Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase.
Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.
Institute of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Jamel
J
Mankouri
Philip R
PR
Tedbury
Sarah
S
Gretton
Mair E
ME
Hughes
Stephen D C
SD
Griffin
Mark L
ML
Dallas
Kevin A
KA
Green
D Grahame
DG
Hardie
Chris
C
Peers
Mark
M
Harris
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology*; D016679:Genome, Viral; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000378:metabolism / Q000821:virology*; D006801:Humans; D008055:Lipids / Q000235:genetics*; D018613:Microscopy, Confocal / Q000379:methods; D008954:Models, Biological; D010766:Phosphorylation; D015398:Signal Transduction; D014779:Virus Replication
D000998:Antiviral Agents; D008055:Lipids; D055372:AMP-Activated Protein Kinases; D005947:Glucose