title: Hepatitis C virus mediated changes in miRNA-449a modulates inflammatory biomarker YKL40 through components of the NOTCH signaling pathway.
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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Nayan J
authors.initials: NJ
authors.lastname: Sarma
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: Vijay
authors.initials: V
authors.lastname: Subramanian
authors.forename: Surendra
authors.initials: S
authors.lastname: Shenoy
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Crippin
authors.forename: William C
authors.initials: WC
authors.lastname: Chapman
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D000071451:Chitinase-3-Like Protein 1; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000150:complications / Q000235:genetics / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics*; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D054392:Adipokines; D015415:Biomarkers; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D014409:Tumor Necrosis Factor-alpha