Journal Article

Hepatitis C Virus Mediated Changes in miRNA-449a Modulates Inflammatory Biomarker YKL40 through Components of the NOTCH Signaling Pathway

Mohanakumar, Thalachallour, Chapman, William C., Sarma, Nayan J., Crippin, Jeffrey S., Subramanian, Vijay, Shenoy, Surendra, Tiriveedhi, Venkataswarup

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipokines - genetics / Adipokines - metabolism / Adult / Analysis / Base Sequence / Binding sites / Bioindicators / Biology / Biomarkers / Biomarkers - metabolism / Biopsy / CCAAT-Enhancer-Binding Proteins - metabolism / CCAAT/enhancer-binding protein / Cell cycle / Cell growth / Chitinase-3-Like Protein 1 / Cytokines / Deoxyribonucleic acid / DNA / Down-Regulation - drug effects / Down-Regulation - genetics / Female / Fibrosis / Gene expression / Health aspects / Hepacivirus - physiology / Hepatitis / Hepatitis C / Hepatitis C - complications / Hepatitis C - genetics / Hepatitis C - virology / Hepatitis C virus / Hepatocytes / Hepatocytes - drug effects / Hepatocytes - metabolism / Hepatology / Humans / Infection / Infections / Inflammation / Inflammation - complications / Inflammation - genetics / Lectins - genetics / Lectins - metabolism / Liver / Liver cancer / Liver cirrhosis / Liver Cirrhosis - complications / Liver Cirrhosis - genetics / Liver Cirrhosis - pathology / Liver diseases / Liver transplantation / Liver transplants / Localization / Male / Medicine / MicroRNA / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / miRNA / Models, Biological / Molecular Sequence Data / Mutation - genetics / NF-kappa B - metabolism / Notch protein / Notch1 protein / Nucleotide sequence / Organ transplant recipients / Organ transplantation / Patients / Promoter Regions, Genetic - genetics / Prostate cancer / Protein binding / Receptor, Notch1 - metabolism / Regulatory mechanisms (biology) / Ribonucleic acid / RNA / Rodents / Signal transduction / Signal Transduction - drug effects / Signal Transduction - genetics / Signaling / Surgery / Transcription / Transcription factors / Transcription, Genetic - drug effects / Transplants & implants / Tumor Necrosis Factor-alpha - metabolism / Tumor Necrosis Factor-alpha - pharmacology / Tumor necrosis factor-α / Up-Regulation - drug effects / Up-Regulation - genetics / Viral infections / Viruses