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Gene expression data from primary human hepatocytes treated with tolvaptan for 4, 24, or 72 h

ABSTRACT: A micropatterned coculture model (HepatoPac®) was used to explore the possibility that changes in exosome content precede overt necrosis in response to tolvaptan, a drug known to cause idiosyncratic drug-induced liver injury. Hepatocytes from 3 human donors were exposed to a range of tolvaptan concentrations bracketing plasma Cmax (0.01 - 50 µM) or DMSO control continuously for 4, 24, or 72 h. While ALT release was not significantly affected, tolvaptan exposure resulted in increased release of exosomal microRNA-122 (miR-122) into the medium. Microarray analysis was used to idenfity the activation of molecular stress response pathways most associated with increases in exosomal miR-122.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99878 | GEO | 2017/06/10

SECONDARY ACCESSION(S): PRJNA389817

REPOSITORIES: GEO

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Project description:Background/Aim: We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results: NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion: Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.

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Gene expression data from primary human hepatocytes treated with tolvaptan for 4, 24, or 72 h

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