Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase

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.

Hepatitis c virus and host cell lipids: An intimate connection

“…Thus, inhibition of AMPK by HCV would favor a reduction in fatty acid oxidation and thus an increase in hepatic lipid accumulation. 89 In contrast, Diamond and co-workers reported a sustained increase in fatty acid oxidation upon HCV infection, but also a stimulation of lipid biosynthesis. Although the significance of this simultaneous induction in lipid anabolism and catabolism remains unclear, the authors argue that β-oxidation may help to maintain elevated ATP levels to support energy-dependent biosynthetic processes as well as to limit the accumulation and toxic effect of ceramide overload.…”

“…Indeed, recent studies based on transcriptome and proteomic analyses have demonstrated that expression of host genes involved in the biosynthesis, degradation and transport of intracellular lipids is profoundly altered upon infection. [86][87][88][89] The expression of SREBPs, which control transcription of genes required for cholesterol biosynthesis, 90 is stimulated both by HCV infection and It was demonstrated that NS proteins associate with cholesterol-rich lipid rafts and that depletion of cholesterol with statins selectively reduces HCV RNA replication. 104 However, statins are inhibitors of the mevalonate pathway, 99 which produces not only cholesterol, but also non-sterol isoprenoids, including geranylgeranyl and farnesyl.…”

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

“…In both cases, the biosynthetic machinery of the cell has been usurped by abnormal genes, by viral genes in the former case, and by oncogenic mutations or loss of tumor suppressors in the latter. The effects of viral infection on AMPK were recently studied using an in vitro model system in which a human hepatoma cell line was infected using hepatitis C virus (HCV) (Mankouri et al 2010). When HCV infects host cells it switches on both protein synthesis (making a single polyprotein that is cleaved into the 10 proteins encoded by the viral RNA genome) and fatty acid/triglyceride synthesis, which are required for the viral lipid envelope.…”

“…When HCV infects host cells it switches on both protein synthesis (making a single polyprotein that is cleaved into the 10 proteins encoded by the viral RNA genome) and fatty acid/triglyceride synthesis, which are required for the viral lipid envelope. One might expect that the large increase in demand for ATP caused by rapid protein and lipid synthesis would lead to activation of AMPK, but in fact the opposite occurs, in that phosphorylation of Thr172 on AMPK is reduced relative to uninfected controls (Mankouri et al 2010). The mechanism responsible appears to be that one of the viral proteins (NS5A) binds to and activates phosphatidylinositol (PI) 3-kinase, leading to activation of the phosphatidylinositol trisphosphate (PIP 3 ) -activated kinase PKB/Akt (Street et al 2004).…”

Metformin and Hepatic Carcinogenesis

“…It is intriguing, however, that separate research has shown that experimental hepatitis C infection is associated with downregulation of AMPK activity, and that restoring AMPK activation by metformininduced energy stress reduces viral infection and some of its consequences (16). Another example of interesting research in this context is evidence that insulin (which reaches the liver in high concentrations in the hyperinsulinemic phase of type II diabetes) is sufficient to induce liver cancer (17,18); thus, information concerning insulin levels and signaling downstream of the insulin receptor in the presence and absence of metformin in the model of Bhalla and colleagues (2) would be of interest.…”