Metformin attenuates motility, contraction, and fibrogenic response of hepatic stellate cells  in vivo  and  in vitro  by activating AMP-activated protein kinase

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Abstract

AIM

To investigate the effect of metformin on activated hepatic stellate cells (HSCs) and the possible signaling pathways involved.

METHODS

A fibrotic mouse model was generated by intraperitoneal injection of carbon tetrachloride (CCl ₄) and subsequent treatment with or without metformin. The level of fibrosis was detected by hematoxylin-eosin staining, Sirius Red staining, and immunohistochemistry. The HSC cell line LX-2 was used for in vitro studies. The effect of metformin on cell proliferation (CCK8 assay), motility (scratch test and Transwell assay), contraction (collagen gel contraction assay), extracellular matrix (ECM) secretion (Western blot), and angiogenesis (ELISA and tube formation assay) was investigated. We also analyzed the possible signaling pathways involved by Western blot analysis.

RESULTS

Mice developed marked liver fibrosis after intraperitoneal injection with CCl ₄ for 6 wk. Metformin decreased the activation of HSCs, reduced the deposition of ECM, and inhibited angiogenesis in CCl ₄-treated mice. Platelet-derived growth factor (PDGF) promoted the fibrogenic response of HSCs in vitro, while metformin inhibited the activation, proliferation, migration, and contraction of HSCs, and reduced the secretion of ECM. Metformin decreased the expression of vascular endothelial growth factor (VEGF) in HSCs through inhibition of hypoxia inducible factor (HIF)-1α in both PDGF-BB treatment and hypoxic conditions, and it down-regulated VEGF secretion by HSCs and inhibited HSC-based angiogenesis in hypoxic conditions in vitro. The inhibitory effects of metformin on activated HSCs were mediated by inhibiting the Akt/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) pathways via the activation of adenosine monophosphate-activated protein kinase (AMPK).

CONCLUSION

Metformin attenuates the fibrogenic response of HSCs in vivo and in vitro, and may therefore be useful for the treatment of chronic liver diseases.

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Author and article information

Contributors

Zhen Li

Qian Ding

Li-Ping Ling

Ying Wu

Dong-Xiao Meng

Xiao Li

Chun-Qing Zhang

Journal

Journal ID (nlm-ta): World J Gastroenterol

Journal ID (iso-abbrev): World J. Gastroenterol

Journal ID (publisher-id): WJG

Title: World Journal of Gastroenterology

Publisher: Baishideng Publishing Group Inc

ISSN (Print): 1007-9327

ISSN (Electronic): 2219-2840

Publication date (Print): 21 February 2018

Publication date (Electronic): 21 February 2018

Volume: 24

Issue: 7

Pages: 819-832

Affiliations

Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China