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Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes†
Article first published online: 19 NOV 2008
Copyright © 2008 American Association for the Study of Liver Diseases
Volume 49, Issue 2, pages 627–636, February 2009
How to Cite
Vick, B., Weber, A., Urbanik, T., Maass, T., Teufel, A., Krammer, P. H., Opferman, J. T., Schuchmann, M., Galle, P. R. and Schulze-Bergkamen, H. (2009), Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes. Hepatology, 49: 627–636. doi: 10.1002/hep.22664
Potential conflict of interest: Nothing to report.
- Issue published online: 28 JAN 2009
- Article first published online: 19 NOV 2008
- Accepted manuscript online: 19 NOV 2008 12:00AM EST
- Manuscript Accepted: 19 SEP 2008
- Manuscript Received: 24 APR 2008
- Deutsche Forschungsgemeinschaft. Grant Number: DFG SCHU 1443/3-1
- (MAIFOR) of the University of Mainz
Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. It interacts with proapoptotic Bcl-2 family members, thereby inhibiting mitochondrial activation and induction of apoptosis. Mcl-1 is essential for embryonal development and the maintenance of B cells, T cells, and hematopoietic stem cells. We have recently shown that induction of Mcl-1 by growth factors rescues primary human hepatocytes from CD95-mediated apoptosis. This prompted us to further analyze the relevance of Mcl-1 for hepatocellular homeostasis. Therefore, we generated a hepatocyte-specific Mcl-1 knockout mouse (Mcl-1flox/flox-AlbCre). Deletion of Mcl-1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl-1flox/flox-AlbCre mice are smaller compared to control littermates, due to higher apoptosis rates. As a compensatory mechanism, proliferation of hepatocytes is enhanced in the absence of Mcl-1. Importantly, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage. Furthermore, Mcl-1flox/flox-AlbCre mice are more susceptible to hepatocellular damage induced by agonistic anti-CD95 antibodies or concanavalin A. Conclusion: The present study provides in vivo evidence that Mcl-1 is a crucial antiapoptotic factor for the liver, contributing to hepatocellular homeostasis and protecting hepatocytes from apoptosis induction. (HEPATOLOGY 2009.)