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Hepatitis B virus inhibits liver regeneration via epigenetic regulation of urokinase‐type plasminogen activator
Author(s) -
Park EunSook,
Park Yong Kwang,
Shin Chan Young,
Park Seung Hwa,
Ahn Sung Hyun,
Kim Doo Hyun,
Lim KeoHeun,
Kwon So Young,
Kim Kwang Pyo,
Yang SungIl,
Seong Baik L.,
Kim KyunHwan
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26379
Subject(s) - hbx , liver regeneration , biology , hepatitis b virus , epigenetics , hepatocyte , dna methylation , liver cell , plasminogen activator , cancer research , microbiology and biotechnology , regeneration (biology) , virology , virus , gene expression , endocrinology , medicine , gene , biochemistry , in vitro
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. (H epatology 2013;58:762–776)