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Nat Chem Biol. 2016 Dec;12(12):1037-1045. doi: 10.1038/nchembio.2193. Epub 2016 Oct 10.

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

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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.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy.
Faculty of Engineering, Jerusalem College of Technology, Jerusalem, Israel.
Center for Engineering in Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel.
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Institute for Virology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.


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.

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