Hepatitis B virus (HBV) is a small DNA virus that targets the liver and infects humans worldwide. Recently we have shown that the metabolic regulator PGC-1 alpha coactivates HBV transcription thereby rendering the virus susceptible to fluctuations in the nutritional status of the liver. PGC-1 alpha coactivation of HBV is mediated through the liver-enriched nuclear receptor HNF4 alpha and through another yet unknown transcription factor(s), Here we show that the forkhead transcription factor FOXO1, a known target for PGC-1 alpha coactivation and a central mediator of glucose metabolism in the liver, binds HBV core promoter and activates its transcription. This activation is further enhanced in the presence of PGC-1 alpha, implying that FOXO1 is a target for PGC-1 alpha coactivation of HBV transcription. Thus, our results identify another key metabolic regulator as an activator of HBV transcription, thereby supporting the principle that HBV gene expression is regulated in a similar way to key hepatic metabolic genes. (C) 2009 Elsevier Inc. All rights reserved.