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LncRNA Airn alleviates liver fibrosis and maintains LSECs differentiation via the KLF2-eNOS-sGC pathway

ABSTRACT: Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases. It has been suggested that dysregulation of liver sinusoidal endothelial cells (LSECs) phenotype is a critical early event in the fibrotic process. However, the biological function of lncRNAs in LSECs still remains unclear. Here, we identified that lncRNA-Airn was significantly up-regulated in liver tissues and LSECs of CCl4-induced liver fibrosis. Moreover, the expression of AIRN in human cirrhotic liver tissues and serums was remarkably increased as compared with healthy controls. In vivo studies showed that Airn deficiency aggravated CCl4- and BDL-induced liver fibrosis, while Airn overexpression by adeno-associated viral vector serotype 8 vector alleviated CCl4-induced liver fibrosis. Furthermore, we revealed that Airn maintained LSECs differentiation in vivo and in vitro. Additionally, Airn inhibited hepatic stellate cells (HSCs) activation indirectly by regulating LSECs differentiation and promoted hepatocytes (HCs) proliferation by the increased paracrine secretion of Wnt2a and HGF from LSECs. Mechanistically, our results demonstrated that Airn maintained LSECs differentiation through KLF2-endothelial nitric oxide synthase (eNOS)-soluble guanylate cyclase (sGC) pathway, thereby promoting HSCs quiescence and HCs proliferation. In conclusion, our work identified that Airn is beneficial to liver fibrosis by maintaining LSECs differentiation and might be a novel serum biomarker for liver fibrogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE174175 | GEO | 2021/05/11

REPOSITORIES: GEO

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Project description:Background & Aims: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSECs-expressed POFUT1 in liver fibrosis. Methods: Endothelial-specific Pofut1 knockout mice were generated and subjected to experimental liver fibrosis by chronic carbon tetrachloride exposure or by common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA-seq, qPCR, and Western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSECs cultures. Liver single-cell RNA-seq data sets from cirrhotic patients and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. Results: POFUT1 loss promoted injury-induced LSECs capillarization and HSC activation, leading to aggravated liver fibrosis. RNA-seq analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of cirrhotic patients. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to treatment with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. Conclusions: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen which function as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases.

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LncRNA Airn alleviates liver fibrosis and maintains LSECs differentiation via the KLF2-eNOS-sGC pathway

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