The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGF\u03b2 and Notch pathways

Kun Zhang,Yawei Han,Qingbin Yao,Zhemin Shi,Maojie Si,Tao Han,Zhen Zhang,Xiaohui Han,Lina Zheng,Zhi Yao,Yanan Chang,Zhimei Hu,Hongmei Cui,Chan Li,Wei Hong,Guiming Shu,Ting Chen

doi:10.1038/s41467-017-00204-4

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 TGFβ-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 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.

Highlights

Long noncoding RNAs play important roles in various biological processes such as proliferation, cell death and differentiation
In a systematic approach to identify Long noncoding RNAs (lncRNAs) involved in liver fibrosis, we applied the well-established model of CCl4 treatment for hepatic fibrogenesis in mice
Various cytokines, growth factors and miRNAs have been shown to regulate the genes that orchestrate activation, apoptosis and proliferation in liver fibrogenesis[1, 2]; little information exists on the lncRNAs that regulate liver fibrogenesis

Summary

Introduction

Long noncoding RNAs (lncRNAs) play important roles in various biological processes such as proliferation, cell death and differentiation. We demonstrate that lnc-LFAR1 silencing impairs hepatic stellate cells (HSCs) activation, reduces TGFβ-induced hepatocytes apoptosis in vitro and attenuates both CCl4- and bile duct ligation-induced liver fibrosis in mice. The number of human protein-coding genes is less than 2% of the whole genome sequence, whereas the vast majority of transcripts consist of the noncoding RNAs, among which are long noncoding RNAs (lncRNAs) that are transcribed mainly by RNA polymerase II, 5'-capped and polyadenylated like most mRNAs, yet this class of transcripts has limited coding potential[4] Despite their poor conservation and low levels of expression compared with protein-coding genes, lncRNAs are often regulated by transcription factors and are expressed in a cell- or tissue-specific manner[5, 6]. No studies have identified any lncRNAs with global effect on pro-fibrotic signaling in the liver, which could be more efficient than targeting a single gene

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Results

Conclusion