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Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Liver fibrosis is an aberrant wound healing response to tissue injury characterized by excessive extracellular matrix deposition and loss of normal liver architecture. Hepatic stellate cells (HSCs) activation is regards to be the major process in liver fibrogenesis which is dynamic and reversible. Both Hippo signaling core factor Yap and Hedgehog (Hh) signaling promote HSCs transdifferentiation thereby regulating the repair process of liver injury. However, the molecular function of YAP and the regulation between Yap and Hh during fibrogenesis remain uncertain. In this study, the essential roles of Yap in liver fibrosis were investigated. Yap was detected to be increased in liver fibrotic tissue by the thioacetamide (TAA)-induced zebrafish embryonic and adult models. Inhibition of Yap by both embryonic morpholino interference and adult’s inhibitor treatment was proved to alleviate TAA-induced liver lesions by and histology and gene expression examination. Transcriptomic analysis and gene expression detection showed that Yap and Hh signaling pathway have a cross talking upon TAA-induced liver fibrosis. In addition, TAA induction promoted the nuclear colocalization of YAP and Hh signaling factor GLI2α. This study demonstrates that Yap and Hh play synergistic protective roles in liver fibrotic response and provides new theoretical insight concerning the mechanisms of fibrosis progression.

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Acknowledgements

We thank Professor Zhiyuan Gong in National University of Singapore and Professor Qingshun Zhao in Nanjing University in China for valuable discussions about this research.

Funding

This work was supported by grants from National Natural Science Foundation of China (No. 31701279) and Xiamen Municipal Science and Technology Bureau-Xiamen City Division of Funding Management Project (No. 3502Z20203016).

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  1. Ye Zhao and Huiling Wang have contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China

    Ye Zhao, Huiling Wang, Tianhua He, Bo Ma & Guoguang Chen

  2. School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361005, China

    Chimeng Tzeng

  3. Translational Medicine Research Center-Key Laboratory for Cancer T-Cell Theragnostic and Clinical Translation, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China

    Chimeng Tzeng

  4. Xiamen Chang Gung Hospital Medical Research Center, Xiamen, Fujian, China

    Chimeng Tzeng

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Contributions

YZ, CT conceived and designed the experiments; YZ, HW and TH performed all experiments; YZ, HW analyzed data; YZ, HW, BM, GC and CT wrote and reviewed the manuscript.

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Correspondence to Ye Zhao or Chimeng Tzeng.

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Zhao, Y., Wang, H., He, T. et al. Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals. J. Cell Commun. Signal. 17, 1335–1354 (2023). https://doi.org/10.1007/s12079-023-00775-6

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