肝星状细胞
肝纤维化
炎症
纤维化
基因沉默
癌症研究
蛋白激酶B
生物
细胞生物学
体内
信号转导
免疫学
医学
内科学
基因
内分泌学
生物化学
生物技术
作者
Xiaohui Han,Beichen Guo,Sicong Zhao,Yehua Li,Jun Zhu,Yaqin He,Jiajun Wang,Qingbin Yao,Shuai Shao,Lemin Zheng,Zhemin Shi,Tao Han,Hong Wang,Kun Zhang
标识
DOI:10.1186/s11658-023-00492-3
摘要
Abstract Background Hepatic fibrosis is a common consequence of chronic liver diseases without approved antifibrotic therapies. Long noncoding RNAs (lncRNAs) play an important role in various pathophysiological processes. However, the functions of certain lncRNAs involved in mediating the antifibrotic role remain largely unclear. Methods The RNA level of lnc-High Expressed in Liver Fibrosis (Helf) was detected in both mouse and human fibrotic livers. Furthermore, lnc-Helf-silenced mice were treated with carbon tetrachloride (CCl 4 ) or bile duct ligation (BDL) to investigate the function of lnc-Helf in liver fibrosis. Results We found that lnc-Helf has significantly higher expression in human and mouse fibrotic livers as well as M1 polarized hepatic macrophages (HMs) and activated hepatic stellate cells (HSCs). In vivo studies showed that silencing lnc-Helf by AAV8 vector alleviates CCl 4 - and BDL-induced hepatic inflammation and fibrosis. Furthermore, in vitro experiments revealed that lnc-Helf promotes HSCs activation and proliferation, as well as HMs M1 polarization and proliferation in the absence or presence of cytokine stimulation. Mechanistically, our data illustrated that lnc-Helf interacts with RNA binding protein PTBP1 to promote its interaction with PIK3R5 mRNA, resulting in increased stability and activating the AKT pathway, thus promoting HSCs and HMs activation and proliferation, which augments hepatic inflammation and fibrosis. Conclusion Our results unveil a lnc-Helf/PTBP1/PIK3R5/AKT feedforward, amplifying signaling that exacerbates the process of hepatic inflammation and fibrosis, thus providing a possible therapeutic strategy for hepatic fibrosis.
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