Overexpression of Mcl-1 attenuates liver injury and fibrosis in the bile duct-ligated mouse

KAHRAMAN, ALISAN; MOTT, JUSTIN L.; BRONK, STEVEN F.; WERNEBURG, NATHAN W.; BARREYRO, FERNANDO J.; GUICCIARDI, MARIA E.; AKAZAWA, YUKO; BRALEY, KAREN; CRAIG, RUTH W.; GORES, GREGORY J.

DIGESTIVE DISEASE AND SCIENCES

SPRINGER

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. © 2008 Springer Science+Business Media, LLC.