Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis
Pasquale Piccolo, Rosa Ferriero, Anna Barbato, Sergio Attanasio, M. Monti, Claudia Perna, Florie Borel, Patrizia Annunziata, Annamaria Carissimo, Rossella De Cegli, Luca Quagliata, Luigi Terracciano, Chantal Housset, Jeffrey Teckman, Christian Mueller, Nicola Brunetti‐Pierri
Abstract
Significance α1-Antitrypsin deficiency is one of the most common genetic diseases. Homozygous and heterozygous carriers of the Z allele of α1-antitrypsin are susceptible to developing liver fibrosis and cirrhosis. In mouse and human samples expressing the Z allele of α1-antitrypsin, we found both miR-34b and miR-34c are up-regulated by activation of FOXO3 upon JNK phosphorylation on Ser 574 . Deletion of miR-34b/c resulted in early development of liver fibrosis and increased signaling of the PDGF pathway, a target of miR-34b/c. JNK-activated FOXO3 and miR-34b/c up-regulation also occur in several mouse models of liver fibrosis. Fibrosis is a major health problem and unravelling its underlying pathogenic mechanisms has potential for the development of targeted therapeutic agents.