title: Hepatitis B virus inhibits liver regeneration via epigenetic regulation of urokinase-type plasminogen activator.
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.
  
  
  CONCLUSIONS
  Taken together, these results suggest that infection of HBV impairs liver regeneration through the epigenetic dysregulation of liver regeneration signals by HBx.
authors.affiliation: Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Republic of Korea.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Park
authors.forename: Yong Kwang
authors.initials: YK
authors.lastname: Park
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Seung Hwa
authors.initials: SH
authors.lastname: Park
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Ahn
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Keo-Heun
authors.initials: KH
authors.lastname: Lim
authors.forename: So Young
authors.initials: SY
authors.lastname: Kwon
authors.forename: Kwang Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Sung-Il
authors.initials: SI
authors.lastname: Yang
authors.forename: Baik L
authors.initials: BL
authors.lastname: Seong
authors.forename: Kyun-Hwan
authors.initials: KH
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology; D000090205:DNA Methyltransferase 3A; D004279:DNA, Viral / Q000235:genetics; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000502:physiology*; D006498:Hepatectomy; D006509:Hepatitis B / Q000473:pathology / Q000503:physiopathology*; D006515:Hepatitis B virus / Q000235:genetics* / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000502:physiology; D022781:Hepatocytes / Q000473:pathology; D066298:In Vitro Techniques; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D004279:DNA, Viral; C000717967:DNMT3A protein, human; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D017228:Hepatocyte Growth Factor; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D014568:Urokinase-Type Plasminogen Activator