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

Kun Zhang, Xiaohui Han, Zhen Zhang, Lina Zheng, Zhimei Hu, Qingbin Yao, Hongmei Cui, Guiming Shu, Maojie Si, Chan Li, Zhemin Shi, Ting Chen, Yawei Han, Yanan Chang, Zhi Yao, Tao Han () and Wei Hong ()
Additional contact information
Kun Zhang: Tianjin Medical University
Xiaohui Han: Tianjin Medical University
Zhen Zhang: Tianjin Medical University
Lina Zheng: Tianjin Medical University
Zhimei Hu: Tianjin Medical University
Qingbin Yao: Tianjin Medical University
Hongmei Cui: Tianjin Medical University
Guiming Shu: The Third Central Clinical College of Tianjin Medical University, Tianjin Third Central Hospital
Maojie Si: The Third Central Clinical College of Tianjin Medical University, Tianjin Third Central Hospital
Chan Li: The Third Central Clinical College of Tianjin Medical University, Tianjin Third Central Hospital
Zhemin Shi: Tianjin Medical University
Ting Chen: Tianjin Medical University
Yawei Han: Tianjin Medical University
Yanan Chang: Tianjin Medical University
Zhi Yao: Tianjin Medical University
Tao Han: The Third Central Clinical College of Tianjin Medical University, Tianjin Third Central Hospital
Wei Hong: Tianjin Medical University

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00204-4

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