LncRNA Airn maintains LSEC differentiation to alleviate liver fibrosis via the KLF2-eNOS-sGC pathway

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.

LncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway attenuated ferroptosis and contributed to liver fibrosis

“…USP13 expression was reduced in LPS-induced synoviocytes, and USP13 overexpression suppressed oxidative stress and ROS production in vitro and collagen-induced arthritis mice model 53. In this study, USP13 was targeted by miR-491-5p, and lncRNA FRMD6-AS1/miR-491-5p/USP13 pathway promoted ferroptosis, reduced ECM deposition and facilitated liver fibrosis in activated HSC-T6 cells.The results of restored liver tissue structure and liver function in CCL4 liver fibrosis mouse models could verify the effective therapeutic methods of lncRNAs in the modulation of liver fibrosis 54,55. In thisstudy, knockdown of lncRNA FRMD6-AS1 restored liver tissue structure, abrogated fibrosis in livers, and reduced liver index (liver weight/ body weight).…”

Role of noncoding RNAs in liver fibrosis

“…NcRNAs are able to target various inflammation-related signaling pathways to reduce liver fibrosis. The latest studies have found that miR-20b-5p[ 97 ] and lncRNA Antisense Igf2r RNA (lncRNA Airn)[ 98 ] can inhibit HSCs activation to alleviate liver fibrosis process. Salvianolic acid B treatment relieved the activation of HSCs through decreasing the expression of lncRNA regulator of reprogramming (lncRNA-ROR)[ 99 ], which providing new targets for the treatment of liver fibrosis.…”

Pathological Changes in Hepatic Sinusoidal Endothelial Cells in Schistosoma japonicum-Infected Mice

“…Some studies have shown that the administration of statin treatment or actin depolymerization to maintain the LSEC phenotype could decrease portal pressure and improve NASH features in an early NASH model [ 33 , 40 ]. Long noncoding RNAs can interact with EZH2, and maintain LSEC differentiation through KLF2-eNOS-sGC pathway and alleviate CCl 4 -induced liver fibrosis [ 41 ].…”