UCLA

Viral infections can induce changes in host metabolism, either as a result of viral manipulations or host anti-viral responses. These metabolic changes in turn may result in various disorders. The liver, as the critical organ in maintaining metabolic homeostasis, is particularly susceptible to such changes during viral infections, and alterations in hepatic function can quickly result in severe metabolic imbalances. Viral infections can even contribute to liver failure by causing tissue damage through cytotoxicity and inflammation, as well as impaired drug metabolism. It is unclear to what extent these deleterious effects are due to viral manipulations or the host response. Here, we provide several mechanisms that illuminate the contribution of the host anti-viral responses to metabolic imbalances and tissue damage. First, we provide a mechanism by which activation of antiviral responses downregulates expression of nuclear hormone receptor retinoic X receptor-α (RXRα) and its heterodimeric partner pregnane X receptor (PXR) in mice, resulting in suppression of key downstream cytochrome P450 enzymes involved in metabolism of acetaminophen. Second, in addition to impairing drug metabolism, viral infections may result in liver damage by directly inducing cytopathic effects in infected cells, as well as by indirectly inducing host inflammatory responses that injure tissue. We have found that liver injury induced by mouse hepatitis virus is mediated by high-mobility group box 1 (HMGB1), a previously identified endogenous danger signal that can activate immune pathways. We further characterize an inhibitor of HMGB1, glycyrrhizic acid, as a hepatoprotective agent in both sterile and infectious challenges. Finally, in addition to effects on liver, we explore the cross-talk between anti-viral immune responses and cellular metabolism. Viruses rely on the metabolic network of the host cells for their replication, and while recent studies suggest that key genes in lipid metabolism are specifically modulated by viruses, it is unclear whether the host also modulates its own lipid metabolism to counter viral infection. We demonstrate that expression of fatty acid synthase (FASN), a critical gene in lipid metabolism, is regulated by the activation of innate immune pathways. Our findings offer novel mechanisms by which host-mediated downregulation of FASN can inhibit viral infections. Overall, these studies provide better understanding of the mechanisms underlying the cross-talk between innate immune pathways and metabolic imbalances.