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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Elsevier
2021-01-01
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Series: | Cellular and Molecular Gastroenterology and Hepatology |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21001569 |
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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 |
collection | DOAJ |
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. |
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spelling | doaj.art-beabaa901cb04e698d21b5567b0393e52022-12-22T04:04:42ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0112517891807Protective Role of microRNA-31 in Acetaminophen-Induced Liver Injury: A Negative Regulator of c-Jun N-Terminal Kinase (JNK) Signaling PathwaySummaryJianxin Zheng0Hong Zhou1Taihua Yang2Jinchuan Liu3Tian Qin4Xiangqian Gu5Ji Wu6Yi Zhang7Honglin Wang8Yuanjia Tang9Feng Xue10Yimin Mao11Qiang Xia12Department of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Urology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, ChinaCenter for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaABLife Institute of BioBigData, East Lake High-Tech Development Zone, Wuhan, ChinaCenter for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China; Honglin Wang, PhD, Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, No. 280 Chongqing Road, Shanghai 200025, China. fax: (86) 21-64660996.Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Yuanjia Tang, PhD, Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 145 Shandong (M) Road, Shanghai, 200001, China. fax: (86) 21-58752345.Department of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Correspondence Address correspondence to: Feng Xue, PhD, Department of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 160 Pujian Road, Shanghai 200127, China. fax: (86) 21-58737232.Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaDepartment of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, ChinaBackground & 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.http://www.sciencedirect.com/science/article/pii/S2352345X21001569microRNADrug-Induced Liver InjuryDamage ResponsiveNegative FeedbackNecrosis |
spellingShingle | 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 Cellular and Molecular Gastroenterology and Hepatology microRNA Drug-Induced Liver Injury Damage Responsive Negative Feedback Necrosis |
title | 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_short | 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 |
topic | microRNA Drug-Induced Liver Injury Damage Responsive Negative Feedback Necrosis |
url | http://www.sciencedirect.com/science/article/pii/S2352345X21001569 |
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