title: Attenuated liver fibrosis after bile duct ligation and defective hepatic stellate cell activation in neural cell adhesion molecule knockout mice.
abstract: OBJECTIVE
  Neural cell adhesion molecule (N-CAM) is expressed by activated hepatic stellate cells (HSC), portal fibroblasts, cholangiocytes and hepatic progenitor cells during liver injury. Its functional role in liver disease and fibrogenesis is unknown. The aim of this study was to investigate the role of N-CAM in liver fibrogenesis.
  
  
  METHODS
  To induce fibrosis, N-CAM knockout mice and wild-type controls were subjected to bile duct ligation (BDL) or repeated carbon tetrachloride (CCl(4) ) injections. Fibrosis was quantified by hydroxyproline, immunhistochemistry staining and image analysis. Protein levels were determined with immunoblotting. HSCs were isolated by ultracentrifugation in a Larcoll gradient and thereafter in vitro stimulated with recombinant transforming growth factor (TGF)-β1.
  
  
  RESULTS
  Two weeks after BDL, wild-type mice had developed pronounced liver fibrosis while N-CAM-/- mice had less such alterations. N-CAM-/- mice had less deposition of collagen and fibronectin seen in immunhistochemistry. The protein levels of fibronectin were higher in the liver from the wild type, while laminin were unaltered. CCl(4) -treated N-CAM-/- and wild-type mice showed no significant difference in the extent of liver fibrosis or the expression levels of the above-mentioned genes. HSC isolated from N-CAM-/- mice showed declined levels of smooth muscle actin and desmin after stimulation in vitro with TGF-β1.
  
  
  CONCLUSIONS
  Loss of N-CAM results in decreased hepatic collagen and fibronectin deposition in mice subjected to BDL, but not in animals exposed to repeated CCl(4) injections. HSC isolated from N-CAM null mice show impaired activation in vitro. This indicates a role of N-CAM in cholestatic liver disease and HSC activation.
authors: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden. peter.rosenberg@ki.se
authors: Peter
authors: P
authors: Rosenberg
authors: Mattias
authors: M
authors: Sjöström
authors: Cecilia
authors: C
authors: Söderberg
authors: Nils
authors: N
authors: Kinnman
authors: Per
authors: P
authors: Stål
authors: Rolf
authors: R
authors: Hultcrantz
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002251:Carbon Tetrachloride; D002469:Cell Separation; D002478:Cells, Cultured; D001651:Cholestasis, Extrahepatic / Q000150:complications* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D003135:Common Bile Duct / Q000601:surgery*; D003893:Desmin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D003893:Desmin; D005353:Fibronectins; D007797:Laminin; D019006:Neural Cell Adhesion Molecules; D053773:Transforming Growth Factor beta1; D003094:Collagen; D002251:Carbon Tetrachloride; D006909:Hydroxyproline