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Enhanced Sensitivity to CD95-Induced Apoptosis in ob/ob Mice

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Abstract

Hepatocyte apoptosis was recently described for NASH patients. The pathomechanisms are incompletely understood, but upregulation of the death receptor Fas was detectable on hepatocytes of NASH patients. We analyzed the sensitivity of fatty liver against CD95/Fas-mediated apoptotic cell death by injection of agonistic anti-Fas antibody (Jo2) in obese ob/ob mice and lean control animals. Ob/ob mice died within 12 hrs, whereas control animals survived. Liver enzymes were significantly increased compared to those in control mice (P < 0.001). Histological analysis and also TUNEL assay of liver sections from ob/ob mice exhibited massive liver injury. Activity of caspase 3 was significantly more enhanced in livers of ob/ob mice after Jo2 challenge. The increased sensitivity was confirmed in vitro by using ob/ob-derived primary hepatocytes. CD95 expression was similar in ob/ob and control mice. However, hepatocytes from ob/ob mice revealed a decreased mitochondrial membrane potential, suggesting that mitochondria play a potential role in this increased susceptibility.

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Acknowledgments

We thank Sonja Klein for excellent technical assistance and Prof. A. Wendel and Dr. M. Latta, Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany, for critical and helpful discussions.

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Authors and Affiliations

  1. Department of Medicine, University of Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Juergen Siebler, Markus Schuchmann, Susanne Strand, Markus F. Neurath & Peter R. Galle

  2. Department of Pathology, University of Lausanne, Lausanne, Switzerland

    Hans A. Lehr

Authors
  1. Juergen Siebler
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  2. Markus Schuchmann
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  3. Susanne Strand
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  4. Hans A. Lehr
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  5. Markus F. Neurath
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  6. Peter R. Galle
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Correspondence to Juergen Siebler.

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Juergen Siebler and Markus Schuchmann contributed equally to the work.

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Siebler, J., Schuchmann, M., Strand, S. et al. Enhanced Sensitivity to CD95-Induced Apoptosis in ob/ob Mice. Dig Dis Sci 52, 2396–2402 (2007). https://doi.org/10.1007/s10620-006-9148-7

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  • DOI: https://doi.org/10.1007/s10620-006-9148-7

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