MCL-1 is important for integrity and survival of hepatocytes

Background and aims: Mcl-1 is an anti-apoptotic member of the Bcl-2 family of proteins. It inhibits apoptosis induction by interacting with pro-apoptotic family members. We recently have shown that Mcl-1 expression is induced in primary human hepatocytes after treatment with growth factors such as HGF, thereby protecting these cells against CD95-mediated apoptosis. The aim of this study was to further analyse the role of Mcl-1 for liver cell homeostasis and CD95-induced liver failure.

Methods: A liver-specific Mcl-1 knock-out mouse was generated by mating Mcl-1^flox/flox-mice[1] with mice expressing the Cre-recombinase under the control of an albumin-promoter. Mcl-1^flox/flox/AlbCre-mice were compared to their Mcl-1^flox/wt/AlbCre littermates with respect to immunohistochemical findings and apoptosis induction.

Results: At the age of 8 weeks, Mcl-1^flox/flox/AlbCre-mice show a reduced body weight and a drastically reduced liver mass. Furthermore, basal serum transaminases were highly increased in these mice, indicating a basal liver damage. Mcl-1 expression was completely abrogated in hepatocytes of Mcl-1^flox/flox/AlbCre-mice. This loss of Mcl-1 expression was not compensated by an increase of Bcl-x_L expression, another anti-apoptotic Bcl-2 protein expressed in the liver. Liver damage was further increased in Mcl-1^flox/flox/AlbCre-mice compared to control animals, both after induction of fulminant hepatic failure by injecting an agonistic CD95-antibody and after LPS/D-Galactosamin treatment, as could be detected by enhanced hepatocyte apoptosis, liver tissue damage, and caspase-activation. Furthermore, hepatic pericellular fibrosis occurs in Mcl-1 negative livers in response to chronic liver damage.

Conclusion: Our results suggest that Mcl-1 is an important anti-apoptotic factor and crucial for integrity and survival of hepatocytes