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Up-regulation of miR-34b/c by JNK and FOXO3 protects from liver fibrosis

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 Ser574. 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. α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the SERPINA1 gene encoding AAT and the common mutant Z allele of SERPINA1 encodes for Z α1-antitrypsin (ATZ), a protein forming hepatotoxic polymers retained in the endoplasmic reticulum of hepatocytes. PiZ mice express the human ATZ and are a valuable model to investigate the human liver disease of AAT deficiency. In this study, we investigated differential expression of microRNAs (miRNAs) between PiZ and control mice and found that miR-34b/c was up-regulated and its levels correlated with intrahepatic ATZ. Furthermore, in PiZ mouse livers, we found that Forkhead Box O3 (FOXO3) driving microRNA-34b/c (miR‐34b/c) expression was activated and miR-34b/c expression was dependent upon c-Jun N-terminal kinase (JNK) phosphorylation on Ser574. Deletion of miR-34b/c in PiZ mice resulted in early development of liver fibrosis and increased signaling of platelet-derived growth factor (PDGF), a target of miR-34b/c. Activation of FOXO3 and increased miR-34c were confirmed in livers of humans with AAT deficiency. In addition, JNK-activated FOXO3 and miR-34b/c up-regulation were detected in several mouse models of liver fibrosis. This study reveals a pathway involved in liver fibrosis and potentially implicated in both genetic and acquired causes of hepatic fibrosis.