Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice

J Hepatol. 2005 Nov;43(5):799-807. doi: 10.1016/j.jhep.2005.03.027. Epub 2005 May 31.

Abstract

Background/aims: Liver regeneration following hepatectomy is complicated and involves a variety of interacting factors. The present study was designed to study the roles of proliferation and hypertrophy of hepatocytes in liver regeneration following hepatectomy in liver-specific STAT3-knockout (LS3-KO) mice lacking mitogenic activity.

Methods: Partial hepatectomy was performed in LS3-KO and control mice. Liver regeneration was estimated by the liver weight, cell proliferation and cell size, and the related cellular signals were analyzed.

Results: Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Analysis of hepatocellular growth revealed that cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70S6K, mTOR and GSK-3beta in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy.

Conclusions: PI3-K/Akt-mediated responsive hepatocellular hypertrophy may be essential for liver regeneration following hepatectomy and sufficiently compensated liver regeneration even in STAT3-deficient liver, in which cell proliferation is impaired.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cell Proliferation
  • Cell Size
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hepatectomy
  • Hepatocytes / cytology
  • Hepatocytes / physiology*
  • Hypertrophy
  • Liver Regeneration*
  • Liver* / anatomy & histology
  • Liver* / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Serum Albumin / metabolism
  • TOR Serine-Threonine Kinases

Substances

  • STAT3 Transcription Factor
  • Serum Albumin
  • Stat3 protein, mouse
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Glycogen Synthase Kinase 3