Overexpression of Mcl-1 Attenuates Liver Injury and Fibrosis in the Bile Duct–Ligated Mouse

• DOI: 10.1007/s10620-008-0583-5
• Publication Date: 2008-12-02T18:41:39Z
• Authors: Alisan Kahraman; Justin L. Mott; Steven F. Bronk; Nathan W. Werneburg; Fernando J. Barreyro; Maria E. Guicciardi; Yuko Akazawa; Karen Braley; Ruth W. Craig; Gregory J. Gores
• Keywords: 0301 basic medicine; Liver fibrosis; Apoptosis; Mice, Transgenic; Medical Biochemistry; Cholestasis, Intrahepatic; Inbred C57BL; Transgenic; Mice; 03 medical and health sciences; Animals; Humans; Ligation; Intrahepatic; Cholestasis; Fibrosis; Bile infarct; Mice, Inbred C57BL; Liver; Proto-Oncogene Proteins c-bcl-2; Medical Molecular Biology; Hepatocytes; Stellate cells; Myeloid Cell Leukemia Sequence 1 Protein; Biological Markers; Bile Ducts; Biomarkers

Hepatocyte apoptosis contributes to liver injury and fibrosis after cholestatic injury. Our aim was to ascertain if the anti-apoptotic protein Mcl-1 alters liver injury or fibrosis in the bile duct-ligated mouse. Markers of apoptosis and fibrosis were compared in wild-type and transgenic mice expressing human Mcl-1 after bile duct ligation. Compared to hMcl-1 transgenic animals, ligated wild-type mice displayed a significant increase in TUNEL-positive cells and in caspase 3/7-positive hepatocytes. Consistent with apoptotic injury, the pro-apoptotic protein Bak underwent a conformational change to an activated form upon cholestatic injury, a change mitigated by hMcl-1 overexpression. Likewise, liver histology, number of bile infarcts, serum ALT values, markers of hepatic fibrosis, and animal survival were improved in bile duct-ligated mice transgenic for hMcl-1 as compared to wild-type mice. In conclusion, increased Mcl-1 expression plays a role in hepatoprotection upon cholestatic liver injury.