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.
Highlights
Alcohol-associated liver disease (ALD) is the leading cause of liver-related morbidity and mortality worldwide, contributing to approximately half of liver cirrhosis cases in Western countries [1,2,3]
Microarray analysis revealed a significant modulation of 46 oxidative stress–associated genes in ethanol for 8 weeks (E8w)+1B mice compared with E8w mice
Among the most highly upregulated genes, Mt1 and Mt2 were elevated by 33-fold and 20-fold, respectively (Figure 1A). This result was further confirmed by reverse transcription quantitative PCR (RT-qPCR), showing Mt1 and Mt2 upregulation of 60-fold and 40-fold in ethanol for 8 weeks plus binge (E8w+1B) mice compared with E8w mice, respectively
Summary
Alcohol-associated liver disease (ALD) is the leading cause of liver-related morbidity and mortality worldwide, contributing to approximately half of liver cirrhosis cases in Western countries [1,2,3]. Significant scientific progress has been made in understanding the disease process, the pathogenesis of ALD remains elusive, with significant impact on the discovery of mechanism-based therapies [1,2,3]. The development of such therapies requires translational studies using human samples and suitable animal models that reproduce clinical and histological features of alcoholic hepatitis.
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