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The hepatocyte-specifically expressed lnc-HSER alleviates hepatic fibrosis by inhibiting hepatocyte apoptosis and epithelial-mesenchymal transition.
Theranostics ( IF 12.4 ) Pub Date : 2019-10-12 , DOI: 10.7150/thno.36942
Kun Zhang 1 , Mengxia Zhang 1 , Qingbin Yao 1 , Xiaohui Han 1 , Yanmian Zhao 1 , Lina Zheng 1 , Guantong Li 2 , Qi Liu 1 , Yanan Chang 3 , Peijun Zhang 4 , Hongmei Cui 1 , Zhemin Shi 1 , Ting Chen 1 , Zhi Yao 5 , Tao Han 2 , Wei Hong 1
Affiliation  

Liver fibrosis leading to cirrhosis is one of the major health burdens worldwide with currently limited therapeutic options available. Long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes in a cell- or tissue-specific manner. However, there is still an important gap in the understanding of the role of hepatocyte-specific lncRNAs in liver fibrosis. Methods: The expressions of lnc-Hser in human and mice fibrotic livers as well as primary hepatocytes (HCs) of mice developing liver fibrosis were determined by real-time RT-PCR. The roles and mechanisms of lnc-Hser in HCs and liver fibrosis were determined in vitro and in vivo. Results: In this study, we have identified a hepatocyte-specifically expressed lnc-Hser, which was reduced in human and mice fibrotic livers as well as primary HCs of mice developing liver fibrosis. We have shown that silencing lnc-Hser aggravated liver fibrosis both in vitro and in vivo through inducing the epithelial-mesenchymal transition (EMT) and the apoptosis of HCs. In addition, knockdown of lnc-Hser promoted hepatic stellate cells (HSCs) activation through the signals derived from injured HCs. Mechanistically, we have revealed that lnc-Hser inhibited HCs apoptosis via the C5AR1-Hippo-YAP pathway and suppressed HCs EMT via the Notch signaling. Conclusions: Our work has identified a hepatocyte-specific lnc-HSER that regulates liver fibrosis, providing a proof that this molecule is a novel biomarker for damaged HCs and a potential target for anti-fibrotic therapy.

中文翻译:

肝细胞特异性表达的lnc-HSER通过抑制肝细胞凋亡和上皮-间质转化减轻肝纤维化。

导致肝硬化的肝纤维化是世界范围内的主要健康负担之一,目前可用的治疗选择有限。长非编码RNA(lncRNA)以细胞或组织特异性方式在各种生物学和病理学过程中发挥重要作用。但是,在了解肝细胞特异性lncRNA在肝纤维化中的作用方面仍然存在重要的差距。方法:通过实时RT-PCR检测lnc-Hser在人和小鼠肝纤维化以及肝纤维化小鼠原代肝细胞(HCs)中的表达。体外和体内测定了lnc-Hser在HCs和肝纤维化中的作用和机制。结果:在这项研究中,我们确定了肝细胞特异性表达的lnc-Hser,在人和小鼠的肝纤维化以及发展为肝纤维化的小鼠的原发性HCs中减少。我们已经表明沉默lnc-Hser通过诱导上皮-间质转化(EMT)和HCs的凋亡在体内和体外加重了肝纤维化。另外,敲低lnc-Hser通过源自受损HC的信号促进了肝星状细胞(HSC)的活化。从机理上讲,我们已经揭示了lnc-Hser通过C5AR1-Hippo-YAP途径抑制了HCs的凋亡,并通过Notch信号抑制了HCs的EMT。结论:我们的工作已经确定了调节肝纤维化的肝细胞特异性lnc-HSER,提供了该分子是受损HCs的新型生物标志物和抗纤维化治疗的潜在靶标的证据。我们已经表明沉默lnc-Hser通过诱导上皮-间质转化(EMT)和HCs的凋亡在体内和体外加重了肝纤维化。另外,敲低lnc-Hser通过源自受损HC的信号促进了肝星状细胞(HSC)的活化。从机理上讲,我们已经揭示了lnc-Hser通过C5AR1-Hippo-YAP途径抑制了HCs的凋亡,并通过Notch信号抑制了HCs的EMT。结论:我们的工作已经确定了调节肝纤维化的肝细胞特异性lnc-HSER,提供了该分子是受损HCs的新型生物标志物和抗纤维化治疗的潜在靶标的证据。我们已经表明沉默lnc-Hser通过诱导上皮-间质转化(EMT)和HCs的凋亡在体内和体外加重了肝纤维化。另外,敲低lnc-Hser通过源自受损HC的信号促进了肝星状细胞(HSC)的活化。从机理上讲,我们已经揭示了lnc-Hser通过C5AR1-Hippo-YAP途径抑制了HCs的凋亡,并通过Notch信号抑制了HCs的EMT。结论:我们的工作已经确定了调节肝纤维化的肝细胞特异性lnc-HSER,提供了该分子是受损HCs的新型生物标志物和抗纤维化治疗的潜在靶标的证据。Lnc-Hser的基因敲低通过来自受损HC的信号促进了肝星状细胞(HSC)的活化。从机理上讲,我们已经揭示了lnc-Hser通过C5AR1-Hippo-YAP途径抑制了HCs的凋亡,并通过Notch信号抑制了HCs的EMT。结论:我们的工作已经确定了调节肝纤维化的肝细胞特异性lnc-HSER,提供了该分子是受损HCs的新型生物标志物和抗纤维化治疗的潜在靶标的证据。Lnc-Hser基因敲低通过来自受损HC的信号促进了肝星状细胞(HSC)的活化。从机制上,我们已经揭示了lnc-Hser通过C5AR1-Hippo-YAP途径抑制HCs凋亡,并通过Notch信号抑制HCs EMT。结论:我们的工作已经确定了调节肝纤维化的肝细胞特异性lnc-HSER,提供了该分子是受损HCs的新型生物标志物和抗纤维化治疗的潜在靶标的证据。
更新日期:2019-10-14
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