LncRNA Airn maintains LSEC differentiation to alleviate liver fibrosis via the KLF2-eNOS-sGC pathway
Ting Chen,
Zhemin Shi,
Yanmian Zhao,
Xiaoxiang Meng,
Sicong Zhao,
Lina Zheng,
Xiaohui Han,
Zhimei Hu,
Qingbin Yao,
Huajiang Lin,
Xiaoxiao Du,
Kun Zhang,
Tao Han,
Wei Hong
Affiliations
Ting Chen
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Zhemin Shi
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Yanmian Zhao
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Xiaoxiang Meng
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Sicong Zhao
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Lina Zheng
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Xiaohui Han
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Zhimei Hu
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Qingbin Yao
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Huajiang Lin
Department of Hepatology and Gastroenterology, Tianjin Union Medical Center, Tianjin Medical University, Tianjin Union Medical Center affiliated to Nankai University
Xiaoxiao Du
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Kun Zhang
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Tao Han
Department of Hepatology and Gastroenterology, Tianjin Union Medical Center, Tianjin Medical University, Tianjin Union Medical Center affiliated to Nankai University
Wei Hong
Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University
Abstract Background Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases. The dysregulation of liver sinusoidal endothelial cell (LSEC) phenotype is a critical early event in the fibrotic process. However, the biological function of lncRNAs in LSEC still remains unclear. Methods The expression level of lncRNA Airn was evaluated in both human fibrotic livers and serums, as well as mouse fibrotic livers. Gain- and loss-of-function experiments were performed to detect the effect of Airn on LSEC differentiation and hepatic stellate cell (HSC) activation in liver fibrosis. Furthermore, RIP, RNA pull-down-immunoblotting, and ChIP experiments were performed to explore the underlying mechanisms of Airn. Results We have identified Airn was significantly upregulated in liver tissues and LSEC of carbon tetrachloride (CCl4)-induced liver fibrosis mouse model. Moreover, the expression of AIRN in fibrotic human liver tissues and serums was remarkably increased compared with healthy controls. In vivo studies showed that Airn deficiency aggravated CCl4- and bile duct ligation (BDL)-induced liver fibrosis, while Airn over-expression by AAV8 alleviated CCl4-induced liver fibrosis. Furthermore, we revealed that Airn maintained LSEC differentiation in vivo and in vitro. Additionally, Airn inhibited HSC activation indirectly by regulating LSEC differentiation and promoted hepatocyte (HC) proliferation by increasing paracrine secretion of Wnt2a and HGF from LSEC. Mechanistically, Airn interacted with EZH2 to maintain LSEC differentiation through KLF2-eNOS-sGC pathway, thereby maintaining HSC quiescence and promoting HC proliferation. Conclusions Our work identified that Airn is beneficial to liver fibrosis by maintaining LSEC differentiation and might be a serum biomarker for liver fibrogenesis.
