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


CONCLUSIONS
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.
Department of Endocrinology, Diabetes & Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Simon M
SM
Schultze
Maren
M
Dietrich
Debby
D
Hynx
Andreas
A
Geier
Markus
M
Niessen
Giatgen A
GA
Spinas
Brian A
BA
Hemmings
Oliver
O
Tschopp
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005838:Genotype; D006003:Glycogen / Q000378:metabolism; D057895:Haploinsufficiency; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin; D006003:Glycogen; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
NAFLD; liver; metabolism