Exosomal miR-181a-2-3p derived from citreoviridin-treated hepatocytes activates hepatic stellate cells trough inducing mitochondrial calcium overload
Exosomal miR-181a-2-3p derived from citreoviridin-treated hepatocytes activates hepatic stellate cells trough inducing mitochondrial calcium overload
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来源于黄绿青霉素处理的肝细胞的外泌体miR-181 a-2- 3 p通过诱导线粒体钙超载激活肝星状细胞
DOI：
10.1016/j.cbi.2022.109899
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发表时间：
2022-03-21
影响因子：
5.1
通讯作者：
Yao, Xiaofeng
中科院分区：
文献类型：
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作者：
Dong, Zhanchen;Yang, Xuejun;Yao, Xiaofeng
越来越多的证据表明外泌体介导的细胞间通讯在肝纤维化的发病机制中起着重要作用。然而，其基本机制仍然没有明确界定。在这项研究中，我们发现，黄绿青霉素（CIT），真菌毒素和异位ATP合成酶（e-ATPS）抑制剂，诱导小鼠肝纤维化。来源于CIT处理的L-02肝细胞的外泌体活化肝星状细胞（HSC）LX-2。通过exosomal small RNA测序，我们在CIT处理的L-02细胞exosomal中发现了156个差异表达的miRNAs，预测的exosomal miRNAs的靶基因在钙信号通路中富集。来自CIT处理的L-02细胞的外泌体诱导LX-2细胞中的线粒体钙积累。药理学抑制线粒体钙摄取减轻了LX-2细胞中外泌体激活的纤维化反应。预测靶向调节线粒体钙摄取1（MICU 1）的miR-181 a-2- 3 p在来自CIT处理的L-02细胞的外来体中显著增加。AntagomiR-181 a-2- 3 p可逆转外泌体诱导的MICU 1减少、线粒体钙超载和LX-2细胞活化。在本研究中，我们指出CIT处理的肝细胞中的外泌体miR-181 a-2- 3 p诱导线粒体钙积聚，随后通过抑制MICU 1的表达激活HSC，为肝纤维化和CIT肝毒性的潜在机制提供了新的见解。
Increasing evidences indicate the vital role of exosomes-mediated intercellular communication in the pathogenesis of liver fibrosis. However, the underlying mechanisms are still not clearly defined. In this study, we found that citreoviridin (CIT), a mycotoxin and ectopic ATP synthase (e-ATPS) inhibitor, induced liver fibrosis in mice. The exosomes derived from CIT-treated L-02 hepatocytes activated hepatic stellate cells (HSC) LX-2. With exosomal small RNA sequencing, we found 156 differentially expressed miRNAs in the exosomes from CITtreated L-02 cells, and the predicted target genes of exosomal miRNAs were enriched in calcium signaling pathway. The exosomes from CIT-treated L-02 cells induced mitochondrial calcium accumulation in LX-2 cells. And pharmacological inhibition of mitochondrial calcium uptake relieved exosomes-activated fibrogenic response in LX-2 cells. The miR-181a-2-3p that was predicted to target-regulate mitochondrial calcium uptake 1 (MICU1) was significantly increased in the exosomes from CIT-treated L-02 cells. Exosomes-induced reduction of MICU1, mitochondrial calcium overload and activation of LX-2 cells were reversed by AntagomiR-181a-2-3p. In this study, we pointed out that exosomal miR-181a-2-3p from CIT-treated hepatocytes induced mitochondrial calcium accumulation and activated HSC subsequently through inhibiting the expression of MICU1, shedding new light on the mechanism underlying liver fibrosis and CIT hepatotoxicity.