title: Docosahexaenoic acid modulates the enterocyte Caco-2 cell expression of microRNAs involved in lipid metabolism.
abstract: Consumption of the long-chain ω-3 (n-3) polyunsaturated fatty acid docosahexaenoic acid (DHA) is associated with a reduced risk of cardiovascular disease and greater chemoprevention. However, the mechanisms underlying the biologic effects of DHA remain unknown. It is well known that microRNAs (miRNAs) are versatile regulators of gene expression. Therefore, we aimed to determine if the beneficial effects of DHA may be modulated in part through miRNAs. Loss of dicer 1 ribonuclease type III (DICER) in enterocyte Caco-2 cells supplemented with DHA suggested that several lipid metabolism genes are modulated by miRNAs. Analysis of miRNAs predicted to target these genes revealed several miRNA candidates that are differentially modulated by fatty acids. Among the miRNAs modulated by DHA were miR-192 and miR-30c. Overexpression of either miR-192 or miR-30c in enterocyte and hepatocyte cells suggested an effect on the expression of genes related to lipid metabolism, some of which were confirmed by endogenous inhibition of these miRNAs. Our results show in enterocytes that DHA exerts its biologic effect in part by regulating genes involved in lipid metabolism and cancer. Moreover, this response is mediated through miRNA activity. We validate novel targets of miR-30c and miR-192 related to lipid metabolism and cancer including nuclear receptor corepressor 2, isocitrate dehydrogenase 1, DICER, caveolin 1, ATP-binding cassette subfamily G (white) member 4, retinoic acid receptor β, and others. We also present evidence that in enterocytes DHA modulates the expression of regulatory factor X6 through these miRNAs. Alteration of miRNA levels by dietary components in support of their pharmacologic modulation might be valuable in adjunct therapy for dyslipidemia and other related diseases.
authors.affiliation: Laboratory of Functional Foods, Madrid Institute for Advanced Studies-Food, Madrid, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Gil-Zamorano
authors.forename: Roberto
authors.initials: R
authors.lastname: Martin
authors.forename: Lidia
authors.initials: L
authors.lastname: Daimiel
authors.forename: Kris
authors.initials: K
authors.lastname: Richardson
authors.forename: Elena
authors.initials: E
authors.lastname: Giordano
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nicod
authors.forename: Belén
authors.initials: B
authors.lastname: García-Carrasco
authors.forename: Sara M A
authors.initials: SM
authors.lastname: Soares
authors.forename: Eduardo
authors.initials: E
authors.lastname: Iglesias-Gutiérrez
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lasunción
authors.forename: Aleix
authors.initials: A
authors.lastname: Sala-Vila
authors.forename: Emilio
authors.initials: E
authors.lastname: Ros
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovás
authors.forename: Francesco
authors.initials: F
authors.lastname: Visioli
authors.forename: Alberto
authors.initials: A
authors.lastname: Dávalos
mesh_terms: D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D018938:Caco-2 Cells; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D050171:Dyslipidemias / Q000235:genetics* / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D035683:MicroRNAs / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism
chemical_list: C439766:ABCG4 protein, human; D000070996:ATP Binding Cassette Transporter, Subfamily G; D018528:ATP-Binding Cassette Transporters; D051242:Caveolin 1; D056970:Co-Repressor Proteins; C546783:MIRN192 microRNA, human; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D004281:Docosahexaenoic Acids; D007521:Isocitrate Dehydrogenase; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases