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Insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) contributes to liver inflammation and fibrosis via activation of the ERK1/2 pathway

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Abstract

Background and aim

Previously, we suggested that IGFBPrP1 played a major role in hepatic stellate cell (HSC) activation, yet the molecular mechanism of IGFBPrP1 in hepatic fibrosis is unclear. The ERK pathway is involved in activation of HSCs. This study investigated the involvement of the ERK1/2 pathway in IGFBPrP1-induced liver inflammation and fibrosis.

Methods

An adenoviral vector encoding IGFBPrP1 (AdIGFBPrP1) was constructed. Rats received AdIGFBPrP1 or CAd (vector control) via their tail vein injection. One hour prior to adenoviral injections, rats were intraperitoneally administrated with 10 mg/kg U0126 (a specific MEK/ERK1/2 inhibitor) or DMSO (vehicle control). At weeks 2 or 4 post-gene transduction, serum samples were obtained and the levels of liver enzymes and hydroxyproline were determined. Liver tissue were histologically evaluated for inflammation and fibrosis. The expression of α-SMA and ECM were evaluated by qRT-PCR and western blotting.

Results

After transduction, IGFBPrP1 expression significantly increased in livers and transduced cells. MEK/ERK1/2 inhibition administration of AdIGFBPrP1-treated rats and cells significantly blocked AdIGFBPrP1-induced activation of ERK1/2. U0126 significantly down-regulated the number of F4/80-positive cells and CD3-positive cells (markers of liver inflammation), the expression of α-SMA and the concentration of ECM components in vivo. In addition, α-SMA and TGF-β1 levels in AdIGFBPrP1 HSCs were markedly inhibited by a MEK/ERK1/2 inhibitor, indicating that HSC activation was inhibited.

Conclusion

These findings suggest that IGFBPrP1 acts as an initiator of liver fibrosis by inducing inflammation, HSC activation and ECM deposition through the ERK1/2 pathway.

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Acknowledgements

This work was sponsored by grants from the National Natural Science Foundation of China (No. 81141049) and the Shanxi Province Key Scientific Research Projects for the Returned Scholars (2012–2014). We thank Professor Ren-Ke Li, who holds a Canada Research Chair in Cardiac Regeneration and works at Toronto General Hospital of the University of Toronto, for assistance with manuscript writing. We are also grateful for the native language polishing help from Roy Fyre, who is working as Associate Professor at the Department of Pathology in the University of Pittsburgh.

Compliance with ethical requirements and Conflict of interest

All institutional and national guidelines for the care and use of laboratory animals were followed. Yarong Guo, Yun Zhang, Qianqian Zhang, Xiaohong Guo, Haiyan Zhang, Guoping Zheng and Lixin Liu declare that they have no conflict of interest. The study strictly conformed to the ethical rules of standard experimental animal studies, and was approved by the Ethics Committee of Shanxi Medical University.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, The First Clinical Hospital of Shanxi Medical University, Mailbox 427, 85 Jiefang South Road, Taiyuan, 030001, Shanxi Province, China

    Yarong Guo, Yun Zhang, Qianqian Zhang, Xiaohong Guo, Haiyan Zhang & Lixin Liu

  2. Experimental Center of Science and Research, The First Clinical Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi Province, China

    Qianqian Zhang, Xiaohong Guo, Haiyan Zhang & Lixin Liu

  3. Key Laboratory of Cell Physiology, Provincial Department of the Ministry of Education, Shanxi Medical University, Taiyuan, 030001, Shanxi Province, China

    Qianqian Zhang, Xiaohong Guo, Haiyan Zhang & Lixin Liu

  4. Center for Transplantation and Renal Research, The University of Sydney at Westmead Millennium Institute, Sydney, NSW, 2145, Australia

    Guoping Zheng

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  1. Yarong Guo
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Correspondence to Lixin Liu.

Additional information

Yarong Guo and Yun Zhang contributed equally to this work.

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Guo, Y., Zhang, Y., Zhang, Q. et al. Insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) contributes to liver inflammation and fibrosis via activation of the ERK1/2 pathway. Hepatol Int 9, 130–141 (2015). https://doi.org/10.1007/s12072-014-9578-9

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