Molecular mechanisms of insulin resistance in chronic liver disease.
PhD Thesis, University of Basel,
Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_8384
The work presented here analyses the role of PP2A in the dysregulation of glucose metabolism in the setting of chronic hepatitis C. We propose a new model for virus induced insulin resistance development through the overexpression of PP2A in the liver that leads to hyperglycemia mainly through the inappropriate inhibition of hepatic gluconeogenesis. By dephosphorylation of key targets, PP2A upregulation interferes with three differently regulated pathways that control hepatic glucose metabolism schematically shown in figure 11. First, it interferes with the insulin signaling cascade (right) by dephosphorylation of PKB/Akt, thereby upregulating gluconeogenesis and inhibiting glycogensynthesis. Second, it dephosphorylates AMPK and therefore again increases gluconeogenesis (center). And finally glucose induced regulation of gluconeogenesis is impaired through PP2A upregulation and eventually involves regulation of LXR (left). This concept has been developed in cell culture, but in a model of HCV transgenic mice we show that hepatic PP2A overexpression and dysregulation of these signaling pathways presents concomitantly with an insulin resistant phenotype. Similary, in patients infected with chronic hepatitis C we observed upregulation of PP2A and inhibition of hepatic insulin signaling, supporting its significance in vivo. A model explaining HCV induced insulin resistance development can help to understand disease progression to liver cirrhosis and resistance to antiviral therapy. It further discloses new drug targets in order to prevent these complications.
Concerning the clinical course of NAFLD and NASH, respectively, preliminary data from
our observational study support the importance of insulin resistance and liver cell apoptosis
in the pathophysiology of disease progression. We further confirm the use of CK-18
fragmentation in the blood as a non-invasive marker predicting NASH.
|Advisors:||Heim, Markus Hermann|
|Committee Members:||Hemmings, Brian A.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Hepatology Laboratory (Heim)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||62|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||13 Feb 2009 16:38|
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