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

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. [ABSTRACT FROM AUTHOR]