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

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

DIGESTIVE DISEASE AND SCIENCES

Springer Netherlands

Año: 2009 vol. 54 p. 1908 - 1917

0163-2116

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.