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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.

SUBMITTER: Piccolo P

PROVIDER: S-EPMC7958360 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Piccolo Pasquale P Ferriero Rosa R Barbato Anna A Attanasio Sergio S Monti Marcello M Perna Claudia C Borel Florie F Annunziata Patrizia P Carissimo Annamaria A De Cegli Rossella R Quagliata Luca L Terracciano Luigi M LM Housset Chantal C Teckman Jeffrey H JH Mueller Christian C Brunetti-Pierri Nicola N

Proceedings of the National Academy of Sciences of the United States of America 20210301 10

α1-Antitrypsin (AAT) deficiency is a common genetic disease presenting with lung and liver diseases. AAT deficiency results from pathogenic variants in the <i>SERPINA1</i> gene encoding AAT and the common mutant Z allele of <i>SERPINA1</i> 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 ...[more]

PMID: 33649241

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Project description:Primary liver cancer usually occurs in the context of chronic liver disease (CLD), in association with fibrosis. Platelets have emerged as important regulators of CLD and liver cancer, although their precise function and mechanism of action need to be clarified. C3G (RapGEF1) regulates platelet activation, adhesion, and secretion. Here we evaluate the role of platelet C3G in chemically induced fibrosis and liver cancer associated with fibrosis using genetically modified mouse models. We found that while overexpression of full-length C3G in platelets decreased liver fibrosis induced by chronic treatment with CCl4, overexpressed C3G lacking the catalytic domain did not, although in both cases platelet recruitment to the liver was similar. In addition, C3G deletion in platelets (PF4-C3GKO mouse model) increased CCl4-induced liver damage and hepatic fibrosis, reducing liver platelets and macrophages. Moreover, early liver immune response to CCl4 was altered in PF4-C3GKO mice, with a remarkable lower activation of macrophages and increased monocyte-derived macrophages compared to WT mice. On the other hand, in response to DEN+CCl4, PF4-C3G WT mice exhibited more and larger liver tumors than PF4-C3GKO mice, accompanied by the presence of more platelets, despite having less fibrosis in previous steps. Liver immune cell populations were also differentially regulated in PF4-C3GKO mice, highlighting the higher number of macrophages, likely with a pro-inflammatory phenotype, present in the liver in response to chronic DEN+CCl4 treatment. Proteins upregulated or downregulated in platelet-rich plasma from PF4-C3GKO compared to WT mice might regulate the immune response and tumor development. In this regard, enrichment analyses using proteomic data showed changes in several proteins involved in platelet activation and immune response pathways. Additionally, the higher secretion of CD40L by PF4-C3GKO platelets could contribute to their antitumor effect. Therefore, platelet C3G presents antifibrotic and protumor effects in the liver, likely mediated by changes in the immune response. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Dataset Information

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

Publications

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

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