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.

Gene Expression Profiling of Different Huh7 Variants Reveals Novel Hepatitis C Virus Host Factors

“…As described above, PPARγ activation has been implicated with HCV replication, but literature reports are not entirely coherent. Recently, other nuclear receptors have also been shown to be dysregulated in HCV infection and partially usurped by the virus, e.g., PPARα, LXR, RXR and FXR [18,24]. Particularly FXR also has a strong link to NR0B2, acting upstream of it and inducing its expression as part of a negative feedback loop in the bile acid metabolism in liver cells; while FXR gets activated by bile acids, NR0B2 inhibits bile acid synthesis (see Figure 8A) [79,80].…”

“…Replication takes place in the cytoplasm at specialized, ER-derived mono-, double-, or multi-membrane vesicles, designated the "membranous web" [14] and is tightly linked to lipid droplets [15]. HCV hijacks many cellular pathways to establish and maintain a productive infection, e.g., autophagy [16] as well as glucose [17][18][19][20] and cholesterol metabolism [21,22]. Recent evidence implies that nuclear receptors contribute to mediating these changes and are, thus, important players during HCV infection [18,23,24].…”

Perturbation of Intracellular Cholesterol and Fatty Acid Homeostasis During Flavivirus Infections

“…Most viruses are known to induce aerobic glycolysis akin to the Warburg effect (2,3). More recently, perturbation in lipid metabolic pathways has also been reported for several classes of pathogens (4,5).…”

“…With the advent of omics-based studies, it is increasingly becoming obvious that viruses induce large-scale alterations in host cellular metabolism (3,(34)(35)(36)(37). Among other examples are the induction of fatty acid synthesis by hepatitis C virus (HCV) in human hepatocytes, and the utilization of cellular lipid stores of hepatocytes by dengue virus.…”

Long noncoding RNAs: Novel regulators of virus‐host interactions

“…Hence, viruses act to regulate the metabolism of the host to improve their own replication efficiency. HNF4α is a nuclear receptor that serves as a master regulator of hepatocyte differentiation by functioning in the activation of glycolysis in hepatocytes, inhibition of apoptosis of host cells, and promotion of flavivirus hepatitis C replication . It has also been revealed by lipidomics that fatty acid and lipid mediators are critical in the replication of IAV in A549 cells .…”