title: Apoptotic pathway related to oval cell proliferation.
abstract: OBJECTIVE
  Oval cells, liver stem cell-derived cells, are generated from the liver periportal region and spread into the parenchyma by an autocrine signaling pathway. The mechanism behind how oval cells take their place among packed silent hepatocytes, however, is not well understood. We hypothesized that apoptosis involves a decrease in hepatocytes surrounding oval cells.
  
  
  METHODS
  Male Fisher rats were treated using the AAF/PH protocol to induce oval cells in the liver. Apoptosis was assessed by measuring the activity of caspase-3, -8 and -9, and apoptosis-related molecules such as caspase-3, Fas, Fas-L and Bax were also assessed by immunohistochemical analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). Apoptosis was confirmed by TUNEL staining. Regarding antiapoptotic factors, nuclear factor-kappaB (NF-kappaB) DNA binding activity and proliferating cell nuclear antigen (PCNA) expression were examined.
  
  
  RESULTS
  NF-kappaB elevated at the early stage of oval cell proliferation. Conversely, caspase activity increased after NF-kappaB elevation. The mRNA of caspase-3, Fas, Fas-L and Bax was induced during and after AAF/PH treatment. Immunohistochemically, oval cells lacked the expression of these proteins, whereas the hepatocytes, particularly those surrounding oval cells, expressed strongly.
  
  
  CONCLUSIONS
  The present study suggests that the apoptosis in hepatocytes through both extrinsic and intrinsic pathways mediates oval cell proliferation.
authors.affiliation: Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yano
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Tadahisa
authors.initials: T
authors.lastname: Teramoto
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nakaji
authors.forename: Peter
authors.initials: P
authors.lastname: Nagy
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ninomiya
authors.forename: Atsushi
authors.initials: A
authors.lastname: Wada
authors.forename: Midori
authors.initials: M
authors.lastname: Hirai
authors.forename: Soo Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Seo
authors.forename: Seitetsu
authors.initials: S
authors.lastname: Yoon
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D053222:Fas Ligand Protein; D022781:Hepatocytes / Q000166:cytology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases