title: Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure.
abstract: BACKGROUND
  Human hepassocin (HPS) was originally detected by subtractive and differential cDNA cloning as a liver-specific gene that was markedly upregulated during liver regeneration. Previous studies suggested that HPS showed mitogenic activity on isolated hepatocytes in vitro. However, its in vivo functions remained largely unknown. Therefore, the function of recombinant human HPS during liver regeneration and chemically induced liver injury was investigated.
  
  
  METHODS
  The proliferation of primary hepatocytes was examined by [(3)H]thymidine incorporation and immunohistological staining of proliferating cell nuclear antigen (PCNA). RNA interference was performed to knock down the endogenous expression of HPS. The proliferation of L02 cells was examined by MTS assay. The phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1/2) was investigated by western blotting analysis. Assessment of liver injury (histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels) and of apoptosis, by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay, was performed.
  
  
  RESULTS
  Purified recombinant human HPS showed specific mitogenic activity on primary hepatocytes and normal liver cell lines in a mitogen-activated protein kinase (MAPK)-dependent manner and stimulated the proliferation of hepatocytes in rats with 70% partial hepatectomy. Administration of HPS to rats after d-galactose and carbon tetrachloride (CCl(4)) treatment protected against liver injury (minimal liver necrosis, depressed ALT and AST levels, and decreased lethality), reduced apoptosis and enhanced proliferation. Knock-down of endogenous HPS in vivo enhanced the liver injury induced by d-galactose by increasing the apoptosis and elevating ALT and AST levels.
  
  
  CONCLUSIONS
  HPS is a hepatic growth factor which can accelerate hepatocyte proliferation in vivo and protect against liver injury. These data point to the potential interest of HPS in the treatment of fulminant hepatic failure.
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing 100850, PR China.
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Li
authors.forename: Chuan-Zeng
authors.initials: CZ
authors.lastname: Cao
authors.forename: Wang-Xiang
authors.initials: WX
authors.lastname: Xu
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Cao
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Lan
authors.initials: L
authors.lastname: Dong
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Zhan
authors.forename: Ya-Bing
authors.initials: YB
authors.lastname: Gao
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Wang
authors.forename: Chang-Hui
authors.initials: CH
authors.lastname: Ge
authors.forename: Qing-Ming
authors.initials: QM
authors.lastname: Wang
authors.forename: Rui-Yun
authors.initials: RY
authors.lastname: Peng
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005340:Fibrinogen; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009363:Neoplasm Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C485894:FGL1 protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D005340:Fibrinogen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3