Virus-induced over-expression of protein phosphatase 2A inhibits insulin signalling in chronic hepatitis C.
OBJECTIVE
Hepatitis C virus (HCV) infection disturbs glucose and lipid metabolism contributing to the development of liver steatosis, insulin resistance and type 2 diabetes mellitus. On the other hand, insulin resistance and steatosis have been found to be associated with increased rates of fibrosis progression and lower rates of response to interferon therapy in chronic hepatitis C (CHC). The molecular mechanisms contributing to insulin resistance in CHC are not well understood. We have shown previously that protein phosphatase 2A (PP2A) is over-expressed in biopsies from patients with CHC. In this study, we tested if PP2A over-expression leads to insulin resistance.


METHODS
We studied insulin signalling in cell lines that allow the regulated over-expression of HCV proteins and of the PP2A catalytic subunit (PP2Ac). Insulin signalling and PP2Ac expression were also studied in HCV transgenic mice and in liver biopsies from patients with CHC.


RESULTS
Over-expression of PP2Ac in cells inhibited insulin signalling by dephosphorylation of PKB/Akt. PP2Ac over-expression and impaired insulin signalling were found in the liver of HCV transgenic mice and in liver biopsies of patients with CHC.


CONCLUSIONS
HCV-induced over-expression of PP2A in the liver contributes to the pathogenesis of insulin resistance in patients with CHC.
Bernsmeier
Christine
C
Department of Biomedicine, Division of Gastroenterology and Hepatology, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland.
Duong
Francois H T
FH
Christen
Verena
V
Pugnale
Paolo
P
Negro
Francesco
F
Terracciano
Luigi
L
Heim
Markus H
MH
D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D000368:Aged; D000818:Animals; D001706:Biopsy; D002460:Cell Line; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D011494:Protein Kinases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D000091162:AMP-Activated Protein Kinase Kinases; D054648:Protein Phosphatase 2