Time-course changes in the expression levels of microRNA as a biomarker in mouse drug induced liver injury (DILI) model

Abstract

Liver is a major site of metabolism and exposed to various kinds of xenobiotic substances. Therefore, liver frequently becomes a target organ of hepatotoxicants and finally results in drug-induced liver injury (DILI). However, the diagnosis and treatment for DILI is complicated. Therefore, there is an urgent need for more specific biomarker for DILI which have better diagnostic and prognostic potential. microRNA (miRNA) is a small non-coding RNA that regulates gene expression, and mediates normal homeostasis, development, physiology, and even disease pathogenesis. Therefore the possible correlation of miRNA and DILI is needs to be investigated for excavation of potential miRNA biomarkers.

In this study, acetaminophen (APAP), isoniazid (INH), and Tamoxifen (TAM) are used to induce liver injury in CD-1 (ICR) mice. The expression levels of pre-selected miRNAs extracted from liver tissue and levels of serum biomarkers are measured at 5 timepoints throughout a day (0, 2, 6, 12, and 24 h). Histopathological analysis was also conducted at same timepoints. Notably, over the time-course of liver injury, miRNAs from tissue showed changes in expression levels. miRNAs have been reported to mediate apoptosis or cellular protection showed significant changes in expression at early to middle phase. On the contrary, miRNAs regulate inflammatory pathway or immune response changed at middle to late phase.

At present, the serum ALT and AST levels are used to determine the degree of liver injury and the diagnosis for DILI. However, there have been shortcomings of these biomarker in DILI diagnosis. Although ALT is liver specific, AST is affected by other organs than liver. Moreover, the exact stages of liver injury, for example, metabolization, apoptosis, initiation of innate immune system, or inflammation and hepatocyte necrosis. Therefore, more specific, and fast biomarkers for DILI is needed in order to differentiate other liver diseases from DILI.

In conclusion, the present study suggests several miRNA biomarkers in three DILI models at different timepoints. Particularly miR-677, which is seemed to be involved in the inflammatory response, showed significant changes in all three DILI models. These results are associated with inflammatory cell infiltration in histopathological analysis. The exact function of miRNA-1839 in liver injury has not been studied and its function in other organs are still unclear. Recent study suggested correlation with liver cell apoptosis, but it could have other functions in liver injury models.