2022
Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling
Canfrán-Duque A, Rotllan N, Zhang X, Andrés-Blasco I, Thompson B, Sun J, Price N, Fernández-Fuertes M, Fowler J, Gómez-Coronado D, Sessa W, Giannarelli C, Schneider R, Tellides G, McDonald J, Fernández-Hernando C, Suárez Y. Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling. Circulation 2022, 147: 388-408. PMID: 36416142, PMCID: PMC9892282, DOI: 10.1161/circulationaha.122.059062.Peer-Reviewed Original ResearchConceptsLipid-loaded macrophagesLineage-tracing mouse modelsSREBP transcriptional activityCholesterol biosynthetic intermediatesWestern diet feedingAccessible cholesterolDifferent macrophage populationsTranscriptomic analysisKey immune regulatorsPlasma membraneAtherosclerosis progressionImmune activationTranscriptional activityGene expressionDiet feedingInflammatory responseMouse bone marrowLiver X receptorBiosynthetic intermediatesSterol metabolismApoptosis susceptibilityToll-like receptor 4Proinflammatory gene expressionHuman coronary atherosclerotic lesionsMouse atherosclerotic plaques
2021
Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis
Zhang X, McDonald JG, Aryal B, Canfrán-Duque A, Goldberg EL, Araldi E, Ding W, Fan Y, Thompson BM, Singh AK, Li Q, Tellides G, Ordovás-Montanes J, García Milian R, Dixit VD, Ikonen E, Suárez Y, Fernández-Hernando C. Desmosterol suppresses macrophage inflammasome activation and protects against vascular inflammation and atherosclerosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2107682118. PMID: 34782454, PMCID: PMC8617522, DOI: 10.1073/pnas.2107682118.Peer-Reviewed Original ResearchConceptsCholesterol biosynthetic intermediatesBiosynthetic intermediatesDependent inflammasome activationSingle-cell transcriptomicsMitochondrial reactive oxygen species productionFoam cell formationMacrophage foam cellsReactive oxygen species productionHuman coronary artery lesionsConversion of desmosterolTranscriptomic analysisMacrophage cholesterol metabolismPhysiological contextOxygen species productionLiver X receptor ligandsApoptosis-associated speck-like proteinRetinoid X receptor activationX receptor ligandsInflammasome activationAtherosclerotic plaquesSpeck-like proteinCholesterol homeostasisMacrophage inflammasome activationKey moleculesCell formationMMAB promotes negative feedback control of cholesterol homeostasis
Goedeke L, Canfrán-Duque A, Rotllan N, Chaube B, Thompson BM, Lee RG, Cline GW, McDonald JG, Shulman GI, Lasunción MA, Suárez Y, Fernández-Hernando C. MMAB promotes negative feedback control of cholesterol homeostasis. Nature Communications 2021, 12: 6448. PMID: 34750386, PMCID: PMC8575900, DOI: 10.1038/s41467-021-26787-7.Peer-Reviewed Original ResearchMeSH KeywordsAlkyl and Aryl TransferasesAnimalsCell Line, TumorCholesterolCholesterol, LDLFeedback, PhysiologicalGene Expression ProfilingHeLa CellsHep G2 CellsHomeostasisHumansHydroxymethylglutaryl CoA ReductasesLiverMice, Inbred C57BLMice, KnockoutPromoter Regions, GeneticReceptors, LDLRNA InterferenceSterol Regulatory Element Binding Protein 2ConceptsCholesterol biosynthesisCholesterol homeostasisMouse hepatic cell lineIntegrative genomic strategyIntricate regulatory networkMaster transcriptional regulatorCellular cholesterol levelsHMGCR activityLDL-cholesterol uptakeCholesterol levelsHuman hepatic cellsSterol contentGenomic strategiesTranscriptional regulatorsRegulatory networksIntracellular cholesterol levelsGene expressionUnexpected roleHepatic cell linesBiosynthesisMMABIntracellular levelsCell linesHomeostasisExpression of SREBP2MicroRNA regulation of cholesterol metabolism
Citrin KM, Fernández‐Hernando C, Suárez Y. MicroRNA regulation of cholesterol metabolism. Annals Of The New York Academy Of Sciences 2021, 1495: 55-77. PMID: 33521946, PMCID: PMC8938903, DOI: 10.1111/nyas.14566.Peer-Reviewed Original ResearchConceptsDifferent cell typesCell typesMultiple mRNA targetsCholesterol homeostasisSmall noncoding RNAsMicroRNA activityCholesterol-laden cellsMicroRNA regulationCholesterol metabolismMRNA targetsNoncoding RNAsPosttranscriptional levelGene expressionSpecialized functionsMicroRNAsCurrent knowledgeTarget interactionsHomeostasisMetabolismPathwayExpressionMultiple stagesRNARegulationDistinctive effectsLoss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis
Price NL, Zhang X, Fernández-Tussy P, Singh AK, Burnap SA, Rotllan N, Goedeke L, Sun J, Canfrán-Duque A, Aryal B, Mayr M, Suárez Y, Fernández-Hernando C. Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2006478118. PMID: 33495342, PMCID: PMC7865172, DOI: 10.1073/pnas.2006478118.Peer-Reviewed Original ResearchConceptsMiR-33 deficiencyHDL-C levelsMiR-33Body weightAtherosclerotic plaque sizeAtherosclerotic plaque burdenDevelopment of fibrosisCholesterol transport capacityCholesterol transporter ABCA1High-density lipoprotein biogenesisSREBP2 transcription factorKnockout mouse modelConditional knockout mouse modelPlaque burdenCardiometabolic diseasesChow dietLiver functionMetabolic dysfunctionHDL metabolismHyperlipidemic conditionsMouse modelGlucose homeostasisCholesterol effluxLipid metabolismObesity
2019
Specific Disruption of Abca1 Targeting Largely Mimics the Effects of miR-33 Knockout on Macrophage Cholesterol Efflux and Atherosclerotic Plaque Development
Price NL, Rotllan N, Zhang X, Canfrán-Duque A, Nottoli T, Suarez Y, Fernández-Hernando C. Specific Disruption of Abca1 Targeting Largely Mimics the Effects of miR-33 Knockout on Macrophage Cholesterol Efflux and Atherosclerotic Plaque Development. Circulation Research 2019, 124: 874-880. PMID: 30707082, PMCID: PMC6417928, DOI: 10.1161/circresaha.118.314415.Peer-Reviewed Original ResearchConceptsMacrophage cholesterol effluxAtherosclerotic plaque formationCholesterol effluxMiR-33Proatherogenic effectsABCA1 expressionBone marrowDeficient animalsPlaque formationMiR-33-deficient miceHigh-fat diet feedingHepatic ABCA1 expressionAtherosclerotic plaque burdenFat diet feedingDevelopment of obesityNovel mouse modelAtherosclerotic plaque developmentFoam cell formationPlaque burdenDeficient miceDiet feedingMetabolic dysfunctionSpecific disruptionMouse modelKnockout mice
2017
Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis
Price NL, Rotllan N, Canfrán-Duque A, Zhang X, Pati P, Arias N, Moen J, Mayr M, Ford DA, Baldán Á, Suárez Y, Fernández-Hernando C. Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis. Cell Reports 2017, 21: 1317-1330. PMID: 29091769, PMCID: PMC5687841, DOI: 10.1016/j.celrep.2017.10.023.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAtherosclerosisATP Binding Cassette Transporter 1Blood GlucoseCells, CulturedCholesterolCholesterol, HDLDisease ProgressionGene Regulatory NetworksMacrophages, PeritonealMaleMiceMice, Inbred C57BLMice, KnockoutMicroRNAsMitochondrial Trifunctional Protein, beta SubunitMyocardiumReceptors, LDLConceptsPlaque burdenMiR-33MiR-33-deficient miceReduced plaque burdenProgression of atherosclerosisPro-atherogenic effectsMacrophage cholesterol effluxDecreases lipid accumulationTreatment of atherosclerosisMacrophage-specific lossMiR-33 deficiencyPromotes obesityHDL levelsInsulin resistancePlaque macrophagesProtective effectHyperlipidemic conditionsCholesterol effluxPlaque developmentLipid metabolismAtherosclerosisLipid accumulationHDL biogenesisPromising targetMacrophages
2015
Endothelial Glucocorticoid Receptor Suppresses Atherogenesis—Brief Report
Goodwin JE, Zhang X, Rotllan N, Feng Y, Zhou H, Fernández-Hernando C, Yu J, Sessa WC. Endothelial Glucocorticoid Receptor Suppresses Atherogenesis—Brief Report. Arteriosclerosis Thrombosis And Vascular Biology 2015, 35: 779-782. PMID: 25810297, PMCID: PMC4375730, DOI: 10.1161/atvbaha.114.304525.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaAortic DiseasesApolipoproteins EAtherosclerosisBody WeightBrachiocephalic TrunkCholesterolDiet, High-FatDisease Models, AnimalEndothelial CellsGenotypeMacrophagesMice, Inbred C57BLMice, KnockoutPhenotypeReceptors, GlucocorticoidSeverity of Illness IndexTime FactorsTriglyceridesConceptsEndothelial glucocorticoid receptorGlucocorticoid receptorHigh-fat diet feedingApoE knockout backgroundSevere atherosclerotic lesionsGroups of micePathogenesis of atherosclerosisAortic sinusTotal cholesterolAtherosclerosis progressionBrachiocephalic arteryControl miceInflammatory milieuTonic inhibitionDiet feedingMacrophage recruitmentAtherosclerotic lesionsBody weightMiceKnockout backgroundReceptorsLesionsAtherosclerosisInflammationArteryDietary lipids modulate the expression of miR‐107, an miRNA that regulates the circadian system
Daimiel‐Ruiz L, Klett‐Mingo M, Konstantinidou V, Micó V, Aranda JF, García B, Martínez‐Botas J, Dávalos A, Fernández‐Hernando C, Ordovás JM. Dietary lipids modulate the expression of miR‐107, an miRNA that regulates the circadian system. Molecular Nutrition & Food Research 2015, 59: 552-565. PMID: 25522185, PMCID: PMC4591752, DOI: 10.1002/mnfr.201400616.Peer-Reviewed Original ResearchConceptsCardiovascular diseaseMiR-107Cardio-protective effectsType 2 diabetesUnhealthy dietary habitsCircadian rhythmCaco-2 cellsCVD riskConjugated linoleic acidPharmacological treatmentProtective effectDietary habitsMetabolic disordersDietary lipidsPutative target genesDocosahexanoic acidRelevant transcription factorsMultiple metabolic pathwaysRole of miRNAsOwn promoterTranscription factorsTarget genesDiseaseGene resultsGene expression
2014
Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis
Rodlan N, Chamorro‐Jorganes A, Araldi E, Wanschel AC, Aryal B, Aranda JF, Goedeke L, Salerno AG, Ramírez CM, Sessa WC, Suárez Y, Fernández‐Hernando C. Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis. The FASEB Journal 2014, 29: 597-610. PMID: 25392271, PMCID: PMC4314230, DOI: 10.1096/fj.14-262097.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisBlood GlucoseBone Marrow CellsBone Marrow TransplantationCell MovementCholesterolCytokinesDisease ProgressionInflammationInsulinLeukocytesLipidsLipoproteins, LDLMacrophagesMaleMiceMice, Inbred C57BLMice, KnockoutMicroscopy, ConfocalMicroscopy, FluorescencePlaque, AtheroscleroticProto-Oncogene Proteins c-aktReceptors, LDLConceptsProgression of atherosclerosisSerine-threonine protein kinaseBone marrow cellsAkt2-deficient miceInsulin-responsive tissuesWild-type bone marrow cellsProtein kinaseMarrow cellsAkt2 deficiencyAkt2Higher plasma lipidsWild-type miceMice resultsProatherogenic cytokinesObese subjectsPlasma lipidsProinflammatory cytokinesInsulin resistanceInflammatory responseGlucose levelsAtherosclerotic plaquesCholesterol metabolismAtherosclerosisMacrophage migrationMarked reduction
2013
Curcumin promotes exosomes/microvesicles secretion that attenuates lysosomal cholesterol traffic impairment
Canfrán‐Duque A, Pastor Ó, Quintana‐Portillo R, Lerma M, de la Peña G, Martín‐Hidalgo A, Fernández‐Hernando C, Lasunción MA, Busto R. Curcumin promotes exosomes/microvesicles secretion that attenuates lysosomal cholesterol traffic impairment. Molecular Nutrition & Food Research 2013, 58: 687-697. PMID: 24288129, DOI: 10.1002/mnfr.201300350.Peer-Reviewed Original ResearchConceptsExosomes/microvesiclesMicrovesicle secretionEndosomes/lysosomesEndolysosomal originFlotillin-2Release of cholesterolTHP-1 differentiated macrophagesMultivesicular bodiesDifferent cell linesExosome markersSmall vesiclesTrafficking impairmentDifferentiated macrophagesTraffic impairmentCholesterol cell contentLysosomal storage diseaseCell linesEffect of curcuminCholesterol accumulationMicrovesiclesSecretion fluidVesiclesCellsCD63Cell content
2012
MicroRNAs regulating lipid metabolism in atherogenesis
Rayner K, Fernandez-Hernando C, Moore K. MicroRNAs regulating lipid metabolism in atherogenesis. Thrombosis And Haemostasis 2012, 107: 642-647. PMID: 22274626, PMCID: PMC3618663, DOI: 10.1160/th11-10-0694.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAtherosclerosisATP Binding Cassette Transporter 1ATP-Binding Cassette TransportersCholesterolDisease Models, AnimalFatty AcidsGene Expression RegulationHumansLipid MetabolismLipoproteins, HDLLipoproteins, VLDLLiverMiceMicroRNAsModels, BiologicalSterol Regulatory Element Binding Protein 1Sterol Regulatory Element Binding Protein 2TriglyceridesConceptsSmall non-coding RNAsImportant post-transcriptional regulatorsCellular sterol levelsPost-transcriptional regulatorsNon-coding RNAsVariety of genesSterol response elementFatty acid homeostasisIntronic microRNAsLipid metabolismFatty acid synthesisHost genesTranscription factorsProtein geneCholesterol exportMetabolic programsKey regulatorFatty acid oxidationResponse elementHigh-density lipoproteinMicroRNAsRelated metabolic diseasesGenesABCA1 pathwayAcid homeostasis
2011
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling
Dávalos A, Goedeke L, Smibert P, Ramírez CM, Warrier NP, Andreo U, Cirera-Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, Esplugues E, Fisher EA, Penalva LO, Moore KJ, Suárez Y, Lai EC, Fernández-Hernando C. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 9232-9237. PMID: 21576456, PMCID: PMC3107310, DOI: 10.1073/pnas.1102281108.Peer-Reviewed Original ResearchConceptsFatty acid metabolismFatty acid oxidationMiR-33aInsulin receptor substrate 2Sirtuin 6Acid metabolismInsulin-signaling pathwayIntronic microRNAsSterol regulatory element-binding protein 2Acid oxidationHost genesKey enzymeHepatic cell linesMetabolic syndromeCarnitine palmitoyltransferase 1AMetabolic pathwaysSubstrate 2Cellular imbalanceProtein 2Cholesterol homeostasisGenesCell linesLevels of HDLPathwayMetabolism results
2010
MiR-33 Contributes to the Regulation of Cholesterol Homeostasis
Rayner KJ, Suárez Y, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, Fernández-Hernando C. MiR-33 Contributes to the Regulation of Cholesterol Homeostasis. Science 2010, 328: 1570-1573. PMID: 20466885, PMCID: PMC3114628, DOI: 10.1126/science.1189862.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApolipoprotein A-IATP Binding Cassette Transporter 1ATP Binding Cassette Transporter, Subfamily G, Member 1ATP-Binding Cassette TransportersCarrier ProteinsCell LineCholesterolCholesterol, DietaryDietary FatsGene Expression RegulationHomeostasisHumansHypercholesterolemiaIntracellular Signaling Peptides and ProteinsIntronsLipoproteinsLipoproteins, HDLLiverMacrophagesMacrophages, PeritonealMembrane GlycoproteinsMiceMice, Inbred C57BLMicroRNAsNiemann-Pick C1 ProteinProteinsSterol Regulatory Element Binding Protein 2TransfectionConceptsSterol regulatory element-binding factor-2MiR-33Cellular cholesterol transportCholesterol effluxExpression of genesIntronic microRNAsTranscriptional regulatorsTriphosphate-binding cassette transportersAdenosine triphosphate-binding cassette transportersCellular cholesterol effluxCassette transportersHDL biogenesisHuman cellsCellular levelCholesterol homeostasisABCA1 expressionFactor 2Mouse macrophagesGenesLentiviral deliveryCholesterol transportExpressionABCA1Cholesterol metabolismEffluxHaloperidol disrupts lipid rafts and impairs insulin signaling in SH-SY5Y cells
Sánchez-Wandelmer J, Dávalos A, de la Peña G, Cano S, Giera M, Canfrán-Duque A, Bracher F, Martín-Hidalgo A, Fernández-Hernando C, Lasunción M, Busto R. Haloperidol disrupts lipid rafts and impairs insulin signaling in SH-SY5Y cells. Neuroscience 2010, 167: 143-153. PMID: 20123000, DOI: 10.1016/j.neuroscience.2010.01.051.Peer-Reviewed Original ResearchConceptsEffects of haloperidolCholesterol contentLipid raft compositionCholesterol biosynthesisCell cholesterol contentSH-SY5Y cellsNeuroblastoma SH-SY5YHL-60 human cell linesDopamine receptorsMetabolic effectsTherapeutic effectHaloperidolInsulin-Akt signalingImpairs insulinCellular cholesterol homeostasisLipid raftsSH-SY5YFree cholesterolCholesterol homeostasisDependent insulinDrug inhibitionHuman cell linesCell linesPhysiological vehicleInsulin