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Identification of Specific MicroRNA Biomarkers in Early Stage of Hepatocellular injury, Cholestasis, and Steatosis in Rat

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE112934 | GEO | 2018/09/26

REPOSITORIES: GEO

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Project description:We tested the hypothesis that a panel of placental mammal-specific miRNAs and their targets play important to establish receptivity to implantation and their dysregulated expression may be a feature in women with early pregnancy loss. Relative expression levels of miR-340-5p, −542-3p, and −671-5p all increased following treatment of Ishikawa cells with progesterone (10 μg/ml) for 24 hrs (p < 0.05). RNA sequencing of these P4-treated cells identified co-ordinate changes to 6,367 transcripts of which 1713 were predicted targets of miR-340-5p, 670 of miR-542-3p, and 618 of miR-671-5p. Quantitative proteomic analysis of Ishikawa cells transfected with mimic or inhibitor (48 hrs: n=3 biological replicates) for each of the P4-regulated miRNAs was carried out to identify targets of these miRNAs. Excluding off target effects, mir-340-5p mimic altered 1,369 proteins while inhibition changed expression of 376 proteins (p < 0.05) of which, 72 were common to both treatments. A total of 280 proteins were identified between predicted (mirDB) and confirmed (in vitro) targets. In total, 171 proteins predicted to be targets by mirDB were altered in vitro by treatment with miR-340-5p mimic or inhibitor and were also altered by treatment of endometrial epithelial cells with P4. In vitro targets of miR-542-3p identified 1,378 proteins altered by mimic while inhibition altered 975 a core of 200 proteins were changed by both. 100 protein targets were predicted and only 46 proteins were P4 regulated. miR-671-mimic altered 1,252 proteins with inhibition changing 492 proteins of which 97 were common to both, 95 were miDB predicted targets and 46 were also P4-regulated. All miRNAs were detected in endometrial biopsies taken from patients during the luteal phase of their cycle, irrespective of prior or future pregnancy outcomes Expression of mir-340-5p showed an overall increase in patients who had previously suffered a miscarriage and had a subsequent miscarriage, as compared to those who had infertility or previous miscarriage and subsequently went on to have a life birth outcome. The regulation of these miRNAs and their protein targets regulate the function of transport and secretion, and adhesion of the endometrial epithelia required for successful implantation in humans. Dysfunction of these miRNAs (and therefore the targets they regulate) may contribute to endometrial-derived recurrent pregnancy loss in women.

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Identification of Specific MicroRNA Biomarkers in Early Stage of Hepatocellular injury, Cholestasis, and Steatosis in Rat

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