Hepatitis B virus inhibits liver regeneration via epigenetic regulation of urokinase-type plasminogen activator

Eun Sook Park, Yong Kwang Park, Chan Young Shin, Seung Hwa Park, Sung Hyun Ahn, Doo Hyun Kim, Keo Heun Lim, So Young Kwon, Kwang Pyo Kim, Sung Il Yang, Baik L. Seong, Kyun Hwan Kim

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Abstract

Liver regeneration after liver damage caused by toxins and pathogens is critical for liver homeostasis. Retardation of liver proliferation was reported in hepatitis B virus (HBV) X protein (HBx)-transgenic mice. However, the underlying mechanism of the HBx-mediated disturbance of liver regeneration is unknown. We investigated the molecular mechanism of the inhibition of liver regeneration using liver cell lines and a mouse model. The mouse model of acute HBV infection was established by hydrodynamic injection of viral DNA. Liver regeneration after partial hepatectomy was significantly inhibited in the HBV DNA-treated mice. Mechanism studies have revealed that the expression of urokinase-type plasminogen activator (uPA), which regulates the activation of hepatocyte growth factor (HGF), was significantly decreased in the liver tissues of HBV or HBx-expressing mice. The down-regulation of uPA was further confirmed using liver cell lines transiently or stably transfected with HBx and the HBV genome. HBx suppressed uPA expression through the epigenetic regulation of the uPA promoter in mouse liver tissues and human liver cell lines. Expression of HBx strongly induced hypermethylation of the uPA promoter by recruiting DNA methyltransferase (DNMT) 3A2. Conclusion: Taken together, these results suggest that infection of HBV impairs liver regeneration through the epigenetic dysregulation of liver regeneration signals by HBx.

Original languageEnglish
Pages (from-to)762-776
Number of pages15
JournalHepatology
Volume58
Issue number2
DOIs
Publication statusPublished - 2013 Aug 1

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All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Park, E. S., Park, Y. K., Shin, C. Y., Park, S. H., Ahn, S. H., Kim, D. H., Lim, K. H., Kwon, S. Y., Kim, K. P., Yang, S. I., Seong, B. L., & Kim, K. H. (2013). Hepatitis B virus inhibits liver regeneration via epigenetic regulation of urokinase-type plasminogen activator. Hepatology, 58(2), 762-776. https://doi.org/10.1002/hep.26379