SREBP-1a activation by HBx and the effect on hepatitis B virus enhancer II/core promoter

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Hepatitis B virus (HBV) X protein (HBx) plays an important role in HBV pathogenesis by regulating gene expression. Sterol regulatory element binding protein-1a (SREBP-1a) is a key transcriptional factor for modulating fatty acid and cholesterol synthesis. Here we demonstrated that HBx increased mature SREBP-1a protein level in the nucleus and its activity as a transcription factor. We further showed that the up-regulation of SREBP-1a by HBx occurred at the transcriptional level after ectopic expression and in the context of HBV replication. Deletional analysis using SREBP-1a promoter revealed that the sequence from −436 to −398 in the promoter was required for its activation by HBx. This promoter region possesses the binding sequences for two basic leucine zipper (b-ZIP) transcription factors, namely C/EBP and E4BP4. Mutagenesis of the binding sequences on the SREBP-1a promoter and ectopic expression experiments demonstrated that C/EBPα enhanced SREBP-1a activation by HBx, while E4BP4 had an inhibitory effect. C/EBPα was able to significantly reverse the inhibitory activity of E4BP4 on SREBP-1a promoter. These results demonstrated that HBx activates SREBP-1a activity at the transcription level through a complex mechanism involving two bZIP transcription factors C/EBP and E4BP4 with C/EBP being the dominant positive factor. Finally, we showed that knocking down SREBP-1 abolishes HBV enhancer II/core promoter activation by HBx.