Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary

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 re...

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Autores principales:	Jianxin Zheng, Hong Zhou, Taihua Yang, Jinchuan Liu, Tian Qin, Xiangqian Gu, Ji Wu, Yi Zhang, Honglin Wang, Yuanjia Tang, Feng Xue, Yimin Mao, Qiang Xia
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	microRNA Drug-Induced Liver Injury Damage Responsive Negative Feedback Necrosis Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/beabaa901cb04e698d21b5567b0393e5
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spelling	oai:doaj.org-article:beabaa901cb04e698d21b5567b0393e52021-11-12T04:39:11ZProtective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary2352-345X10.1016/j.jcmgh.2021.07.011https://doaj.org/article/beabaa901cb04e698d21b5567b0393e52021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001569https://doaj.org/toc/2352-345XBackground & 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. 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. 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. 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.Jianxin ZhengHong ZhouTaihua YangJinchuan LiuTian QinXiangqian GuJi WuYi ZhangHonglin WangYuanjia TangFeng XueYimin MaoQiang XiaElsevierarticlemicroRNADrug-Induced Liver InjuryDamage ResponsiveNegative FeedbackNecrosisDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 5, Pp 1789-1807 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	microRNA Drug-Induced Liver Injury Damage Responsive Negative Feedback Necrosis Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	microRNA Drug-Induced Liver Injury Damage Responsive Negative Feedback Necrosis Diseases of the digestive system. Gastroenterology RC799-869 Jianxin Zheng Hong Zhou Taihua Yang Jinchuan Liu Tian Qin Xiangqian Gu Ji Wu Yi Zhang Honglin Wang Yuanjia Tang Feng Xue Yimin Mao Qiang Xia Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary
description	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. 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. 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. 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.
format	article
author	Jianxin Zheng Hong Zhou Taihua Yang Jinchuan Liu Tian Qin Xiangqian Gu Ji Wu Yi Zhang Honglin Wang Yuanjia Tang Feng Xue Yimin Mao Qiang Xia
author_facet	Jianxin Zheng Hong Zhou Taihua Yang Jinchuan Liu Tian Qin Xiangqian Gu Ji Wu Yi Zhang Honglin Wang Yuanjia Tang Feng Xue Yimin Mao Qiang Xia
author_sort	Jianxin Zheng
title	Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary
title_short	Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary
title_full	Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary
title_fullStr	Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary
title_full_unstemmed	Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummary
title_sort	protective role of microrna-31 in acetaminophen-induced liver injury: a negative regulator of c-jun n-terminal kinase (jnk) signaling pathwaysummary
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/beabaa901cb04e698d21b5567b0393e5
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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 PathwaySummary

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