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Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling Pathway.
- Source :
-
Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2021; Vol. 12 (5), pp. 1789-1807. Date of Electronic Publication: 2021 Jul 24. - Publication Year :
- 2021
-
Abstract
- Background & Aims: Sustained c-Jun N-terminal kinase (JNK) activation plays a major role in drug-induced liver injury (DILI). Stress-responsive microRNA-31 (miR-31) has been implicated in regulating different cellular damage, and JNK activation could induce miR-31 expression. However, the regulatory role of miR-31 in DILI has not been studied previously. We aimed to investigate whether miR-31 could ameliorate DILI and ascertain potential molecular mechanism.<br />Methods: miR-31 gene knockout (31-KO) and wild-type C57BL/6J mice were used to construct an acetaminophen (APAP)-induced DILI model. Primary mouse hepatocytes, as well as alpha mouse liver 12 (AML-12) cell lines, were used for in vitro experiments. Argonaute 2-associated RNA immunoprecipitation combined with high-throughput sequencing were performed to identify specific targets of miR-31.<br />Results: 31-KO mice showed a higher mortality rate, liver transaminase levels, and hepatic necrosis compared with those in wild-type mice after APAP-induced hepatotoxicity. The protective role of miR-31 on hepatocytes has been analyzed via constructing bone marrow chimeric mice. Mechanistically, we found that hepatic JNK phosphorylation increased significantly in 31-KO mice. This caused mitochondrial phosphorylated Src (p-Src) inactivation and more reactive oxygen species production, which directly amplifies hepatocyte necrotic cell death, while administration of JNK-specific inhibitor SP600125 could abrogate the differences. Moreover, bioinformatics analysis of RNA immunoprecipitation combined with high-throughput sequencing identified that guanosine triphosphatase, cell division cycle protein 42 (Cdc42), the upstream molecule of JNK signaling, was the specific target of miR-31 and could form a miR-31/Cdc42/phosphorylated mixed-lineage kinase 3 (p-MLK3) negative feedback loop to restrict JNK overactivation. Clinically, both miR-31 and phosphorylated JNK (p-JNK) were highly increased in liver tissues of DILI patients with different etiologies.<br />Conclusions: miR-31 can down-regulate Cdc42 to restrict overactivation of reactive oxygen species/JNK/mitochondria necrotic death loop in hepatocytes of APAP-induced DILI, which might provide a new therapeutic target for alleviating JNK overactivation-based liver injury.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Biomarkers
Chemical and Drug Induced Liver Injury, Chronic pathology
Disease Models, Animal
Disease Susceptibility
Immunohistochemistry
Immunophenotyping
Mice
Mice, Knockout
Models, Biological
Acetaminophen adverse effects
Chemical and Drug Induced Liver Injury, Chronic etiology
Chemical and Drug Induced Liver Injury, Chronic metabolism
JNK Mitogen-Activated Protein Kinases metabolism
MAP Kinase Signaling System
MicroRNAs genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2352-345X
- Volume :
- 12
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cellular and molecular gastroenterology and hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 34311140
- Full Text :
- https://doi.org/10.1016/j.jcmgh.2021.07.011