“
“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 Selleckchem Selinexor 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 drug discovery 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;) Hepatocytes are highly sensitive to death receptor-mediated apoptosis.1, 2 The extrinsic apoptotic pathways in hepatocytes involve receptors such as FAS, Fossariinae tumor necrosis factor (TNF), and TNF-related apoptosis inducing ligand (TRAIL).3, 4 FAS receptors and downstream apoptotic events have been implicated in hepatitis including hepatitis B and hepatitis C virus infection, fulminant liver failure, nonalcoholic fatty liver disease, and hepatocellular carcinoma (HCC).4 A number of pro- and

antiapoptotic proteins including caspases mediate hepatocyte apoptosis, all of which are regulated at the transcriptional and/or translational level.4 Among the posttranscriptional regulators, microRNAs (miRNAs) are new players, which inhibit protein translation.5-7 One of the first reports demonstrating the involvement of miRNAs in apoptosis came from studies using the model organism Drosophila melanogaster, in which two miRNAs, miR-14 and Bantam, were reported to control apoptosis.8, 9 A number of reports describe a role for miRNAs in hepatic apoptosis.10-12 However, their direct involvement in apoptosis of primary hepatocytes during hepatitis and fulminant liver failure has not yet been elucidated in detail. In the current study we aimed to evaluate the role of miRNAs in apoptosis during fulminant liver failure in mice. Our results indicate that miRNAs are important regulators of apoptosis. Furthermore, overexpression of miR-221 protects hepatocytes from apoptosis and delays fulminant liver failure in mice.