Human antigen R contributes to hepatic stellate cell activation and liver fibrosis

Authors

  • Ashwin Woodhoo,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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    • Joint first authors.

  • Marta Iruarrizaga-Lejarreta,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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    • Joint first authors.

  • Naiara Beraza,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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  • Juan L García-Rodríguez,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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  • Nieves Embade,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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  • David Fernández-Ramos,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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  • Nuria Martínez-López,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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  • Virginia Gutiérrez-De Juan,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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  • Beatriz Arteta,

    1. School of Medicine and Dentistry, University of the Basque Country, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain
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  • Juan Caballeria,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
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  • Shelly C Lu,

    1. Division of Gastrointestinal and Liver Diseases, University of Southern California Research Center for Liver Diseases, Southern California Research Center for Alcoholic and Pancreatic Diseases & Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, CA
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  • José M Mato,

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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  • Marta Varela-Rey,

    Corresponding author
    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
    • CIC bioGUNE, Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain
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    • fax: +34-944-061301

    • Joint senior authors.

  • María L Martínez-Chantar

    1. CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, Derio, Bizkaia, Spain
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    • Joint senior authors.


  • Potential conflict of interest: Nothing to report.

  • This work was supported by the National Institutes of Health (grant nos.: RO1AT-1576 and RO1AT-004896; to S.C.L., M.L.M-C., and J.M.M.), SAF 2011-29851 (to J.M.M.), ETORTEK-2011, Sanidad Gobierno Vasco 2008, Educación Gobierno Vasco 2011 (PI2011/29), and FIS (PI11/01588) (to M.L.M-C.), Sanidad Gobierno Vasco 2012 (to M.V.R.), FIS PS09/00094, Fundación Científica de la Asociación Española Contra el Cáncer (Cancer Infantil) (to A.W.), and the Program Ramón y Cajal, Ministry of Science and Innovation, Spain (to A.W. and N.B.). FIS PS09/02010 were awarded to N.B., and FIS PS09/01164 was awarded to J.C. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd) is funded by the Instituto de Salud Carlos III.

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. Conclusion: 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. (HEPATOLOGY 2012;56:1870–1882)

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