| Abstract
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Hepatitis B virus is a hepatotrophic virus that infects the liver almost exclusively. As a small DNA virus, HBV gene expression is mainly regulated at the transcriptional level. Liver-enriched nuclear receptors, such as HNF4α, bind to HBV promoters and drive the synthesis of its transcripts. Interestingly, some of these nuclear receptors actively regulate the expression of genes implicated in the regulation of key hepatic metabolic processes, such as glucose and fat synthesis and utilization. In the first part of my work, I show that Peroxisome Proliferator-Activated Receptor-γ Coactivator 1α (PGC-1α) that coactivates the transcription of genes implicated in glucose and fat metabolism mainly through liver-enriched nuclear receptors, is a strong coactivator of HBV transcription. This coactivation is mediated mainly through HNF4α. Physiologically, HBV gene expression is robustly induced upon starvation in a PGC-1α dependent manner, in both, a tissue culture and an animal model. I conclude that PGC-1α controls HBV gene expression and replication through nutritional signals. My findings reveal a unique interplay between the virus and its host, mediated by the nutrition state of the body. These results may shed a new light on previously unexplained issues regarding the pathogenesis and the epidemiology of HBV infection, such as the more prevalent and aggressive course of HBV infection in poorer countries where food is scarce. In the second part of my study I investigated the regulation of PGC-1α protein stability and its control by metabolic circuits implicated in glucose homeostasis. During shifts in the nutritional state, PGC-1α level in the liver is induced almost entirely at the transcriptional level upon starvation. Although being a short-lived protein, only little is known about the regulation of PGC-1α protein stability and whether this regulation is linked to alterations in the metabolic state. Here I show that PGC-1α is a short-lived protein predicted to be a highly unstructured one, that may undergo a ubiquitine-independent degradation by the 20S proteasome catalytic core subunit. This degradation occurs “by default” without prior modification. In the presence of the phase II detoxifying enzyme NQO1, PGC-1α is protected from 20S–mediated degradation. Physiologically, I show that NQO1-mediated PGC-1α protein stabilization is NADH-dependent, since NQO1 physically interacts with PGC-1a to stabilize it in an NADH-dependent manner and pharmacological inhibition of NQO1 by competing for NADH binding results in PGC-1α degradation by default. I conclude that PGC-1α is rendered susceptible to degradation by the default, and that this mode of degradation has a significant role in PGC-1α protein stability. In addition, the alterations in the cellular NAD+/NADH ratio during transition from fed to starvation states provide the molecular link between nutritional cues and the regulation of PGC-1α protein stability.
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