Attenuated liver fibrosis after bile duct ligation and defective hepatic stellate cell activation in neural cell adhesion molecule knockout mice
Article first published online: 2 MAR 2011
© 2011 John Wiley & Sons A/S
Volume 31, Issue 5, pages 630–641, May 2011
How to Cite
Rosenberg, P., Sjöström, M., Söderberg, C., Kinnman, N., Stål, P. and Hultcrantz, R. (2011), Attenuated liver fibrosis after bile duct ligation and defective hepatic stellate cell activation in neural cell adhesion molecule knockout mice. Liver International, 31: 630–641. doi: 10.1111/j.1478-3231.2011.02486.x
- Issue published online: 3 APR 2011
- Article first published online: 2 MAR 2011
- Received 18 November 2009, Accepted 27 January 2011
- knockout mice;
Aim: 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 (CCl4) 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. CCl4-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 CCl4 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.