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首页> 外文期刊>American Journal of Physiology >Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease
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Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease

机译：线粒体DNA能够在非酒精性脂肪肝疾病中实现AIM2炎症活化和肝细胞糊化症

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Nonalcoholic fatty liver disease (NAFLD) is typified by accumulating excess liver triacylglycerol, inflammation, and liver dysfunction. This study was aimed to investigate the role of mitochondrial DNA synthesis-induced activation of Absent in melanoma 2 (AIM2) inflammasome and pyroptosis in NAFLD. Mice were raised on a high-fat diet for 24 wk to establish NAFLD models. F4/80 immunofluorescence was performed to reflect the inflammatory response in the liver of mice. Western blot, ELISA, and immuno-fluorescence were adopted to determine the expression of AIM2 inflammasome-related proteins and factors. 5-Ethynyl-2'-deoxy-uridine (EdU) immunofluorescence was applied for the examination of mitochondrial DNA expression and flow cytometry for cell pyroptosis. Agarose gel electrophoresis was used to detect the integrity of extracted mouse mitochondrial DNA (mtDNA). The levels of AIM2 inflammasome-related proteins in the liver and the levels of IL-1β and IL-18 in serum were elevated in high-fat diet-induced NAFLD mice. AIM2 inflammasome activation and pyroptosis were triggered, and suppressed activation of AIM2 inflammasome alleviated the inflammation and pyroptosis in the liver of NAFLD mice. Mitochondria were severely damaged, and mtDNA was synthesized after NAFLD modeling. Furthermore, mtDNA treatment could promote palmitate (PA)-induced activation of AIM2 inflammasome and pyroptosis. Moreover, inhibition of interferon regulatory factor 1 (IRF-1) gene alleviated PA-induced AIM2 inflammasome activation and pyroptosis. In conclusion, mitochondrial DNA synthesis could enable AIM2 inflammasome activation and induce the hepatocyte pyroptosis, thereby exacerbating NAFLD. NEW & NOTEWORTHY Mitochondria damage exacerbates NAFLD through trigerring AIM2 inflammasome activation and hepatocyte pyroptosis. This study provides novel insights into the underlying mechanisms of mitochondrial DNA synthesis in NAFLD and also suggests potential therapeutic targets for the treatment of NAFLD.
机译：非酒精性脂肪性肝病（NAFLD）的典型症状是积累过多的肝三酰甘油、炎症和肝功能障碍。本研究旨在探讨线粒体DNA合成诱导的缺失激活在NAFLD中黑色素瘤2（AIM2）炎症体和热下垂中的作用。将小鼠在高脂饮食中饲养24周，以建立NAFLD模型。采用F4/80免疫荧光法反映小鼠肝脏的炎症反应。采用Western blot、ELISA和免疫荧光法检测AIM2炎症相关蛋白和因子的表达。应用5-乙炔基-2'-脱氧尿苷（EdU）免疫荧光法检测线粒体DNA表达，流式细胞术检测细胞热下垂。琼脂糖凝胶电泳检测提取的小鼠线粒体DNA（mtDNA）的完整性。在高脂饮食诱导的NAFLD小鼠中，肝脏中AIM2炎症相关蛋白的水平以及血清中IL-1β和IL-18的水平升高。AIM2炎性体激活和热下垂被触发，抑制AIM2炎性体激活可减轻NAFLD小鼠肝脏的炎症和热下垂。NAFLD模型建立后，线粒体严重受损，线粒体DNA合成。此外，线粒体DNA治疗可促进棕榈酸酯（PA）诱导的AIM2炎症体激活和热下垂。此外，干扰素调节因子1（IRF-1）基因的抑制减轻了PA诱导的AIM2炎症体激活和热下垂。总之，线粒体DNA合成可激活AIM2炎性体并诱导肝细胞热下垂，从而加重NAFLD。新的和值得注意的线粒体损伤通过触发AIM2炎症体激活和肝细胞热下垂加剧NAFLD。这项研究为NAFLD中线粒体DNA合成的潜在机制提供了新的见解，也为NAFLD的治疗提供了潜在的治疗靶点。

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