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

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Abstract

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.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

α-SMA:

α-Smooth muscle actin

BDL:

Bile duct ligation/–ligated

hMcl-1:

Human myeloid cell leukemia-1

HSC:

Hepatic stellate cell

Tg:

Transgenic

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

wt:

Wild-type

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Acknowledgments

This work was supported by a fellowship grant from the Association for Scientific Research and Science at the Department of Gastroenterology and Hepatology, University Clinic Essen, Duisburg-Essen University, 45122—Germany to A. K. and by Grant DK 41876 from the National Institute of Health to G. J. G., as well as the Mayo Foundation Rochester, Minnesota, USA. The authors thank Erin Nystuen-Bungum for her excellent secretarial assistance and James Tarara from the Division of Biochemistry and Molecular Biology (Mayo Clinic, Rochester, MN) for quantitation of the Sirius red images.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

    Alisan Kahraman, Justin L. Mott, Steven F. Bronk, Nathan W. Werneburg, Fernando J. Barreyro, Maria E. Guicciardi, Yuko Akazawa & Gregory J. Gores

  2. Department of Gastroenterology and Hepatology, University Clinic Essen, 45122, Essen, Germany

    Alisan Kahraman

  3. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, 03755-3835, USA

    Karen Braley & Ruth W. Craig

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  1. Alisan Kahraman
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  2. Justin L. Mott
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  3. Steven F. Bronk
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Correspondence to Gregory J. Gores.

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Kahraman, A., Mott, J.L., Bronk, S.F. et al. Overexpression of Mcl-1 Attenuates Liver Injury and Fibrosis in the Bile Duct–Ligated Mouse. Dig Dis Sci 54, 1908–1917 (2009). https://doi.org/10.1007/s10620-008-0583-5

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