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

ABSTRACT

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 TGFß-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 TGFßR1 and its phosphorylation in the cytoplasm. Lnc-LFAR1 binds directly to Smad2/3 and promotes transcription of TGFß, Smad2, Smad3, Notch2 and Notch3 which, in turn, results in TGFß and Notch pathway activation. We show that the TGFß1/Smad2/3/lnc-LFAR1 pathway provides a positive feedback loop to increase Smad2/3 response and a novel link connecting TGFß 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 TGFß and Notch signaling.