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

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 TGF beta-induced hepatocytes apoptosis in vitro and attenuates both CCl4- and bile duct ligation-induced liver fibrosis in mice. Lnc-LFAR1 promotes the binding of Smad2/3 to TGF beta R1 and its phosphorylation in the cytoplasm. Lnc-LFAR1 binds directly to Smad2/3 and promotes transcription of TGF beta, Smad2, Smad3, Notch2 and Notch3 which, in turn, results in TGF beta and Notch pathway activation. We show that the TGF beta 1/Smad2/3/lnc-LFAR1 pathway provides a positive feedback loop to increase Smad2/3 response and a novel link connecting TGF beta with Notch pathway. Our work identifies a liver-enriched lncRNA that regulates liver fibrogenesis and suggests it as a potential target for fibrosis treatment.