title: MicroRNA-221 regulates FAS-induced fulminant liver failure.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, Germany. sharma.amar@mh-hannover.de
authors.forename: Amar Deep
authors.initials: AD
authors.lastname: Sharma
authors.forename: Nidhi
authors.initials: N
authors.lastname: Narain
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Händel
authors.forename: Marcus
authors.initials: M
authors.lastname: Iken
authors.forename: Nishant
authors.initials: N
authors.lastname: Singhal
authors.forename: Toni
authors.initials: T
authors.lastname: Cathomen
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.forename: Michael
authors.initials: M
authors.lastname: Ott
authors.forename: Tobias
authors.initials: T
authors.lastname: Cantz
mesh_terms: D000818:Animals; D017209:Apoptosis; D022781:Hepatocytes; D017114:Liver Failure, Acute / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
chemical_list: C546122:MIRN221 microRNA, mouse; D035683:MicroRNAs; D019014:fas Receptor