Abstract
Liver disease due to hepatitis C virus (HCV) infection is an important health problem worldwide. HCV induced changes in microRNAs (miRNA) are shown to mediate inflammation leading to liver fibrosis. Gene expression analyses identified dysregulation of miRNA-449a in HCV patients but not in alcoholic and non-alcoholic liver diseases. By sequence analysis of the promoter for YKL40, an inflammatory marker upregulated in patients with chronic liver diseases with fibrosis, adjacent binding sites for nuclear factor of Kappa B/P65 and CCAAT/enhancer-binding protein alpha (CEBPα) were identified. P65 interacted with CEBPα to co-operatively activate YKL40 expression through sequence specific DNA binding. In vitro analysis demonstrated that tumor necrosis factor alpha (TNFα) mediated YKL40 expression is regulated by miRNA-449a and its target NOTCH1 in human hepatocytes.NOTCH1 facilitated nuclear localization of P65 in response to TNFα. Further, HCV patients demonstrated upregulation of NOTCH1 along with downregulation of miRNA-449a. Taken together it is demonstrated that miRNA-449a plays an important role in modulating expression of YKL40 through targeting the components of the NOTCH signaling pathway following HCV infection. Therefore, defining transcriptional regulatory mechanisms which control inflammatory responses and fibrosis will be important towards developing strategies to prevent hepatic fibrosis especially following HCV recurrence in liver transplant recipients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipokines / genetics
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Adipokines / metabolism*
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Adult
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Base Sequence
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Biomarkers / metabolism
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CCAAT-Enhancer-Binding Proteins / metabolism
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Chitinase-3-Like Protein 1
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Female
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Hepacivirus / physiology*
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Hepatitis C / complications
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Hepatitis C / genetics
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Hepatitis C / virology
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Inflammation / complications
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Inflammation / genetics*
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Lectins / genetics
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Lectins / metabolism*
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Liver Cirrhosis / complications
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Liver Cirrhosis / genetics
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Liver Cirrhosis / pathology
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Male
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Middle Aged
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Models, Biological
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Molecular Sequence Data
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Mutation / genetics
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NF-kappa B / metabolism
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Promoter Regions, Genetic / genetics
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Receptor, Notch1 / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics*
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Transcription, Genetic / drug effects
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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Adipokines
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Biomarkers
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, human
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CHI3L1 protein, human
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Chitinase-3-Like Protein 1
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Lectins
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MIRN449 microRNA, human
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MicroRNAs
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NF-kappa B
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NOTCH1 protein, human
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Receptor, Notch1
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Tumor Necrosis Factor-alpha
Grants and funding
This work was supported by the Barnes-Jewish Foundation at Barnes-Jewish Hospital, St. Louis, MO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.