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

Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2025242118. doi: 10.1073/pnas.2025242118.


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.

Keywords: FOXO3; JNK; liver fibrosis; miR-34b/c; α1 antitrypsin deficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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