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

Abstract

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.

• Authors: Pasquale Piccolo, Rosa Ferriero, Anna Barbato, Sergio Attanasio, Marcello Monti, Claudia Perna, Florie Borel, Patrizia Annunziata, Annamaria Carissimo, Rossella De Cegli, Luca Quagliata, Luigi M Terracciano, Chantal Housset, Jeffrey H Teckman, Christian Mueller, Nicola Brunetti-Pierri
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 10 (03 09 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 33649241 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Box Protein O3
• FoxO3 protein, mouse
• MIRN34b microRNA, mouse
• MIRN34c microRNA, mouse
• MicroRNAs
• Serpina1a protein, mouse
• alpha 1-Antitrypsin
• MAP Kinase Kinase 4

Topics

• Animals
• Disease Models, Animal
• Forkhead Box Protein O3 (genetics, metabolism)
• Liver Cirrhosis (genetics, metabolism, prevention & control)
• MAP Kinase Kinase 4 (genetics, metabolism)
• Male
• Mice
• Mice, Knockout
• MicroRNAs (biosynthesis, genetics)
• Up-Regulation
• alpha 1-Antitrypsin (genetics, metabolism)