TY - JOUR
T1 - Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection
AU - Levy, Gahl
AU - Habib, Naomi
AU - Guzzardi, Maria Angela
AU - Kitsberg, Daniel
AU - Bomze, David
AU - Ezra, Elishai
AU - Uygun, Basak E.
AU - Uygun, Korkut
AU - Trippler, Martin
AU - Schlaak, Joerg F.
AU - Shibolet, Oren
AU - Sklan, Ella
AU - Cohen, Merav
AU - Timm, Joerg
AU - Friedman, Nir
AU - Nahmias, Yaakov
N1 - Publisher Copyright:
© Nature America, Inc.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84990886692&partnerID=8YFLogxK
U2 - 10.1038/nchembio.2193
DO - 10.1038/nchembio.2193
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AN - SCOPUS:84990886692
SN - 1552-4450
VL - 12
SP - 1037
EP - 1045
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 12
ER -