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Effect of SEPT6 on the biological behavior of hepatic stellate cells and liver fibrosis in rats and its mechanism

Laboratory Investigationvolume 99pages1736 (2019) | Download Citation

Abstract

Hepatic stellate cells (HSCs) are key effectors during the development of liver fibrosis. Septin 6 (SEPT6) is a highly evolutionarily conserved GTP-binding protein that regulates various cell biological behaviors. The expression and function of SEPT6 in HSCs remain unknown. Here we demonstrate that SEPT6 expression is significantly elevated following the activation of primary rat HSCs, the human hepatic stellate cell line LX-2 and the rat hepatic stellate cell line HSC-T6, as well as in both human and rat fibrotic liver tissue. In vitro, the overexpression of SEPT6 promoted HSCs activation, proliferation, cell cycle progression and migration and inhibited HSCs apoptosis. In contrast, knockdown of SEPT6 exerted the opposite effects on HSCs. Mechanistically, SEPT6 exerted its pro-fibrogenic effect by promoting the expression of TGF-β1 and the phosphorylation of Smad2, Smad3, extracellular-signal-regulated kinase, c-Jun NH2-terminal kinase, stress-activated protein kinase-2, and protein kinase B. However, in HSC-T6 cells, blockade of the TGF-β1/Smad signaling pathway by SB431542 significantly decreased the expression of α-smooth muscle actin, cyclin D1, BCL2, and matrix metalloproteinase-2 and -9, which had been enhanced by SEPT6 overexpression. In vivo, adenovirus-mediated SEPT6 inhibition attenuated thioacetamide (TAA)-induced liver fibrosis in rats by decreasing the deposition of the extracellular matrix (ECM). SEPT6 inhibition decreased the proliferation capacity of HSCs and induced apoptosis of HSCs. Collectively, our results reveal that SEPT6 regulates various biological behaviors in HSCs through TGF-β1/Smad, mitogen-activated protein kinases and phosphatidylinositol-3-kinase/protein kinase B signaling pathways, thus promoting liver fibrosis.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81272657, No. 81572422).

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Affiliations

  1. Institute of Liver Diseases, Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China

    • Yuhui Fan
    • , Zhipeng Du
    • , Qiang Ding
    • , Panpan Lu
    • , Dean Tian
    •  & Mei Liu
  2. Department of Medicine II, Liver Center Munich (LCM), Klinikum der Universität München (KUM), Grosshadern, Ludwig-Maximilians University, Marchioninistrasse 15, 81377, Munich, Germany

    • Christian J. Steib

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The authors declare that they have no conflict of interest.

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Correspondence to Mei Liu.

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https://doi.org/10.1038/s41374-018-0133-5