title: MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis.
abstract: OBJECTIVE
  MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis.
  
  
  METHODS
  Wild type (WT) and miR-155-deficient (KO) mice were fed methionine-choline-deficient (MCD) or -supplemented (MCS) control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed.
  
  
  RESULTS
  MCD diet resulted in steatohepatitis and increased miR-155 expression in total liver, hepatocytes and Kupffer cells. Steatosis and expression of genes involved in fatty acid metabolism were attenuated in miR-155 KO mice after MCD feeding. In contrast, miR-155 deficiency failed to attenuate inflammatory cell infiltration, nuclear factor κ beta (NF-κB) activation and enhanced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and monocyte chemoattractant protein-1 (MCP1) in MCD diet-fed mice. We found a significant attenuation of apoptosis (cleaved caspase-3) and reduction in collagen and α smooth muscle actin (αSMA) levels in miR-155 KO mice compared to WTs on MCD diet. In addition, we found attenuation of platelet derived growth factor (PDGF), a pro-fibrotic cytokine; SMAD family member 3 (Smad3), a protein involved in transforming growth factor-β (TGFβ) signal transduction and vimentin, a mesenchymal marker and indirect indicator of epithelial-to-mesenchymal transition (EMT) in miR-155 KO mice. Nuclear binding of CCAAT enhancer binding protein β (C/EBPβ) a miR-155 target involved in EMT was significantly increased in miR-155 KO compared to WT mice.
  
  
  CONCLUSIONS
  Our novel data demonstrate that miR-155 deficiency can reduce steatosis and fibrosis without decreasing inflammation in steatohepatitis.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Timea
authors.initials: T
authors.lastname: Csak
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bala
authors.affiliation: 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Dora
authors.initials: D
authors.lastname: Lippai
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Arvin
authors.initials: A
authors.lastname: Iracheta-Vellve
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002794:Choline; D004032:Diet; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000150:complications*; D050356:Lipid Metabolism / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications* / Q000235:genetics*; D008715:Methionine; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051900:Smad3 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D008070:Lipopolysaccharides; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D051900:Smad3 Protein; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D008715:Methionine; D002794:Choline