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

Hong Zhou¹  Feng Xue²  Qiang Xia³  Honglin Wang⁴  Yuanjia Tang⁵  Taihua Yang⁵  Tian Qin⁶  Jinchuan Liu⁶  Yi Zhang⁶  Jianxin Zheng⁶  Xiangqian Gu⁶  Ji Wu⁶  Yimin Mao⁷ 

[1] Department of Urology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, 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: [phone].;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: [phone].;ABLife Institute of BioBigData, East Lake High-Tech Development Zone, Wuhan, China;Center for Microbiota and Immunological Diseases, Shanghai General Hospital, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China;Department of Liver Surgery and Liver Transplantation Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;

关键词: microRNA;    Drug-Induced Liver Injury;    Damage Responsive;    Negative Feedback;    Necrosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown