title: Human antigen R contributes to hepatic stellate cell activation and liver fibrosis.
abstract: RNA-binding proteins (RBPs) play a major role in the control of messenger RNA (mRNA) turnover and translation rates. We examined the role of the RBP, human antigen R (HuR), during cholestatic liver injury and hepatic stellate cell (HSC) activation. HuR silencing attenuated fibrosis development in vivo after BDL, reducing liver damage, oxidative stress, inflammation, and collagen and alpha smooth muscle actin (α-SMA) expression. HuR expression increased in activated HSCs from bile duct ligation mice and during HSC activation in vitro, and HuR silencing markedly reduced HSC activation. HuR regulated platelet-derived growth factor (PDGF)-induced proliferation and migration and controlled the expression of several mRNAs involved in these processes (e.g., Actin, matrix metalloproteinase 9, and cyclin D1 and B1). These functions of HuR were linked to its abundance and cytoplasmic localization, controlled by PDGF, by extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3-kinase activation as well as ERK/LKB1 (liver kinase B1) activation, respectively. More important, we identified the tumor suppressor, LKB1, as a novel downstream target of PDGF-induced ERK activation in HSCs. HuR also controlled transforming growth factor beta (TGF-β)-induced profibrogenic actions by regulating the expression of TGF-β, α-SMA, and p21. This was likely the result of an increased cytoplasmic localization of HuR, controlled by TGF-β-induced p38 mitogen-activated protein kinase activation. Finally, we found that HuR and LKB1 (Ser428) levels were highly expressed in activated HSCs in human cirrhotic samples.
  
  
  CONCLUSIONS
  Our results show that HuR is important for the pathogenesis of liver fibrosis development in the cholestatic injury model, for HSC activation, and for the response of activated HSC to PDGF and TGF-β.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Derio, Bizkaia, Spain.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Woodhoo
authors.forename: Marta
authors.initials: M
authors.lastname: Iruarrizaga-Lejarreta
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
authors.forename: Juan L
authors.initials: JL
authors.lastname: García-Rodríguez
authors.forename: Nieves
authors.initials: N
authors.lastname: Embade
authors.forename: David
authors.initials: D
authors.lastname: Fernández-Ramos
authors.forename: Nuria
authors.initials: N
authors.lastname: Martínez-López
authors.forename: Virginia
authors.initials: V
authors.lastname: Gutiérrez-De Juan
authors.forename: Beatriz
authors.initials: B
authors.lastname: Arteta
authors.forename: Juan
authors.initials: J
authors.lastname: Caballeria
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D002251:Carbon Tetrachloride; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003135:Common Bile Duct; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008026:Ligation; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000954:Antigens, Surface; D002070:Butadienes; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D009570:Nitriles; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016212:Transforming Growth Factor beta; C113580:U 0126; D002251:Carbon Tetrachloride; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases