GSE112934
Identification of Specific MicroRNA Biomarkers in Early Stage of Hepatocellular injury, Cholestasis, and Steatosis in Rat
Recently, study on circulating microRNAs (miRNAs) as potential biomarkers of drug-induced liver injury (DILI), has received increasing attention. It has been demonstrated that miR-122 and miR-192, which are liver enriched, could be potential biomarkers of DILI, however, these miRNAs cannot discern types of injuries. In the present study, we comprehensively analyzed time-dependent plasma miRNA profiles in rats with drug- or chemical-induced hepatocellular injury, cholestasis, and steatosis with high-throughput miRNA sequencing. To enable comparison of miRNA expression levels between DILI models with different severity and peaks of injuries, stages of injury were defined as early, middle and late, according to cluster patterns of miRNA expression profiles. Through differential analysis, we characterized miRNAs that were specifically up- or down-regulated in each DILI model. Interestingly, several miRNAs were dramatically changed earlier than traditional biomarkers such as ALT and AST. For example, in APAP-induced hepatocellular injury model, let-7b-5p was up-regulated as early as 3 h after dosing, while significant change in ALT level was observed at 24 h. Thereafter, we focused on the DILI type-specific miRNAs which were up-regulated at early stage of injury. RT-qPCR study validated that let-7b-5p and miR-1-3p for hepatocellular injury, miR-143-3p and miR-218a-5p for cholestasis, and miR-320-3p for steatosis models have shown significant increase in the early stage of the injuries. The present study suggests the utility of miRNAs as specific biomarkers for early detection of DILI. Overall design: Time-dependent plasma miRNA profiles in rats with hepatocellular injury, cholestasis, and steatosis were comprehensively analyzed with MiSeq system (Illumina).