Reply: Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation.
Reply: Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation.
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答复：肝脏 DRP1 缺失会诱导巨线粒体和线粒体适应不良，从而加剧酒精性肝炎。
DOI：
10.1097/hep.0000000000000541
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ding,Wen-Xing
中科院分区：
文献类型：
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作者：
Ma,Xiaowen;Ding,Wen-Xing
我们感谢刘博士及同事对我们最近的工作的关注，在这些工作中，我们证明了Drp1的缺失会损害酒精诱导的线粒体适应，导致线粒体DNA释放增加，cGAS-STINGIRF3/7介导的先天性免疫反应，以及细胞死亡，从而加剧酒精相关性肝病(ALD)。然而，刘博士及其同事关注小鼠ALD模型中由mtDNA激活的cGAS-STING通路与人类酒精性肝炎的相关性。[1]人类酒精性肝炎以纤维化、导管反应、免疫细胞浸润增加和肝细胞变性为特征。[2]目前没有一种小鼠模型能复制人类酒精性肝炎。本研究中广泛使用的酒精中毒模型仅代表ALD的早期阶段，表现为脂肪变性增加、肝细胞死亡、轻度中性粒细胞浸润和少量纤维化，以及肝大线粒体。因此，单靠酗酒对cGAS刺痛通路的影响并不令人惊讶。CGAS-STING通路的激活可能主要是由于人类长期饮酒而导致的慢性肝巨细胞线粒体积聚，而不是由小鼠高饮酒引起的。小鼠肝脏中Drp1的丢失足以激活cGAS-STING通路，而进一步酗酒几乎没有影响。然而，我们不能排除在Drp1KO小鼠中长期饮酒是否会进一步增强cGAS-STING通路的激活。关于细胞外mtdna，我们发现，在drp1 ko小鼠中，无论饮酒与否，细胞内(肝细胞胞浆)和细胞外(小鼠血清)mtdna释放增加，这与ald的发生更相关，而不是从细胞培养液中检测mtdna。[3]据我们所知，从血清和细胞质中广泛使用的mtdna测量是评估mtDNA释放水平的最现实的定量方法。
We thank Dr. Liu and colleagues for their interest in our recent work, in which we demonstrated that loss of DRP1 impairs alcohol-induced mitochondria adaptation, resulting in increased mtDNA release, cGAS-STINGIRF3/7-mediated innate immune response, and cell death to exacerbate alcohol-associated liver disease (ALD). However, Dr. Liu and colleagues are concerned about the relevance of the cGAS-STING pathway activated by mtDNA in the mouse ALD model to human alcoholic hepatitis.[1]Human alcoholic hepatitis is featured with fibrosis, ductular reaction, increased immune cell infiltration, and hepatocyte degeneration.[2] No current mouse model can phenocopy human alcoholic hepatitis. The widely used “Gao-binge alcohol” model (used in this study) only represents the early stage of ALD that involves increased steatosis, hepatocyte death, mild neutrophil infiltration with little fibrosis, and hepatic megamitochondria. Therefore, it is not surprising that Gao-binge alcohol feeding alone had little effect on the cGAS-STING pathway. The activation of the cGAS-STING pathway is likely mediated primarily by the chronic hepatic megamitochondria accumulation resulting from long-term alcohol consumption in humans but not by Gao-binge alcohol feeding in mice. Loss of hepatic DRP1 in mice is sufficient to activate the cGAS-STING pathway, with little effect from further Gao-binge alcohol feeding. However, we cannot rule out whether prolonged alcohol feeding in DRP1 KO mice may further enhance the activation of the cGAS-STING pathway. Regarding extracellular mtDNA, we showed increased intracellular (hepatocyte cytoplasm) and extracellular (mouse serum) mtDNA release in DRP1 KO mice regardless of alcohol feeding, which is more relevant to ALD development as opposed to detecting mtDNA from a cell culture medium.[3] To our knowledge, the widely used mtDNA measurements from serum and cytoplasm are the most realistic quantitative methods to assess the levels of mtDNA release