title: Notch signaling affects biliary fibrosis via transcriptional regulation of RBP-jκ in an animal model of chronic liver disease.
abstract: Liver repair in patients with a chronic liver disease requires the orchestrated action of epithelial, mesenchymal, and inflammatory cells. Notch components are expressed in both the epithelial and mesenchymal compartments of the adult liver and are differentially regulated after injury. However, the functional role of Notch signaling in regulating epithelial/mesenchymal cross-talk during fibrogenic pathologic repair remains unknown. The aim of this study was to investigate how proliferation of the bile duct influences biliary fibrosis and to recognize the effect of inhibiting Notch signaling in biliary fibrotic tissue of the injured liver. We designed a synthetic decoy oligodeoxynucleotide (ODN) for recombination signal binding protein immunoglobulin kappa J (RBP-jκ), which is a common DNA-binding partner of Notch receptors. The effect of blocking RBP-jκ on fibrogenesis was assessed in the 3,5-Diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet mouse model. We observed the reduced fibrosis and decreased expression of associated signaling molecules after the RBP-jκ decoy ODN treatment. These data demonstrate that Notch signaling may play an important role in progression of ductular reaction and fibrosis. Further studies are required to unveil how ductular cells interact with other liver cell types, such as hepatic stellate cells or Kupffer cells,in patients with cholestatic liver diseases based on Notch signaling. These results suggest that controlling the ductular reaction using a synthetic ring type decoy RBP-jκ ODN will help develop a novel therapeutic approach targeting biliary fibrosis in patients with chronic liver diseases.
authors.affiliation: Department of Pathology, Catholic University of Daegu School of Medicine 3056-6 Daemyung-4 Dong, Nam-Gu, Daegu, Republic of Korea.
authors.forename: Sun-Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Catholic University of Daegu School of Medicine 3056-6 Daemyung-4 Dong, Nam-Gu, Daegu, Republic of Korea.
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Kim
authors.affiliation: School of Biomedical Sciences, Charles Sturt University Bathurst, NSW 2795, Australia.
authors.forename: Sok Cheon
authors.initials: SC
authors.lastname: Pak
authors.affiliation: Department of Pathology, Keimyung University School of Medicine 2800, Dalgubeoldaero, Dalseo-Gu, Daegu, Republic of Korea.
authors.forename: Yu-Na
authors.initials: YN
authors.lastname: Kang
authors.affiliation: Department of Pathology, Kyungpook National University School of Medicine 680 Gukchaebosang-Ro, Jung-Gu, Daegu, 700-842, Republic of Korea.
authors.forename: Ghil-Suk
authors.initials: GS
authors.lastname: Yoon
authors.affiliation: Department of Pathology, Catholic University of Daegu School of Medicine 3056-6 Daemyung-4 Dong, Nam-Gu, Daegu, Republic of Korea.
authors.forename: Kwan-Kyu
authors.initials: KK
authors.lastname: Park
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000096:biosynthesis*; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009838:Oligodeoxyribonucleotides; D051880:Receptors, Notch
keywords: Liver fibrosis; Notch; RBP-jκ; decoy ODN