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

Abstract

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. 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. 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. 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.