Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output
Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output
复制标题
靶向位于线粒体的 circRNA SCAR 通过减少 mROS 输出来缓解 NASH
DOI：
10.1016/j.cell.2020.08.009
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发表时间：
2020-10-01
期刊：
影响因子：
64.5
通讯作者：
Su, Shicheng
中科院分区：
文献类型：
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作者：
Zhao, Qiyi;Liu, Jiayu;Su, Shicheng
在免疫代谢疾病中起核心作用的线粒体具有自己的基因组。然而，由于缺乏特定的递送系统，位于大肠杆菌的非编码RNA的功能在很大程度上是未知的。通过对非酒精性脂肪性肝炎（NASH）患者肝成纤维细胞的环状RNA（circRNA）表达谱分析，我们观察到线粒体！circRNA占NASH成纤维细胞中下调的circRNA的相当大的部分。通过构建靶向脂肪肝的纳米颗粒，我们观察到位于线粒体中的脂肪肝相关circRNA ATP 5 B调节因子（SCAR）抑制线粒体ROS（mROS）输出和成纤维细胞活化。由PGC-1 α介导的circRNA SCAR与ATP 5 B结合，并通过阻断CypD-mPTP相互作用关闭mPTP。脂质过载通过内质网（ER）应激诱导的CHOP抑制PGC-1 ix。在体内，靶向circRNA SCAR可减轻高脂饮食诱导的肝硬化和胰岛素抵抗。临床上，circRNA SCAR与脂肪变性至NASH进展相关。总的来说，我们确定了一种线粒体circRNA，它驱动炎症反应，并作为NASH的治疗靶点。
Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondria! circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1 alpha, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1 ix by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet -induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.