Mitochondrial dysfunction stimulates HBV gene expression through lipogenic transcription factor activation.

In previous studies, we showed two consistent findings regarding the functional relationship between hepatitis B virus (HBV) gene expression and hepatic lipid accumulation. One is that HBV X (HBx) protein expression induces hepatic lipid accumulation via specific transcriptional activation. The other is that hepatic rich lipids increase HBV gene expression. A variety of transcription factors, including nuclear receptors have been defined as regulators of HBV promoters and enhancers. However, the association between these metabolic events and HBV gene expression remains to be clearly elucidated. Here, we showed that lipid accumulation due to mitochondrial dysfunction is associated with an increase in HBV gene expression. Saturated fatty acids increase the expression of lipogenic factors cooperated with C/EBPα and LXRα. In addition, activation of PPARγ and SREBP-1 by fatty acids derived from hepatic lipid accumulation was found to increase HBV gene expression through mitochondrial dysfunction. These results provide that metabolic changes in the hepatic cells play a critical role in the HBV gene induction.