Abstract:
: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.
journal_name
Proc Natl Acad Sci U S Aauthors
Mankouri J,Tedbury PR,Gretton S,Hughes ME,Griffin SD,Dallas ML,Green KA,Hardie DG,Peers C,Harris Mdoi
10.1073/pnas.0912426107subject
Has Abstractpub_date
2010-06-22 00:00:00pages
11549-54issue
25eissn
0027-8424issn
1091-6490pii
0912426107journal_volume
107pub_type
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