamp":1793386033092,"version":"4.5.0"},"reference-count":62,"publisher":"American Society for Clinical Investigation","issue":"14","funder":[{"name":"NIAAA, NIH","award":["Intramural program"],"award-info":[{"award-number":["Intramural program"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,23]]},"abstract":"<jats:p>\n                    Alcohol-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\u2013enriched (mtDNA-enriched) extracellular vesicles (EVs). The aim of the present study was to investigate the role of the stress kinase apoptosis signal\u2013regulating kinase 1 (ASK1) and p38 mitogen-activated protein kinase (p38) in chronic-plus-binge ethanol\u2013induced steatohepatitis and mtDNA-enriched EV release. Microarray analysis revealed the greatest hepatic upregulation of metallothionein 1 and 2 (\n                    <jats:italic>Mt1\/2<\/jats:italic>\n                    ), which encode 2 of the most potent antioxidant proteins. Genetic deletion of the\n                    <jats:italic>Mt1<\/jats:italic>\n                    and\n                    <jats:italic>Mt2<\/jats:italic>\n                    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\n                    <jats:italic>Ask1<\/jats:italic>\n                    or\n                    <jats:italic>p38<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.136496","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T12:04:19Z","timestamp":1592309059000},"source":"Crossref","is-referenced-by-count":64,"title":["Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1\/p38MAPK\u03b1-dependent mechanisms"],"prefix":"10.1172","volume":"5","author":[{"given":"Jing","family":"Ma","sequence":"first","affiliation":[{"name":"State Key Laboratory of Organ Failure Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China."},{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, 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