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

Ashwin Woodhoo, Marta Iruarrizaga-Lejarreta, Naiara Beraza, Juan L. García-Rodríguez, Nieves Embade, David Fernández-Ramos, Nuria Martínez-López, Virginia Gutiérrez-De Juan, Beatriz Arteta, Juan Caballeria, Shelly C. Lu, José M. Mato, Marta Varela-Rey, María L. Martínez-Chantar

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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.

Original languageEnglish (US)
Pages (from-to)1870-1882
Number of pages13
JournalHepatology
Volume56
Issue number5
DOIs
StatePublished - Nov 1 2012

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ASJC Scopus subject areas

  • Hepatology

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Woodhoo, A., Iruarrizaga-Lejarreta, M., Beraza, N., García-Rodríguez, J. L., Embade, N., Fernández-Ramos, D., Martínez-López, N., Gutiérrez-De Juan, V., Arteta, B., Caballeria, J., Lu, S. C., Mato, J. M., Varela-Rey, M., & Martínez-Chantar, M. L. (2012). Human antigen R contributes to hepatic stellate cell activation and liver fibrosis. Hepatology, 56(5), 1870-1882. https://doi.org/10.1002/hep.25828