Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans
Autor: | Kostiantyn Dreval, William B. Mattes, Yongli Guo, Linjuan Zeng, Yaqiong Jin, Weida Tong, Huixiao Hong, Sudeepa Bhattacharyya, Hong Fang, Bridgett Knox, Tieliu Shi, Leming Shi, Yong Wang, Wenming Xiao, Zhen Ren, Igor P. Pogribny, Leihong Wu, Volodymyr Tryndyak, Jinchun Sun, Si Chen, Baitang Ning, Pritmohinder S. Gill, Richard D. Beger, Yinting Chen, Xi Yang, William H. Tolleson, Sandra S. McCullough, Laura K. Schnackenberg, Lei Guo, Nan Mei, Dianke Yu, Laura P. James |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Health Toxicology and Mutagenesis In silico Biology Pharmacology Transfection Toxicology Article Cell Line 03 medical and health sciences microRNA medicine Humans Child Gene Acetaminophen Liver injury Messenger RNA digestive oral and skin physiology HEK 293 cells General Medicine medicine.disease body regions MicroRNAs HEK293 Cells 030104 developmental biology embryonic structures Hepatocytes Female Chemical and Drug Induced Liver Injury Drug Overdose medicine.drug |
Zdroj: | Archives of Toxicology. 92:845-858 |
ISSN: | 1432-0738 0340-5761 |
Popis: | Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) Hep-aRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6–559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes. |
Databáze: | OpenAIRE |
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