Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes
Open Access
- 19 November 2008
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 49 (2), 627-636
- https://doi.org/10.1002/hep.22664
Abstract
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.)Keywords
This publication has 34 references indexed in Scilit:
- The Bcl-2 apoptotic switch in cancer development and therapyOncogene, 2007
- The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophagesBlood, 2006
- Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteinsHepatology, 2006
- The role of apoptosis versus oncotic necrosis in liver injury: Facts or faith?Journal of Hepatology, 2006
- Death by association: BH3 domain-only proteins and liver injuryAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2005
- Mcl-1 overexpression in hepatocellular carcinoma: A potential target for antisense therapyJournal of Hepatology, 2005
- Hepatocyte growth factor induces Mcl-1 in primary human hepatocytes and inhibits CD95-mediated apoptosis via AktHepatology, 2004
- Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1Nature, 2003
- Mouse Reporter Strain for Noninvasive Bioluminescent Imaging of Cells that Have Undergone Cre-Mediated RecombinationMolecular Imaging, 2003
- Primary human hepatocytes – a valuable tool for investigation of apoptosis and hepatitis B virus infectionJournal of Hepatology, 2003