Nuclear receptors have a unique role in governing hepatitis B virus (HBV) transcription and replication. Hepatocyte nuclear factor 4alpha (HNF4alpha) and retinoid X receptor alpha (RXRalpha) plus peroxisome proliferator-activated receptor alpha (PPARalpha) have been shown to support viral biosynthesis in nonhepatoma cells in the absence of additional liver-enriched transcription factors. However, the in vivo importance of these nuclear receptors in HBV biosynthesis has been investigated only to a limited extent. Fasting has been shown to activate gluconeogenesis, in part, by activating PPARgamma coactivator 1 alpha, which in turn leads to activation of HNF4alpha- and RXRalpha/PPARalpha-mediated transcription. As HBV pregenomic RNA synthesis is primarily believed to be regulated by HNF4alpha under normal physiological conditions, it was of interest to determine the effect of fasting on the levels of HBV RNA and DNA synthesis. Fasting was shown to rather modestly increase the levels of viral proteins, transcripts, and replication intermediates in the HBV transgenic mouse model of chronic viral infection, suggesting that caloric restriction may modulate viremia to some extent during natural infection.