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

Author

Listed:
  • 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
    Tianjin Third Central Hospital
    Tianjin Key Laboratory of Artificial Cells, Tianjin Third Central Hospital)

  • Wei Hong

    (Tianjin Medical University)

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.

Suggested Citation

  • 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 & W, 2017. "The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00204-4
    DOI: 10.1038/s41467-017-00204-4
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    Cited by:

    1. Sophie A. Riesmeijer & Zoha Kamali & Michael Ng & Dmitriy Drichel & Bram Piersma & Kerstin Becker & Thomas B. Layton & Jagdeep Nanchahal & Michael Nothnagel & Ahmad Vaez & Hans Christian Hennies & Pau, 2024. "A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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