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MicroRNA‐221 regulates FAS‐induced fulminant liver failure
Author(s) -
Sharma Amar Deep,
Narain Nidhi,
Händel EvaMaria,
Iken Marcus,
Singhal Nishant,
Cathomen Toni,
Manns Michael P.,
Schöler Hans R.,
Ott Michael,
Cantz Tobias
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24243
Subject(s) - microrna , apoptosis , biology , ectopic expression , fas receptor , antagomir , cancer research , fulminant hepatic failure , fas ligand , regulator , microbiology and biotechnology , programmed cell death , immunology , cell culture , gene , medicine , genetics , liver transplantation , transplantation
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;)