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Dietary lipids modulate the expression of miR-107, an miRNA that regulates the circadian system.

ABSTRACT: The increased prevalence of cardiovascular diseases (CVDs) has been hypothesized to be the result of an increased exposure to a host of atherogenic environmental factors, paramount among them being unhealthy dietary habits. Long-chain n-3 polyunsaturated fatty acids have been shown to have cardio protective effects, partially due to their ability to regulate gene expression. In this regard, increasing attention has been devoted to the role of miRNAs as regulators of multiple metabolic pathways whose deregulation has been associated with CVD risk.In this work, we investigated whether miRNA expression was regulated by docosahexanoic acid, conjugated linoleic acid, and cholesterol in Caco-2 cells. The modulated miRNAs, miR-107 was differentially expressed by all treatments and this modulation was independent of its hosting gene, PANK1, possibly through its own promoter, which contains binding sites for metabolically relevant transcription factors. Among the putative target genes of miR-107, we found some genes with key roles in circadian rhythm. Specifically, we demonstrated that binding of miR-107 to the CLOCK gene results in the deregulation of the circadian rhythm of the cells.Since chronodisruption has been linked to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and CVD, our findings suggests that miR-107 could represent a new approach for pharmacological treatment of these diseases.

SUBMITTER: Daimiel-Ruiz L

PROVIDER: S-EPMC4591752 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Dietary lipids modulate the expression of miR-107, an miRNA that regulates the circadian system.

Daimiel-Ruiz Lidia L Klett-Mingo Mercedes M Konstantinidou Valentini V Micó Victor V Aranda Juan F JF García Belén B Martínez-Botas Javier J Dávalos Alberto A Fernández-Hernando Carlos C Ordovás Jose M JM

Molecular nutrition & food research 20150121 3

<h4>Scope</h4>The increased prevalence of cardiovascular diseases (CVDs) has been hypothesized to be the result of an increased exposure to a host of atherogenic environmental factors, paramount among them being unhealthy dietary habits. Long-chain n-3 polyunsaturated fatty acids have been shown to have cardio protective effects, partially due to their ability to regulate gene expression. In this regard, increasing attention has been devoted to the role of miRNAs as regulators of multiple metabo ...[more]

PMID: 25522185

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Project description:UnlabelledHepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBP?, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBP?, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBP?. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA-449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis.ImportanceHepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.

Dataset Information

Dietary lipids modulate the expression of miR-107, an miRNA that regulates the circadian system.

Publications

Dietary lipids modulate the expression of miR-107, an miRNA that regulates the circadian system.

Similar Datasets

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