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dc.contributor.authorMa, Jing
dc.contributor.authorCao, Haixia
dc.contributor.authorRodrigues, Robim M
dc.contributor.authorXu, Mingjiang
dc.contributor.authorRen, Tianyi
dc.contributor.authorHe, Yong
dc.contributor.authorHwang, Seonghwan
dc.contributor.authorFeng, Dechun
dc.contributor.authorRen, Ruixue
dc.contributor.authorYang, Peixin
dc.contributor.authorLiangpunsakul, Suthat
dc.contributor.authorSun, Jian
dc.contributor.authorGao, Bin
dc.date.accessioned2020-08-04T18:43:26Z
dc.date.available2020-08-04T18:43:26Z
dc.date.issued2020-07-23
dc.identifier.urihttp://hdl.handle.net/10713/13468
dc.description.abstractAlcohol-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.en_US
dc.description.urihttps://doi.org/10.1172/jci.insight.136496en_US
dc.language.isoen_USen_US
dc.publisherThe American Society for Clinical Investigationen_US
dc.relation.ispartofJCI insighten_US
dc.subject.meshFatty Liver, Alcoholic--etiologyen_US
dc.subject.meshFatty Liver, Alcoholic--physiopathologyen_US
dc.titleChronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanismsen_US
dc.typeArticleen_US
dc.identifier.doi10.1172/jci.insight.136496
dc.identifier.pmid32544093
dc.source.volume5
dc.source.issue14
dc.source.countryUnited States


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