title: Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection.
abstract: 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.
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Gahl
authors.initials: G
authors.lastname: Levy
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Habib
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy.
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Guzzardi
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kitsberg
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Bomze
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Faculty of Engineering, Jerusalem College of Technology, Jerusalem, Israel.
authors.forename: Elishai
authors.identifier: http://orcid.org/0000-0003-1304-8022
authors.initials: E
authors.lastname: Ezra
authors.affiliation: Center for Engineering in Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Basak E
authors.initials: BE
authors.lastname: Uygun
authors.affiliation: Center for Engineering in Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Korkut
authors.initials: K
authors.lastname: Uygun
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Trippler
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Joerg F
authors.initials: JF
authors.lastname: Schlaak
authors.affiliation: Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Shibolet
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ella H
authors.initials: EH
authors.lastname: Sklan
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Institute for Virology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Joerg
authors.identifier: http://orcid.org/0000-0001-7799-3045
authors.initials: J
authors.lastname: Timm
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Friedman
authors.affiliation: Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.|Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Nahmias
mesh_terms: D006019:Glycolysis; D016174:Hepacivirus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology*; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear