Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.
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.


CONCLUSIONS
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.
Vick
Binje
B
1st Department of Medicine, Johannes Gutenberg-University Mainz, Germany.
Weber
Achim
A
Urbanik
Toni
T
Maass
Thorsten
T
Teufel
Andreas
A
Krammer
Peter H
PH
Opferman
Joseph T
JT
Schuchmann
Marcus
M
Galle
Peter R
PR
Schulze-Bergkamen
Henning
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D001219:Aspartate Aminotransferases / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005786:Gene Expression Regulation; D005838:Genotype; D022781:Hepatocytes / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D008099:Liver / Q000473:pathology*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency* / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification
D017931:DNA Primers; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012313:RNA; D004247:DNA; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D053148:Caspase 3