Reduced hepatic lipid content in Pten-haplodeficient mice because of enhanced AKT2/PKBβ activation in skeletal muscle

Authors

  • Simon M. Schultze,

    1. Department of Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
    2. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    Search for more papers by this author
  • Maren Dietrich,

    1. Department of Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
    Search for more papers by this author
  • Debby Hynx,

    1. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    Search for more papers by this author
  • Andreas Geier,

    1. Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
    2. Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    Search for more papers by this author
  • Markus Niessen,

    1. Department of Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
    2. Competence Centre for Systems Physiology and Metabolic Diseases, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
    Search for more papers by this author
  • Giatgen A. Spinas,

    1. Department of Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
    2. Competence Centre for Systems Physiology and Metabolic Diseases, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
    Search for more papers by this author
  • Brian A. Hemmings,

    1. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
    Search for more papers by this author
  • Oliver Tschopp

    Corresponding author
    1. Department of Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
    2. Competence Centre for Systems Physiology and Metabolic Diseases, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
    • Correspondence

      Oliver Tschopp, MD

      University Hospital Zurich

      Department of Endocrinology, Diabetes and Clinical Nutrition

      Raemistrasse 100; 8091 Zurich, Switzerland

      Tel: +41 (0) 44 255 3620

      Fax: +41 (0) 44 255 4447

      e-mail: oliver.tschopp@usz.ch

    Search for more papers by this author

Abstract

Background & Aims

Non-alcoholic fatty liver disease (NAFLD) is a major health problem and occurs frequently in the context of metabolic syndrome and type 2 diabetes mellitus. Hepatocyte-specific Pten-deficiency in mice was shown previously to result in hepatic steatosis due to hyperactivated AKT2. However, the role of peripheral insulin-sensitive tissues on PTEN- and AKT2-dependent accumulation of hepatic lipids has not been addressed.

Methods

Effects of systemically perturbed PTEN/AKT2 signalling on hepatic lipid content were studied in Pten-haplodeficient (Pten+/−/Akt2+/+) mice and Pten-haplodeficient mice lacking Akt2 (Pten+/−/Akt2−/−). The liver and skeletal muscle were characterized by histology and/or analysis of insulin signalling. To assess the effects of AKT2 activity in skeletal muscle on hepatic lipid content, AKT2 mutants were expressed in skeletal muscle of Pten+/+/Akt2+/+ and Pten+/−/Akt2+/+ mice using adeno-associated virus 8.

Results

Pten+/−/Akt2+/+ mice were found to have a more than 2-fold reduction in hepatic lipid content, at a level similar to that observed in Pten+/−/Akt2−/− mice. Insulin signalling in the livers of Pten+/−/Akt2+/+ mice was enhanced, indicating that extrahepatic factors prevent lipid accumulation. The skeletal muscle of Pten+/−/Akt2+/+ mice also showed enhanced insulin signalling. Skeletal muscle-specific expression of constitutively active AKT2 reduced hepatic lipid content in Pten+/+/Akt2+/+ mice, and dominant negative AKT2 led to an increase in accumulation of hepatic lipids in both Pten+/+/Akt2+/+ and Pten+/−/Akt2+/+ mice.

Conclusion

Our results demonstrate that AKT2 activity in skeletal muscle critically affects lipid accumulation in the livers of Pten+/+/Akt2+/+ and Pten+/−/Akt2+/+ mice, and emphasize the role of skeletal muscle in the pathology of NAFLD.

Ancillary