title: Resistin mediates the hepatic stellate cell phenotype.
abstract: OBJECTIVE
  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  I expression.
  
  
  CONCLUSIONS
  Resistin directly and indirectly modulates HSC behavior towards a more pro-fibrogenic phenotype.
authors.affiliation: Department of Infectious Disease, Rui jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
authors.forename: Zhi-Xia
authors.initials: ZX
authors.lastname: Dong
authors.forename: Lin
authors.initials: L
authors.lastname: Su
authors.forename: Joanne
authors.initials: J
authors.lastname: Brymora
authors.forename: Claire
authors.initials: C
authors.lastname: Bird
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010641:Phenotype; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D052243:Resistin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D016207:Cytokines; D018836:Inflammation Mediators; D052243:Resistin; D019715:Tissue Inhibitor of Metalloproteinase-1; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; C526316:CCN2 protein, rat; C498145:Rela protein, rat; C499623:Retn protein, mouse; C499622:Retn protein, rat; C576839:TIMP1 protein, rat; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat
keywords: Hepatic stellate cell; Kupffer cell; Liver fibrosis; Monocyte chemotactic protein-1; Resistin
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