These authors contributed equally to this work.
The role of the hepatocyte cytokeratin network in bile formation and resistance to bile acid challenge and cholestasis in mice†
Article first published online: 11 MAY 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 50, Issue 3, pages 893–899, September 2009
How to Cite
Fickert, P., Fuchsbichler, A., Wagner, M., Silbert, D., Zatloukal, K., Denk, H. and Trauner, M. (2009), The role of the hepatocyte cytokeratin network in bile formation and resistance to bile acid challenge and cholestasis in mice. Hepatology, 50: 893–899. doi: 10.1002/hep.23068
Potential conflicts of interest: Nothing to report.
- Issue published online: 27 AUG 2009
- Article first published online: 11 MAY 2009
- Accepted manuscript online: 11 MAY 2009 12:00AM EST
- Manuscript Accepted: 3 MAY 2009
- Manuscript Received: 9 JAN 2009
- Austrian Science Foundation. Grant Number: P-15502
- GEN-AU project grant from the Austrian Ministry for Science
The intermediate filament cytoskeleton of hepatocytes is composed of keratin (K) 8 and K18 and has important mechanical and nonmechanical functions. However, the potential role of the K8/K18 network for proper membrane targeting of hepatocellular adenosine triphosphate–binding cassette transporters and bile formation is unknown. We therefore designed a comparative study in K8 and K18 knockout mice and respective wild-type controls to test the hypothesis that intermediate filaments of hepatocytes play a role in normal bile formation. In addition, we challenged mice either with a 1% cholic acid–supplemented diet or a diet containing the porphyrinogenic xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine to determine the effect of K8/K18 loss on bile flow/composition and liver injury under different physiological and toxic stress stimuli. Protein expression levels and membrane localization of various transporters and anion exchangers were compared using western blotting and immunofluorescence microscopy, respectively, and bile flow and composition were determined under various experimental conditions. Our results demonstrate that loss of the intermediate filament network had no significant effect on bile formation and composition, as well as expression levels and membrane targeting of key hepatobiliary transporters under baseline and stress conditions. However, loss of K8 significantly increased liver injury in response to toxic stress. Conclusion: The intermediate filament network of hepatocytes is not specifically required for proper bile formation in mice. (HEPATOLOGY 2009.)