Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1/p38MAPKα-dependent mechanisms
| Autor: | Jing Ma, Peixin Yang, Bin Gao, Robim Marcelino Rodrigues, Seonghwan Hwang, Haixia Cao, Dechun Feng, Ruixue Ren, Suthat Liangpunsakul, Yong He, Jian Sun, Mingjiang Xu, Tianyi Ren |
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| Přispěvatelé: | Pharmaceutical and Pharmacological Sciences, Experimental in vitro toxicology and dermato-cosmetology, Faculty of Economic and Social Sciences and Solvay Business School |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cirrhosis Fatty Liver Alcoholic/etiology Binge Drinking/complications Extracellular Vesicles/drug effects medicine.disease_cause p38 Mitogen-Activated Protein Kinases DNA Mitochondrial/genetics Mice Liver disease 0302 clinical medicine Liver/drug effects Signal Transduction/drug effects ASK1 Liver injury Chemistry p38 Mitogen-Activated Protein Kinases/genetics General Medicine Alcoholism Metallothionein/genetics Liver 030220 oncology & carcinogenesis Alcoholism/complications Matrix Metalloproteinase 14/genetics Hepatocytes/drug effects Research Article Fatty Liver Alcoholic Signal Transduction medicine.medical_specialty Inflammation/etiology MAP Kinase Kinase Kinase 5 DNA Mitochondrial MAP Kinase Kinase Kinase 5/genetics Binge Drinking Proinflammatory cytokine Extracellular Vesicles 03 medical and health sciences Internal medicine Matrix Metalloproteinase 14 medicine Animals Humans Protein kinase A Inflammation medicine.disease Disease Models Animal 030104 developmental biology Endocrinology Alcohols Hepatocytes Alcohols/toxicity Metallothionein Steatohepatitis Oxidative stress |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.136496 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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