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Hepatocyte proliferation during liver regeneration is impaired in mice with liver‐specific IGF‐1R knockout
Author(s) -
DesboisMouthon Christèle,
Wendum Dominique,
Cadoret Axelle,
Rey Colette,
Leneuve Patricia,
Blaise Annick,
Housset Chantal,
Tronche François,
Le Bouc Yves,
Holzenberger Martin
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4704fje
Subject(s) - liver regeneration , cyclin d1 , endocrinology , medicine , regeneration (biology) , hepatocyte , biology , cyclin , cyclin e1 , conditional gene knockout , knockout mouse , insulin like growth factor , cell growth , cell cycle , growth factor , microbiology and biotechnology , receptor , cancer , biochemistry , gene , in vitro , phenotype
Recent evidence indicates that growth hormone (GH) is involved in liver regeneration. To test whether insulin‐like growth factor I (IGF‐I) mediates this effect, we studied liver regeneration induced by partial hepatectomy in liver‐specific IGF type 1 receptor knockout (LIGFREKO) mice. The absence of IGF‐1R caused a significant decrease in hepatocyte proliferation in males (−52%), but not in females, as assessed by Ki67 immunohistochemistry. Cyclin D1 and cyclin A protein levels in the livers of LIGFREKO males were only half those in controls, indicating that cyclin induction during liver regeneration is dependent on IGF‐1R signaling. Analyzing the signaling cascade initiated by IGF‐1R, we observed a lack of IRS‐1 induction in LIGFREKO livers. In contrast, the induction of IRS‐2 synthesis was similar in LIGFREKO and control groups, suggesting the existence of differential regulation of IRS synthesis during liver regeneration. Regenerating livers from LIGFREKO animals also showed significantly less activated ERKs than controls. Our findings demonstrate that IGF‐1R makes a significant contribution to liver regeneration. Using the LIGFREKO model, we provide new evidence that IGF‐1R/IRS‐1/ERK signaling may be the intracellular pathway controlling the cell cycle via cyclin D1 and cyclin A in the regenerating liver.