Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha-1 antitrypsin via inhibition of bad

Authors

  • Stanley D.W. Miller,

    1. Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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    • Both authors contributed equally to this work

  • Catherine M. Greene,

    Corresponding author
    1. Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
    • Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland
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    • Both authors contributed equally to this work

    • fax: (353)-1-8093808

  • Caitriona McLean,

    1. Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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  • Matthew W. Lawless,

    1. Hepatology Research Division, Institute of Molecular Medicine, Trinity Health Science Building, Trinity College, St. James Hospital, Dublin, Ireland
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  • Clifford C. Taggart,

    1. Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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  • Shane J. O'Neill,

    1. Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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  • Noel G. McElvaney

    1. Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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  • Potential conflict of interest: Nothing to report.

Abstract

Z alpha-1 antitrypsin (AAT) deficiency is a genetic disease associated with accumulation of misfolded AAT in the endoplasmic reticulum (ER) of hepatocytes. ZAAT-expressing cells display ER stress responses including nuclear factor kappaB activation and apoptosis. Using an in vitro model of ZAAT ER accumulation, we investigated the mechanism of ZAAT-mediated ER-induced apoptosis and evaluated methods to inhibit this process. Here we demonstrate that expression of ZAAT, but not normal MAAT, in HEK293 cells leads to cleavage and activation of caspase-4 and induces apoptosis that is characterized by activation of caspase-3 and caspase-7 and DNA fragmentation. Similar effects are also induced using the ER agonist thapsigargin. A caspase-4–specific short interfering RNA (siRNA) does not impair ZAAT-induced caspase-3/7 activation or cell death in these cells. However, inhibition studies performed using tauroursodeoxycholic acid (TUDCA) demonstrate its ability to inhibit caspase-4 and caspase-3/7 activation, mitochondrial cytochrome c release, and caspase-3 cleavage induced by ZAAT and to promote cell survival. The mechanism by which TUDCA (tauroursodeoxycholic acid) promotes cell survival in ZAAT-expressing cells involves phosphorylation and inactivation of the proapoptotic factor Bad. TUDCA is unable to rescue cells from apoptosis or phosphorylate Bad in the presence of LY294002, a selective P-I-3-kinase inhibitor. Conclusion: These data show that caspase-4 is not essential for ZAAT-induced apoptosis in HEK293 cells and implicates P-I-3-kinase and Bad as potential therapeutic targets for the liver disease associated with ZAAT deficiency. (HEPATOLOGY 2007.)

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