Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection

Gahl Levy, Naomi Habib, Maria Angela Guzzardi, Daniel Kitsberg, David Bomze, Elishai Ezra, Basak E. Uygun, Korkut Uygun, Martin Trippler, Joerg F. Schlaak, Oren Shibolet, Ella H. Sklan, Merav Cohen, Joerg Timm, Nir Friedman, Yaakov Nahmias*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Viruses lack the basic machinery needed to replicate and therefore must hijack the host's metabolism to propagate. Virus-induced metabolic changes have yet to be systematically studied in the context of host transcriptional regulation, and such studies shoul offer insight into host-pathogen metabolic interplay. In this work we identified hepatitis C virus (HCV)-responsive regulators by coupling system-wide metabolic-flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We found HCV-induced upregulation of glycolysis, ketogenesis and drug metabolism, with glycolysis controlled by activation of HNF4α, ketogenesis by PPARα and FXR, and drug metabolism by PXR. Pharmaceutical inhibition of HNF4α reversed HCV-induced glycolysis, blocking viral replication while increasing apoptosis in infected cells showing virus-induced dependence on glycolysis. In contrast, pharmaceutical inhibition of PPARα or FXR reversed HCV-induced ketogenesis but increased viral replication, demonstrating a novel host antiviral response. Our results show that virus-induced changes to a host's metabolism can be detrimental to its life cycle, thus revealing a biologically complex relationship between virus and host.

Original languageAmerican English
Pages (from-to)1037-1045
Number of pages9
JournalNature Chemical Biology
Issue number12
StatePublished - 1 Dec 2016

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