Title

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

UMMS Affiliation

Department of Pediatrics; Horae Gene Therapy Center

Publication Date

2021-03-09

Document Type

Article

Disciplines

Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics | Translational Medical Research

Abstract

alpha1-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 alpha1-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 Ser(574) 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, UMCCTS funding

DOI of Published Version

10.1073/pnas.2025242118

Source

Piccolo P, Ferriero R, Barbato A, Attanasio S, Monti M, Perna C, Borel F, Annunziata P, Carissimo A, De Cegli R, Quagliata L, Terracciano LM, Housset C, Teckman JH, Mueller C, Brunetti-Pierri N. 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. PMID: 33649241; PMCID: PMC7958360. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

33649241

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