title: Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: a new mechanism of the action of polyphenols.
abstract: BACKGROUND
  Polyphenols are the most abundant antioxidants in the human diet and are widespread constituents of fruits and beverages, such as tea, coffee or wine. Epidemiological, clinical and animal studies support a role of polyphenols in the prevention of various diseases, such as cardiovascular diseases, cancers or neurodegenerative diseases. Recent findings suggest that polyphenols could interact with cellular signaling cascades regulating the activity of transcription factors and consequently affecting the expression of genes. However, the impact of polyphenol on the expression of microRNA, small non-coding RNAs, has not yet been studied. The aim of this study was to investigate the impact of dietary supplementation with polyphenols at nutritional doses on miRNA expression in the livers of apolipoprotein E-deficient mice (apoE⁻/⁻) jointly with mRNA expression profiling.
  
  
  RESULTS
  Using microarrays, we measured the global miRNA expression in the livers of wild-type (C57B6/J) mice or apoE⁻/⁻ mice fed diets supplemented with one of nine different polyphenols or a control diet. This analysis revealed that knock-out of the apoE gene induced significant modulation in the expression of miRNA. Moreover, changes in miRNA expression were observed after polyphenol supplementation, and five miRNAs (mmu-miR-291b-5p, mmu-miR-296-5p, mmu-miR-30c-1*, mmu-miR-467b* and mmu-miR-374*) were identified as being commonly modulated by these polyphenols. We also observed that these polyphenols counteracted the modulation of miRNA expression induced by apoE mutation. Pathway analyses on these five miRNA-target genes revealed common pathways, some of which were also identified from a pathway analysis on mRNA profiles.
  
  
  CONCLUSIONS
  This in vivo study demonstrated for the first time that polyphenols at nutritional doses modulate the expression of miRNA in the liver. Even if structurally different, all polyphenols induced a similar miRNA expression profile. Common pathways were identified from both miRNA-target and mRNA analysis, revealing cellular functions that could be regulated by polyphenols at both the miRNA and mRNA level.
authors.affiliation: INRA, UMR1019, UNH, CRNH Auvergne, Clermont-Ferrand, Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, Clermont-Ferrand, France. dragan.milenkovic@clermont.inra.fr
authors.forename: Dragan
authors.initials: D
authors.lastname: Milenkovic
authors.forename: Christiane
authors.initials: C
authors.lastname: Deval
authors.forename: Erwan
authors.initials: E
authors.lastname: Gouranton
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Landrier
authors.forename: Augustin
authors.initials: A
authors.lastname: Scalbert
authors.forename: Christine
authors.initials: C
authors.lastname: Morand
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mazur
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D016000:Cluster Analysis; D004032:Diet; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D059808:Polyphenols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D035683:MicroRNAs; D059808:Polyphenols; D012333:RNA, Messenger