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Knockout of myeloid cell leukemia‐1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes
Author(s) -
Vick Binje,
Weber Achim,
Urbanik Toni,
Maass Thorsten,
Teufel Andreas,
Krammer Peter H.,
Opferman Joseph T.,
Schuchmann Marcus,
Galle Peter R.,
SchulzeBergkamen Henning
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22664
Subject(s) - apoptosis , myeloid leukemia , leukemia , cancer research , knockout mouse , myeloid , chemistry , immunology , biology , gene , biochemistry
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‐1 flox/flox ‐AlbCre). Deletion of Mcl‐1 in hepatocytes results in liver cell damage caused by spontaneous induction of apoptosis. Livers of Mcl‐1 flox/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‐1 flox/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. (H EPATOLOGY 2009.)