Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanisms

Jing Ma, Haixia Cao, Robim M Rodrigues, Mingjiang Xu, Tianyi Ren, Yong He, Seonghwan Hwang, Dechun Feng, Ruixue Ren, Peixin Yang, Suthat Liangpunsakul, Jian Sun, Bin Gao

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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-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.

Original languageEnglish
Article numbere136496
JournalJCI Insight
Volume5
Issue number14
DOIs
Publication statusPublished - 23 Jul 2020

Keywords

  • Alcoholism/complications
  • Alcohols/toxicity
  • Animals
  • Binge Drinking/complications
  • DNA, Mitochondrial/genetics
  • Disease Models, Animal
  • Extracellular Vesicles/drug effects
  • Fatty Liver, Alcoholic/etiology
  • Hepatocytes/drug effects
  • Humans
  • Inflammation/etiology
  • Liver/drug effects
  • MAP Kinase Kinase Kinase 5/genetics
  • Matrix Metalloproteinase 14/genetics
  • Metallothionein/genetics
  • Mice
  • Signal Transduction/drug effects
  • p38 Mitogen-Activated Protein Kinases/genetics

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