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

Hepatology. 2009 Feb;49(2):627-36. doi: 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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Apoptosis*
  • Aspartate Aminotransferases / blood
  • Caspase 3 / metabolism
  • Cell Differentiation
  • DNA / genetics
  • DNA / isolation & purification
  • DNA Primers
  • Gene Expression Regulation
  • Genotype
  • Hepatocytes / cytology
  • Hepatocytes / pathology
  • Hepatocytes / physiology*
  • Liver / pathology*
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-bcl-2 / deficiency*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA / genetics
  • RNA / isolation & purification

Substances

  • DNA Primers
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • RNA
  • DNA
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Caspase 3