Advertisement

MicroRNA-221 regulates FAS-induced fulminant liver failure

Authors

  • Amar Deep Sharma,

    Corresponding author
    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    • Stem Cell Biology, Cluster of Excellence REBIRTH, Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanz Borst Zentrum J-11-02-6530, OE 8881, Carl-Neuberg-Str-1, D-30625 Hannover, Germany
    Search for more papers by this author
    • These authors share first authorship.

    • fax: 0049 511 532 5234

  • Nidhi Narain,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
    Search for more papers by this author
    • These authors share first authorship.

  • Eva-Maria Händel,

    1. Department of Experimental Hematology, Hannover Medical School, Hannover, Germany
    Search for more papers by this author
  • Marcus Iken,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
    Search for more papers by this author
  • Nishant Singhal,

    1. Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Search for more papers by this author
  • Toni Cathomen,

    1. Department of Experimental Hematology, Hannover Medical School, Hannover, Germany
    Search for more papers by this author
  • Michael P. Manns,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    Search for more papers by this author
  • Hans R. Schöler,

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
    2. Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Search for more papers by this author
  • Michael Ott,

    1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    2. TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany
    Search for more papers by this author
  • Tobias Cantz

    1. Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany
    2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
    3. Max Planck Institute for Molecular Biomedicine, Münster, Germany
    Search for more papers by this author

  • Parts of the study were funded by the German Research Foundation (Cluster of Excellence REBIRTH; EXC 62/1 awarded to Tobias Cantz and SFB 738 awarded to Michael Ott) and the German Ministry of Education and Research (ITCF-01GU0618, awarded to Toni Cathomen. Amar Deep Sharma receives grant support from HILF, Hannover Medical School.

  • Potential conflict of interest: Nothing to report.

Abstract

Death receptor-mediated apoptosis of hepatocytes contributes to hepatitis and fulminant liver failure. MicroRNAs (miRNAs), 19-25 nucleotide-long noncoding RNAs, have been implicated in the posttranscriptional regulation of the various apoptotic pathways. Here we report that global loss of miRNAs in hepatic cells leads to increased cell death in a model of FAS/CD95 receptor-induced apoptosis. miRNA profiling of murine liver identified 11 conserved miRNAs, which were up-regulated in response to FAS-induced fulminant liver failure. We show that ectopic expression of miR-221, one of the highly up-regulated miRNAs in response to apoptosis, protects primary hepatocytes and hepatoma cells from apoptosis. Importantly, in vivo overexpression of miR-221 by adeno-associated virus serotype 8 (AAV8) delays FAS-induced fulminant liver failure in mice. We additionally demonstrate that miR-221 regulates hepatic expression of p53 up-regulated modulator of apoptosis (Puma), a well-known proapoptotic member of the Bcl2 protein family. Conclusion: We identified miR-221 as a potent posttranscriptional regulator of FAS-induced apoptosis. miR-221 may serve as a potential therapeutic target for the treatment of hepatitis and liver failure. (HEPATOLOGY 2011;)

Ancillary