Overexpression of mcl-1 attenuates liver injury and fibrosis in the bile duct-ligated mouse.
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.
Kahraman
Alisan
A
Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Mott
Justin L
JL
Bronk
Steven F
SF
Werneburg
Nathan W
NW
Barreyro
Fernando J
FJ
Guicciardi
Maria E
ME
Akazawa
Yuko
Y
Braley
Karen
K
Craig
Ruth W
RW
Gores
Gregory J
GJ
D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000601:surgery; D015415:Biomarkers / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000473:pathology / Q000503:physiopathology*; D005355:Fibrosis; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008026:Ligation; D008099:Liver / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*
D015415:Biomarkers; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2