Hepatocyte proliferation during liver regeneration is impaired in mice with liver-specific IGF-1R knockout.
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.
Inserm U680, Hôpital St-Antoine, Paris, France.
Christèle
C
Desbois-Mouthon
Dominique
D
Wendum
Axelle
A
Cadoret
Colette
C
Rey
Patricia
P
Leneuve
Annick
A
Blaise
Chantal
C
Housset
François
F
Tronche
Yves
Y
Le Bouc
Martin
M
Holzenberger
D000818:Animals; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases