Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jul 28, 2013; 19(28): 4475-4485
Published online Jul 28, 2013. doi: 10.3748/wjg.v19.i28.4475
Resistin mediates the hepatic stellate cell phenotype
Zhi-Xia Dong, Lin Su, Joanne Brymora, Claire Bird, Qing Xie, Jacob George, Jian-Hua Wang
Zhi-Xia Dong, Qing Xie, Department of Infectious Disease, Rui jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China
Zhi-Xia Dong, Lin Su, Joanne Brymora, Claire Bird, Jacob George, Jian-Hua Wang, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW 2145, Australia
Author contributions: Dong ZX and Su L contributed equally to this work; Dong ZX and Su L performed the majority of experiments and data analysis; Brymora J and Bird C performed part of the in vitro experiments and analyzed the data; Xie Q co-ordinated and was involved in editing the manuscript; George J was involved in editing the manuscript; Wang JH designed the study and wrote the manuscript.
Correspondence to: Jian-Hua Wang, MD, PhD, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, NSW 2145, Australia. jianhua.wang@sydney.edu.au
Telephone: +61-2-98459131 Fax: +61-2-98459103
Received: December 31, 2012
Revised: February 13, 2013
Accepted: March 28, 2013
Published online: July 28, 2013
Abstract

AIM: To describe the role of resistin in liver fibrosis.

METHODS: For the in vivo animal study, Sprague Dawley rats were subjected to bile duct ligation (BDL) for 4 wk. Rat liver, adipose tissue (epididymal fat) and serum were analyzed for resistin expression. For the in vitro experiment, rat primary hepatic stellate cells (HSCs) and Kupffer cells (KCs) were used. HSCs were exposed to recombinant resistin, and collagen I, transforming growth factor β1, α smooth muscle actin, tissue inhibitor of metalloproteinase 1 and connective tissue growth factor expression were analyzed. Resistin gene and protein expression was quantified as was the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8 and monocyte chemotactic protein-1 (MCP-1). The effects of resistin on HSC proliferation, migration and apoptosis were determined. The effects of resistin on KCs were also investigated.

RESULTS: Following BDL, rat epididymal fat and serum rather than liver showed higher resistin expression compared to control rats. In liver, resistin was expressed in quiescent HSCs and KCs. Resistin treatment resulted in enhancement of TNFα, IL-6, IL-8 and MCP-1 gene expression and increased IL-6 and MCP-1 protein in HSCs. Resistin activated HSC phospho-MAPK/p38, and p38 inhibition diminished IL-6 and MCP-1 expression. Furthermore, resistin facilitated HSC proliferation and migration, but decreased apoptosis which was via an IL-6 and MCP-1 mechanism. Finally, resistin-induced transforming growth factor β1 from KCs enhanced HSC collagen Iexpression.

CONCLUSION: Resistin directly and indirectly modulates HSC behavior towards a more pro-fibrogenic phenotype.

Keywords: Resistin, Hepatic stellate cell, Kupffer cell, Liver fibrosis, Monocyte chemotactic protein-1

Core tip: Resistin activated hepatic stellate cells (HSCs) phospho-MAPK/p38, and p38 inhibition diminished interleukin 6 (IL-6) and monocyte chemotactic protein-1 (MCP-1) expression. Furthermore, resistin facilitated HSC proliferation and migration, but decreased apoptosis which was via an IL-6 and MCP-1 mechanism. Finally, resistin-induced transforming growth factor β1 from Kupffer cells enhanced HSC collagen I expression. Resistin directly and indirectly modulates HSC behavior towards a more pro-fibrogenic phenotype.