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MiR-182-5p Is Upregulated in Hepatic Tissues from a Diet-Induced NAFLD/NASH/HCC C57BL/6J Mouse Model and Modulates Cyld and Foxo1 Expression.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is considered a relevant liver chronic disease. Variable percentages of NAFLD cases progress from steatosis to steatohepatitis (NASH), cirrhosis and, eventually, hepatocellular carcinoma (HCC). In this study, we aimed to deepen our understanding of expression levels and functional relationships between miR-182-5p and Cyld-Foxo1 in hepatic tissues from C57BL/6J mouse models of diet-induced NAFL/NASH/HCC progression. A miR-182-5p increase was detected early in livers as NAFLD damage progressed, and in tumors compared to peritumor normal tissues. An in vitro assay on HepG2 cells confirmed Cyld and Foxo1, both tumor-suppressor, as miR-182-5p target genes. According to miR-182-5p expression, decreased protein levels were observed in tumors compared to peritumor tissues. Analysis of miR-182-5p, Cyld and Foxo1 expression levels, based on datasets from human HCC samples, showed results consistent with those from our mouse models, and also highlighted the ability of miR-182-5p to distinguish between normal and tumor tissues (AUC 0.83). Overall, this study shows, for the first time, miR-182-5p overexpression and Cyld-Foxo1 downregulation in hepatic tissues and tumors from a diet-induced NAFLD/HCC mouse model. These data were confirmed by the analysis of datasets from human HCC samples, highlighting miR-182-5p diagnostic accuracy and demonstrating the need for further studies to assess its potential role as a biomarker or therapeutic target.

SUBMITTER: Compagnoni C

PROVIDER: S-EPMC10252350 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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MiR-182-5p Is Upregulated in Hepatic Tissues from a Diet-Induced NAFLD/NASH/HCC C57BL/6J Mouse Model and Modulates Cyld and Foxo1 Expression.

Compagnoni Chiara C Capelli Roberta R Zelli Veronica V Corrente Alessandra A Vecchiotti Davide D Flati Irene I Di Vito Nolfi Mauro M Angelucci Adriano A Alesse Edoardo E Zazzeroni Francesca F Tessitore Alessandra A

International journal of molecular sciences 20230525 11

Non-alcoholic fatty liver disease (NAFLD) is considered a relevant liver chronic disease. Variable percentages of NAFLD cases progress from steatosis to steatohepatitis (NASH), cirrhosis and, eventually, hepatocellular carcinoma (HCC). In this study, we aimed to deepen our understanding of expression levels and functional relationships between miR-182-5p and Cyld-Foxo1 in hepatic tissues from C57BL/6J mouse models of diet-induced NAFL/NASH/HCC progression. A miR-182-5p increase was detected earl ...[more]

PMID: 37298191

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Project description:IntroductionAltered circadian rhythms underlie manifestation of several cardiovascular disorders, however a little is known about the mediating biomolecules. Multiple transcriptional-translational feedback loops control circadian-clockwork wherein; micro RNAs (miRNAs) are known to manifest post transcriptional regulation. This study assesses miR34a-5p as a mediating biomolecule.Method8-10-week-old male C57BL/6J mice (n = 6/group) were subjected to photoperiodic manipulation induced chronodisruption and thoracic aortae were examined for miRNA, gene (qPCR) and protein (Immunoblot) expression studies. Histomorphological changes were assessed for pro-atherogenic manifestations (fibrillar arrangement, collagen/elastin ratio, intima-media thickening). Computational studies for miRNA-mRNA target prediction were done using TargetScan and miRDB. Correlative in vitro studies were done in serum synchronized HUVEC cells. Time point based studies were done at five time points (ZT 0, 6, 12, 18, 24) in 24h.ResultsChronodisruption induced hypomethylation in the promoter region of miR34a-5p, in the thoracic aortae, culminating in elevated miRNA titers. In a software-based detection of circadian-clock-associated targets of miR34a-5p, Clock and Sirt1 genes were identified. Moreover, miR34a-5p exhibited antagonist circadian oscillations to that of its target genes CLOCK and SIRT1 in endothelial cells. Luciferase reporter gene assay further showed that miR34a-5p interacts with the 3'UTR of the Clock gene to lower its expression, disturbing the operation of positive arm of circadian clock system. Elevated miR34a-5p and impeded SIRT1 expression in a chronodisruptive aortae exhibited pro-atherogenic changes observed in form of gene expression, increased collagen/elastin ratio, fibrillar derangement and intimal-media thickening.ConclusionThe study reports for the first time chronodisruption mediated miR34a-5p elevation, its circadian expression and interaction with the 3'UTR of Clock gene to impede its expression. Moreover, elevated miR34a-5p and lowered SIRT1 expression in the chronodisruptive aortae lead off cause-consequence relationship of chronodisruption mediated proatherogenic changes.

Project description:Background: Alcoholic liver disease (ALD) is one of the most common chronic liver diseases worldwide. However, the potential molecular mechanism in ALD development remains unclear. The objective of this work was to identify key molecules and demonstrate the underlying regulatory mechanisms. Methods: RNA-seq datasets were obtained from Gene Expression Omnibus (GEO), and key molecules in ALD development were identified with bioinformatics analysis. Alcoholic liver disease mouse and cell models were constructed using Lieber-DeCarli diets and alcohol medium, respectively. Quantitative real-time PCR and Western blotting were conducted to confirm the differential expression level. Dual-luciferase reporter assays were performed to explore the targeting regulatory relationship. Overexpression and knockdown experiments were applied to reveal the potential molecular mechanism in ALD development. Results: Between ALD patients and healthy controls, a total of 416 genes and 21 microRNAs (miRNAs) with significantly differential expression were screened. A comprehensive miRNA-mRNA network was established; within this network, the miR-182-5p/FOXO1 axis was considered a significant pathway in ALD lipid metabolism. Mouse and cell experiments validated that miR-182-5p was substantially higher in ALD than in normal livers, whereas the expression of FOXO1 was dramatically decreased by alcohol consumption (P < 0.05). Next, dual-luciferase reporter assays demonstrated that miR-182-5p directly targets the binding site of the FOXO1 3'UTR and inhibits its mRNA and protein expression. In addition, miR-182-5p was found to promote hepatic lipid accumulation via targeting the FOXO1 signaling pathway, and inhibition of the miR-182-5p/FOXO1 axis improved hepatic triglyceride (TG) deposition in ALD by regulating downstream genes involved in lipid metabolism. Conclusion: In summary, key molecules were identified in ALD development and a comprehensive miRNA-mRNA network was established. Meanwhile, our results suggested that miR-182-5p significantly increases lipid accumulation in ALD by targeting FOXO1, thereby providing novel scientific insights and potential therapeutic targets for ALD.

Dataset Information

MiR-182-5p Is Upregulated in Hepatic Tissues from a Diet-Induced NAFLD/NASH/HCC C57BL/6J Mouse Model and Modulates Cyld and Foxo1 Expression.

Publications

MiR-182-5p Is Upregulated in Hepatic Tissues from a Diet-Induced NAFLD/NASH/HCC C57BL/6J Mouse Model and Modulates Cyld and Foxo1 Expression.

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