Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver

Authors

  • Yosuke Osawa,

    1. Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY
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  • Yusuf A. Hannun,

    1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC
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  • Richard L. Proia,

    1. Genetics of Disease and Development Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD
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  • David A. Brenner

    Corresponding author
    1. Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY
    • Department of Medicine, Columbia University, College of Physicians and Surgeons, 622 West 168th St., PH 8E-105J, New York, NY 10032
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    • fax: 212-305-9822.


  • Potential conflict of interest: Nothing to report.

Abstract

Tumor necrosis factor (TNF) receptor– and Fas-mediated apoptosis are major death processes of hepatocytes in liver disease. Although antiapoptotic effects in the injured liver promote chronic hepatitis and carcinogenesis, scant information is known about these mechanisms. To explore this issue, we compared acute liver injury after TNF-α or anti-Fas antibody (Jo2) between livers from sham-operated mice and chronic injured liver via bile duct ligation (BDL). BDL inhibited hepatocyte apoptosis induced by TNF-α but not by Jo2. On the other hand, BDL inhibited the massive hemorrhage seen in livers treated with either TNF-α or Jo2. Inactivation of AKT blocked the antiapoptotic effect of BDL. Sphingosine kinase knockout mice also lost the antihemorrhagic effect of BDL and attenuated the antiapoptotic effects of BDL. In bile duct–ligated livers, hepatic stellate cells (HSCs) were activated and produced tissue inhibitor of metalloproteinase 1 in a sphingosine kinase (SphK)-1–dependent mechanism. In conclusion, BDL exerts antiapoptotic effects that appear to require activation of AKT in hepatocytes and SphK in HSCs.(HEPATOLOGY 2005;42:1320–1328.)

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