Reduced hepatic lipid content in Pten‐haplodeficient mice because of enhanced AKT2/PKBβ activation in skeletal muscle. (24th June 2014)

• Record Type: Journal Article
• Authors: Schultze, Simon M.; Dietrich, Maren; Hynx, Debby; Geier, Andreas; Niessen, Markus; Spinas, Giatgen A.; Hemmings, Brian A.; Tschopp, Oliver
• Is Part Of: Liver international. Volume 35:Number 4(2015:Apr.)
• Page Start: 1354
• Page End: 1366
• Publication Date: 2014-06-24
• Subjects: Liver -- Periodicals; Liver -- Diseases -- Periodicals; 616.362
• DOI: 10.1111/liv.12600
• Languages: English
• ISSNs: 1478-3223

Abstract

<abstract abstract-type="main" id="liv12600-abs-0001"> <title>Abstract</title> <sec id="liv12600-sec-0001" sec-type="section"> <title>Background & Aims</title> <p>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 <italic>Pten</italic>‐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.</p> </sec> <sec id="liv12600-sec-0002" sec-type="section"> <title>Methods</title> <p>Effects of systemically perturbed PTEN/AKT2 signalling on hepatic lipid content were studied in <italic>Pten</italic>‐haplodeficient (<italic>Pten</italic><sup><italic>+/−</italic></sup><italic>/Akt2</italic><sup><italic>+/+</italic></sup>) mice and <italic>Pten</italic>‐haplodeficient mice lacking <italic>Akt2</italic> (<italic>Pten</italic><sup><italic>+/−</italic></sup>/<italic>Akt2</italic><sup>−/−</sup>). 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 <italic>Pten</italic><sup><italic>+/+</italic></sup><italic>/Akt2</italic><sup><italic>+/+</italic></sup> and <italic>Pten</italic><sup><italic>+/−</italic></sup><italic>/Akt2</italic><sup><italic>+/+</italic></sup> mice using adeno‐associated virus 8.</p> </sec> <sec id="liv12600-sec-0003" sec-type="section"> <title>Results</title> <p> <italic>Pten</italic> <sup> <italic>+/−</italic> </sup> <italic>/Akt2</italic> <sup> <italic>+/+</italic> </sup> mice were found to have a more than 2‐fold reduction in hepatic lipid content, at a level similar to that observed in <italic>Pten</italic><sup><italic>+/−</italic></sup>/<italic>Akt2</italic><sup>−/−</sup> mice. Insulin signalling in the livers of <italic>Pten</italic><sup><italic>+/−</italic></sup><italic>/Akt2</italic><sup><italic>+/+</italic></sup> mice was enhanced, indicating that extrahepatic factors prevent lipid accumulation. The skeletal muscle of <italic>Pten</italic><sup><italic>+/−</italic></sup><italic>/Akt2</italic><sup><italic>+/+</italic></sup> mice also showed enhanced insulin signalling. Skeletal muscle‐specific expression of constitutively active AKT2 reduced hepatic lipid content in <italic>Pten</italic><sup><italic>+/+</italic></sup><italic>/Akt2</italic><sup>+/+</sup> mice, and dominant negative AKT2 led to an increase in accumulation of hepatic lipids in both <italic>Pten</italic><sup><italic>+/+</italic></sup><italic>/Akt2</italic><sup>+/+</sup> and <italic>Pten</italic><sup><italic>+/−</italic></sup><italic>/Akt2</italic><sup><italic>+/+</italic></sup> mice.</p> </sec> <sec id="liv12600-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Our results demonstrate that AKT2 activity in skeletal muscle critically affects lipid accumulation in the livers of <italic>Pten</italic><sup><italic>+/+</italic></sup><italic>/Akt2</italic><sup>+/+</sup> and <italic>Pten</italic><sup><italic>+/−</italic></sup><italic>/Akt2</italic><sup><italic>+/+</italic></sup> mice, and emphasize the role of skeletal muscle in the pathology of NAFLD.</p> </sec> </abstract>