Regulation of ERK/JNK/p70S6K in two rat models of liver injury and fibrosis

Gianluca Svegliati-Baroni, Francesco Ridolfi, Zaira Caradonna, Domenico Alvaro, Marco Marzioni, Stefania Saccomanno, Cinzia Candelaresi, Luciano Trozzi, Giampiero Macarri, Antonio Benedetti, Franco Folli

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Background/Aims: The regulation of three major intracellular signalling protein kinases was investigated in two models of liver injury leading to hepatic fibrosis, dimethylnitrosamine administration (DMN) and bile duct iigation (BDL). Methods: Extracellular signal-regulated kinases (ERK)1/2, c-Jun terminal kinase (JNK) and p70S6-kinase (p70S6K) were studied in vivo in the whole liver, in liver sections and in isolated hepatocytes, cholangiocytes and hepatic stellate cells (HSC). Results: In the whole liver, activation of these kinases occurred with a different kinetic pattern in both models of liver injury. By immunohistochemistry and Western blot in isolated cells, phosphorylated kinases were detected in proliferating cells (i.e. hepatocytes and cholangiocytes after DMN and BDL, respectively), in addition to stellate-like elements. ERK1/2, JNK and p70S6K activation was associated with hepatocytes proliferation after DMN, while JNK activation was not associated with cholangiocytes proliferation after BDL. In HSC isolated from injured livers, protein kinases were differentially activated after BDL and DMN. Kinases activation in HSC in vivo preceded cell proliferation and alpha-smooth muscle actin appearance, a marker of HSC transformation in myofibroblast-like cells, and collagen deposition. Conclusions: Our findings indicate that these kinases are coordinately regulated during liver regeneration and suggest that their modulation could be considered as a future therapeutic approach in the management of liver damage.

Original languageEnglish (US)
Pages (from-to)528-537
Number of pages10
JournalJournal of Hepatology
Volume39
Issue number4
DOIs
StatePublished - Oct 1 2003

Keywords

  • Cholangiocytes
  • Fibrosis
  • Hepatic stellate cells
  • Hepatocytes
  • Liver injury
  • Proliferation

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Regulation of ERK/JNK/p70<sup>S6K</sup> in two rat models of liver injury and fibrosis'. Together they form a unique fingerprint.

  • Cite this

    Svegliati-Baroni, G., Ridolfi, F., Caradonna, Z., Alvaro, D., Marzioni, M., Saccomanno, S., Candelaresi, C., Trozzi, L., Macarri, G., Benedetti, A., & Folli, F. (2003). Regulation of ERK/JNK/p70S6K in two rat models of liver injury and fibrosis. Journal of Hepatology, 39(4), 528-537. https://doi.org/10.1016/S0168-8278(03)00291-5