The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways

• Published in: Nature communications 2017-07, Vol.8 (1), p.144-16, Article 144
• Main Authors: Zhang, Kun, Han, Xiaohui, Zhang, Zhen, Zheng, Lina, Hu, Zhimei, Yao, Qingbin, Cui, Hongmei, Shu, Guiming, Si, Maojie, Li, Chan, Shi, Zhemin, Chen, Ting, Han, Yawei, Chang, Yanan, Yao, Zhi, Han, Tao, Hong, Wei
• Format: Article
• Language: English
• Subjects: 631/337/384/2568; 631/80/304; 631/80/86/820; 692/699/1503/1607/1605; Animals; Apoptosis - genetics; Bile; Cell Line; Cells, Cultured; Cytokines; Fibrosis; Gene Expression Profiling - methods; HEK293 Cells; Hepatic Stellate Cells - metabolism; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Liver; Liver - metabolism; Liver Cirrhosis - genetics; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Notch protein; Notch2 protein; Notch3 protein; Receptors, Notch - genetics; Receptors, Notch - metabolism; RNA, Long Noncoding - genetics; Science; Science (multidisciplinary); Signal Transduction - genetics; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Smad3 Protein - metabolism; Stellate cells; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00204-4

Long noncoding RNAs (lncRNAs) play important roles in various biological processes such as proliferation, cell death and differentiation. Here, we show that a liver-enriched lncRNA, named liver fibrosis-associated lncRNA1 (lnc-LFAR1), promotes liver fibrosis. We demonstrate that lnc-LFAR1 silencing impairs hepatic stellate cells (HSCs) activation, reduces TGFβ-induced hepatocytes apoptosis in vitro and attenuates both CCl 4 - and bile duct ligation-induced liver fibrosis in mice. Lnc-LFAR1 promotes the binding of Smad2/3 to TGFβR1 and its phosphorylation in the cytoplasm. Lnc-LFAR1 binds directly to Smad2/3 and promotes transcription of TGFβ, Smad2, Smad3, Notch2 and Notch3 which, in turn, results in TGFβ and Notch pathway activation. We show that the TGFβ1/Smad2/3/lnc-LFAR1 pathway provides a positive feedback loop to increase Smad2/3 response and a novel link connecting TGFβ with Notch pathway. Our work identifies a liver-enriched lncRNA that regulates liver fibrogenesis and suggests it as a potential target for fibrosis treatment. Activated hepatic stellate cells are the principal contributors to liver fibrosis by secreting a variety of pro-fibrogenic cytokines . Here Zhang et al. demonstrate that a liver-enriched lncRNA, lnc-LFAR1, promotes liver fibrosis and HSC activation by activating TGFβ and Notch signaling.