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

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.

• Authors: 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
• Journal: JCI insight (JCI Insight) Vol. 5 Issue 14 (07 23 2020) ISSN: 2379-3708 [Electronic] United States
• PMID: 32544093 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alcohols
• DNA, Mitochondrial
• Mt2 protein, mouse
• Metallothionein
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• Matrix Metalloproteinase 14

Topics

• Alcoholism (complications, genetics, pathology)
• Alcohols (toxicity)
• Animals
• Binge Drinking (complications, genetics, pathology)
• DNA, Mitochondrial (genetics)
• Disease Models, Animal
• Extracellular Vesicles (drug effects, genetics)
• Fatty Liver, Alcoholic (etiology, genetics, pathology)
• Hepatocytes (drug effects)
• Humans
• Inflammation (etiology, genetics, pathology)
• 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)