State Key Laboratory of Organ Failure Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA.
JCI Insight. 2020 Jul 23;5(14):136496. doi: 10.1172/jci.insight.136496.
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.
酒精相关性肝病是一种肝脏疾病谱，其组织病理学变化范围从单纯脂肪变性到脂肪性肝炎、肝硬化和肝细胞癌。最近的数据表明，慢性加 binge 乙醇摄入通过促进肝细胞释放富含促炎线粒体 DNA（mtDNA-富集）细胞外囊泡（EVs）来诱导脂肪性肝炎。本研究旨在探讨应激激酶凋亡信号调节激酶 1（ASK1）和 p38 丝裂原活化蛋白激酶（p38）在慢性加 binge 乙醇诱导的脂肪性肝炎和 mtDNA-富集 EV 释放中的作用。微阵列分析显示，金属硫蛋白 1 和 2（Mt1/2）在肝脏中的表达上调最为明显，Mt1/2 编码两种最有效的抗氧化蛋白。Mt1 和 Mt2 基因的遗传缺失加剧了乙醇诱导的肝损伤，血清 ALT 升高、中性粒细胞浸润、氧化应激以及肝内 ASK1/p38 激活均证实了这一点。ASK1 或 p38 的抑制或基因缺失改善了乙醇诱导的肝损伤、炎症、ROS 水平以及肝中吞噬氧化酶和 ER 应激标志物的表达。此外，抑制 ASK1 或 p38 也减弱了乙醇诱导的肝细胞 mtDNA-富集 EV 的分泌。总之，这些发现表明，乙醇诱导的肝脏 mtDNA-富集 EV 的产生依赖于 ASK1 和 p38，从而促进了酒精性脂肪性肝炎。
