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The role of systemically perturbed PTEN and PKBß/AKT2 signaling in accumulation of hepatic lipids

Schultze, Simon Manuel. The role of systemically perturbed PTEN and PKBß/AKT2 signaling in accumulation of hepatic lipids. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10498

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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a major health problem and occurs frequently in the context of obesity and type 2 diabetes mellitus (T2D). Insulin resistance of the liver and/or peripheral tissues is considered to drive ectopic lipid accumulation in hepatocytes, but individual contributions are not fully understood. Hepatocyte-specific Pten-deficiency in mice was shown previously to result in hepatic steatosis due to hyperactivated PKBb in the liver. However, the role of peripheral insulin sensitive tissues on PTEN/PKBb-dependent development of NAFLD has not been addressed.
The aim of this thesis is to characterize the effects of systemically perturbed PTEN/PKBb signaling on hepatic lipid content using Pten-haplodeficient (Pten+/-/Pkbb+/+) mice and Pten-haplodeficient mice lacking Pkbb (Pten+/-/Pkbb-/-). We found that Pten+/-/Pkbb+/+ mice have a more than 2-fold reduction in hepatic lipid content compared to control mice, similar to the low level observed in Pten+/-/Pkbb-/- mice. Pten+/-/Pkbb+/+ mice showed enhanced insulin signaling in the liver indicating that extra-hepatic factors prevent hepatic lipid accumulation. Further results suggested that augmented PKBb activity in the skeletal muscle of Pten+/-/Pkbb+/+ mice might reduce hepatic lipid content. Indeed, skeletal muscle-specific expression of constitutively active PKBb reduced hepatic lipids in Pten+/+Pkbb+/+ mice and dominant negative PKBb increased hepatic lipid content in both Pten+/+Pkbb+/+ and Pten+/-/Pkbb+/+ mice.
The results obtained during this study show that PKBb activity in skeletal muscle regulates lipid accumulation in the livers of Pten+/+Pkbb+/+ and Pten+/-/Pkbb+/+ mice, and emphasizes the role of skeletal muscle in the pathophysiology of NAFLD.
Advisors:Hall, Michael N.
Committee Members:Hemmings, Brian A. and Wymann, Matthias Paul
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
Item Type:Thesis
Thesis no:10498
Bibsysno:Link to catalogue
Number of Pages:119 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:53
Deposited On:02 Oct 2013 14:51

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