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Metformin attenuates motility, contraction, and fibrogenic response of hepatic stellate cells in vivo and in vitro by activating AMP-activated protein kinase.
Li, Zhen; Ding, Qian; Ling, Li-Ping; Wu, Ying; Meng, Dong-Xiao; Li, Xiao; Zhang, Chun-Qing.
Afiliação
  • Li Z; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
  • Ding Q; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
  • Ling LP; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
  • Wu Y; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
  • Meng DX; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
  • Li X; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
  • Zhang CQ; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China. zhangchunqing_sdu@163.com.
World J Gastroenterol ; 24(7): 819-832, 2018 Feb 21.
Article em En | MEDLINE | ID: mdl-29467552
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 (CCl4) 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 CCl4 for 6 wk. Metformin decreased the activation of HSCs, reduced the deposition of ECM, and inhibited angiogenesis in CCl4-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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Movimento Celular / Células Estreladas do Fígado / Proteínas Quinases Ativadas por AMP / Hipoglicemiantes / Cirrose Hepática / Metformina Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: World J Gastroenterol Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Movimento Celular / Células Estreladas do Fígado / Proteínas Quinases Ativadas por AMP / Hipoglicemiantes / Cirrose Hepática / Metformina Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Revista: World J Gastroenterol Ano de publicação: 2018 Tipo de documento: Article