2024
Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring
Sun J, Esplugues E, Bort A, Cardelo M, Ruz-Maldonado I, Fernández-Tussy P, Wong C, Wang H, Ojima I, Kaczocha M, Perry R, Suárez Y, Fernández-Hernando C. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring. Nature Metabolism 2024, 6: 741-763. PMID: 38664583, DOI: 10.1038/s42255-024-01019-6.Peer-Reviewed Original ResearchConceptsFatty acid binding protein 5Tumor-associated macrophagesHepatocellular carcinomaImmunosuppressive phenotype of tumor-associated macrophagesIncreased CD8+ T cell activationCD8+ T cell activationPhenotype of tumor-associated macrophagesPro-inflammatory tumor microenvironmentCo-stimulatory molecules CD80T cell activationHepatocellular carcinoma burdenTransformation of hepatocytesBinding protein 5Potential therapeutic approachImmunosuppressive phenotypeTumor microenvironmentFerroptosis-induced cell deathMale miceEnhanced ferroptosisTherapeutic approachesPharmacological inhibitionGenetic ablationIncreased expressionSingle-cell atlasAnalysis of transformed cells
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 plaquesTargeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression
Zhang X, Rotllan N, Canfrán-Duque A, Sun J, Toczek J, Moshnikova A, Malik S, Price NL, Araldi E, Zhong W, Sadeghi MM, Andreev OA, Bahal R, Reshetnyak YK, Suárez Y, Fernández-Hernando C. Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis Regression. Circulation Research 2022, 131: 77-90. PMID: 35534923, PMCID: PMC9640270, DOI: 10.1161/circresaha.121.320296.Peer-Reviewed Original ResearchConceptsMiR-33Gene expressionNature of miRNAsSingle-cell RNA sequencing analysisSingle-cell RNA transcriptomicsAnti-miRNA technologiesRNA sequencing analysisExpression of miRNAsRNA transcriptomicsNew therapeutic opportunitiesEntire pathwayMiRNA therapeuticsAtherosclerotic plaque macrophagesHuman diseasesMiRNAsSequencing analysisSpecific tissuesMetabolic tissuesTargeted suppressionMiR-33 inhibitionProtective miRNAsNumerous diseasesPharmacological inhibitionLipid accumulationTarget effects
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 SREBP2Deficiency of histone lysine methyltransferase SETDB2 in hematopoietic cells promotes vascular inflammation and accelerates atherosclerosis
Zhang X, Sun J, Canfrán-Duque A, Aryal B, Tellides G, Chang YJ, Suárez Y, Osborne TF, Fernández-Hernando C. Deficiency of histone lysine methyltransferase SETDB2 in hematopoietic cells promotes vascular inflammation and accelerates atherosclerosis. JCI Insight 2021, 6: e147984. PMID: 34003795, PMCID: PMC8262461, DOI: 10.1172/jci.insight.147984.Peer-Reviewed Original ResearchConceptsHematopoietic cellsHistone methylation/acetylationSingle-cell RNA-seq analysisMethylation/acetylationHistone H3 Lys9RNA-seq analysisProgression of atherosclerosisEpigenetic marksLysine methyltransferasesH3 Lys9Epigenetic modificationsDNA methylationNoncoding RNAsCell regulatorsSETDB2Vascular inflammationAtherosclerotic lesionsAtherosclerotic plaquesMyeloid cell recruitmentGenetic deletionLDLR knockout miceEnhanced expressionHepatic lipid metabolismMurine atherosclerotic lesionsGenesKetogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
Ryu S, Shchukina I, Youm YH, Qing H, Hilliard B, Dlugos T, Zhang X, Yasumoto Y, Booth CJ, Fernández-Hernando C, Suárez Y, Khanna K, Horvath TL, Dietrich MO, Artyomov M, Wang A, Dixit VD. Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice. ELife 2021, 10: e66522. PMID: 34151773, PMCID: PMC8245129, DOI: 10.7554/elife.66522.Peer-Reviewed Original ResearchConceptsΓδ T cellsKetogenic dietCoronavirus infectionAged miceT cellsHigher systemic inflammationInfected aged miceCOVID-19 severityCOVID-19 infectionActivation of ketogenesisMouse hepatitis virus strain A59Systemic inflammationInflammatory damageInfluenza infectionClinical hallmarkNLRP3 inflammasomeImmune surveillanceAdipose tissuePotential treatmentInfectionMiceStrongest predictorLungMortalityAgemiR‐33 in cardiometabolic diseases: lessons learned from novel animal models and approaches
Price NL, Goedeke L, Suárez Y, Fernández‐Hernando C. miR‐33 in cardiometabolic diseases: lessons learned from novel animal models and approaches. EMBO Molecular Medicine 2021, 13: emmm202012606. PMID: 33938628, PMCID: PMC8103095, DOI: 10.15252/emmm.202012606.Peer-Reviewed Original ResearchGene Expression Signature in Patients With Symptomatic Peripheral Artery Disease
Newman JD, Cornwell MG, Zhou H, Rockman C, Heguy A, Suarez Y, Cheng HS, Feinberg MW, Hochman JS, Ruggles KV, Berger JS. Gene Expression Signature in Patients With Symptomatic Peripheral Artery Disease. Arteriosclerosis Thrombosis And Vascular Biology 2021, 41: 1521-1533. PMID: 33657880, PMCID: PMC8048111, DOI: 10.1161/atvbaha.120.315857.Peer-Reviewed Original ResearchMicroRNA 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 effects
2020
miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression
Benito-Vicente A, Uribe KB, Rotllan N, Ramírez CM, Jebari-Benslaiman S, Goedeke L, Canfrán-Duque A, Galicia-García U, De Urturi D, Aspichueta P, Suárez Y, Fernández-Hernando C, Martín C. miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression. International Journal Of Molecular Sciences 2020, 21: 8675. PMID: 33212990, PMCID: PMC7698485, DOI: 10.3390/ijms21228675.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin receptor substrate-1Type 2 diabetes mellitusHepatic insulin resistanceInsulin receptorInsulin receptor expressionImplication of microRNAsDiabetes mellitusHeart failureCardiometabolic pathologiesInsulin sensitivityReceptor expressionINSR expressionReceptor substrate-1Human hepatoma cellsHepatic tissueLipid metabolismObesityInsulinHigh expressionMiR-27Hepatoma cellsSubstrate-1Novel roleLiverANGPTL4: a multifunctional protein involved in metabolism and vascular homeostasis.
Fernández-Hernando C, Suárez Y. ANGPTL4: a multifunctional protein involved in metabolism and vascular homeostasis. Current Opinion In Hematology 2020, 27: 206-213. PMID: 32205586, PMCID: PMC9013473, DOI: 10.1097/moh.0000000000000580.Peer-Reviewed Original ResearchConceptsStem cell regulationPotential therapeutic targetLipid metabolismCell-specific functionsSpecific molecular eventsNonmetabolic functionsRegulatory circuitsMultifunctional proteinTherapeutic targetUnanticipated roleInvolvement of ANGPTL4Molecular eventsCell regulationPhysiological roleTherapeutic applicationsPredominant expressionVascular biologyPotential therapeutic applicationsVascular homeostasisPathophysiological conditionsDifferent disease settingsANGPTL4MetabolismFirst discoveryBiological effectsCav-1 (Caveolin-1) Deficiency Increases Autophagy in the Endothelium and Attenuates Vascular Inflammation and Atherosclerosis
Zhang X, Ramírez CM, Aryal B, Madrigal-Matute J, Liu X, Diaz A, Torrecilla-Parra M, Suárez Y, Cuervo AM, Sessa WC, Fernández-Hernando C. Cav-1 (Caveolin-1) Deficiency Increases Autophagy in the Endothelium and Attenuates Vascular Inflammation and Atherosclerosis. Arteriosclerosis Thrombosis And Vascular Biology 2020, 40: 1510-1522. PMID: 32349535, PMCID: PMC7253189, DOI: 10.1161/atvbaha.120.314291.Peer-Reviewed Original ResearchConceptsCav-1 deficiencyCav-1-deficient miceCav-1Autophagic fluxCholesterol-rich membrane domainsCav-1 interactsATG5-ATG12 complexEndothelial Cav-1 expressionRegulation of autophagyNovel molecular mechanismExtracellular matrix remodelingAutophagosome componentsMembrane domainsLipid raftsAutophagosome formationPlasma membraneCav-1 expressionMolecular mechanismsLDL transcytosisCellular localizationImportant regulatorAutophagyAutophagy contributesRelevant regulatorMatrix remodeling
2019
ANGPTL4 in Metabolic and Cardiovascular Disease
Aryal B, Price NL, Suarez Y, Fernández-Hernando C. ANGPTL4 in Metabolic and Cardiovascular Disease. Trends In Molecular Medicine 2019, 25: 723-734. PMID: 31235370, PMCID: PMC6779329, DOI: 10.1016/j.molmed.2019.05.010.Peer-Reviewed Original ResearchConceptsCardiovascular diseaseLipoprotein lipaseRisk of atherosclerosisRole of ANGPTL4Type 2 diabetesLow-density lipoproteinFatty acidsMurine studiesPeripheral tissuesRich lipoproteinsLPL activityANGPTL4 functionsDensity lipoproteinMetabolic diseasesPossible autocrineParacrine formsDiseaseANGPTL4Disease developmentLipoproteinRecent findingsRiskTissueDifferent tissuesAtherosclerosisCaveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation
Ramírez CM, Zhang X, Bandyopadhyay C, Rotllan N, Sugiyama MG, Aryal B, Liu X, He S, Kraehling JR, Ulrich V, Lin CS, Velazquez H, Lasunción MA, Li G, Suárez Y, Tellides G, Swirski FK, Lee WL, Schwartz MA, Sessa WC, Fernández-Hernando C. Caveolin-1 Regulates Atherogenesis by Attenuating Low-Density Lipoprotein Transcytosis and Vascular Inflammation Independently of Endothelial Nitric Oxide Synthase Activation. Circulation 2019, 140: 225-239. PMID: 31154825, PMCID: PMC6778687, DOI: 10.1161/circulationaha.118.038571.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseDiet-induced atherosclerosisNO productionVascular inflammationENOS activationEndothelial nitric oxide synthase activationNitric oxide synthase activationAthero-protective functionsLipid metabolic factorsEndothelial cell inflammationNitric oxide synthaseWild-type miceMice Lacking ExpressionProduction of NOExtracellular matrix remodelingInflammatory primingHyperlipidemic miceInflammatory pathwaysAortic archCell inflammationOxide synthaseMetabolic factorsMouse modelAtherosclerosisInflammation
2018
Inhibition of profibrotic microRNA-21 affects platelets and their releasate
Barwari T, Eminaga S, Mayr U, Lu R, Armstrong PC, Chan MV, Sahraei M, Fernández-Fuertes M, Moreau T, Barallobre-Barreiro J, Lynch M, Yin X, Schulte C, Baig F, Pechlaner R, Langley SR, Zampetaki A, Santer P, Weger M, Plasenzotti R, Schosserer M, Grillari J, Kiechl S, Willeit J, Shah AM, Ghevaert C, Warner TD, Fernández-Hernando C, Suárez Y, Mayr M. Inhibition of profibrotic microRNA-21 affects platelets and their releasate. JCI Insight 2018, 3: e123335. PMID: 30385722, PMCID: PMC6238735, DOI: 10.1172/jci.insight.123335.Peer-Reviewed Original ResearchConceptsMiR-21 inhibitionMiR-21TGF-β1TGF-β1 secretionMiR-21 levelsMiR-21 mimicsMiR-21 inhibitorMurine cardiac fibroblastsBruneck StudyLow plateletsAntifibrotic effectsProfibrotic factorsLeukocyte countSpecific therapyClinical trialsOrgan diseaseTGF-β1 releaseLittermate controlsBone marrowCardiac fibroblastsMegakaryocyte numberMouse heartsFibrosisPlasma samplesPlatelet releaseMicroRNAs in endothelial cell homeostasis and vascular disease
Fernández-Hernando C, Suárez Y. MicroRNAs in endothelial cell homeostasis and vascular disease. Current Opinion In Hematology 2018, 25: 227-236. PMID: 29547400, PMCID: PMC6175704, DOI: 10.1097/moh.0000000000000424.Peer-Reviewed Original ResearchConceptsVascular diseaseVascular disease preventionPotential therapeutic targetEndothelial cell homeostasisEndothelial cell functionEndothelial dysfunctionEndothelial functionVascular dysfunctionTherapeutic applicationsPotential therapeutic applicationsInvolvement of miRNAsDysregulation of miRNAsEndothelial homeostasisTherapeutic targetDisease preventionDiseaseCell functionRegulatory circuitsCritical modulatorUnanticipated roleTarget genesCell homeostasisDysfunctionMiRNAsHomeostasisNon-coding RNA regulation of endothelial and macrophage functions during atherosclerosis
Aryal B, Suárez Y. Non-coding RNA regulation of endothelial and macrophage functions during atherosclerosis. Vascular Pharmacology 2018, 114: 64-75. PMID: 29551552, PMCID: PMC6177333, DOI: 10.1016/j.vph.2018.03.001.Peer-Reviewed Original ResearchConceptsNon-coding RNAsNon-coding RNA regulationSmall non-coding RNAsMultiple cell functionsRNA regulationMacrophage functionRNA moleculesGene expressionPotential regulatorKey playersVascular biologyPathogenesis of atherosclerosisCell functionSpecific roleLncRNAsRegulationRNAMechanism of actionEndothelial cellsInitial eventVascular integrityRecruitment of monocytesMicroRNAsDevelopment of atherosclerosisBiology
2017
Posttranscriptional regulation of lipid metabolism by non-coding RNAs and RNA binding proteins
Singh AK, Aryal B, Zhang X, Fan Y, Price NL, Suárez Y, Fernández-Hernando C. Posttranscriptional regulation of lipid metabolism by non-coding RNAs and RNA binding proteins. Seminars In Cell And Developmental Biology 2017, 81: 129-140. PMID: 29183708, PMCID: PMC5975105, DOI: 10.1016/j.semcdb.2017.11.026.Peer-Reviewed Original ResearchConceptsLipid metabolismNon-coding RNAImportance of microRNAsNumber of miRNAsRole of lncRNAsLipid-related genesTranscriptional regulationCoding RNAsPosttranscriptional regulationPosttranscriptional levelMiRNA expressionHigh abundanceLncRNAsRNACholesterol homeostasisMiR-33MiR-148aSpecific roleMiRNAsRegulationLipoprotein metabolismRecent findingsMetabolismProteinExpressionMacrophage deficiency of miR‐21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis
Canfrán‐Duque A, Rotllan N, Zhang X, Fernández‐Fuertes M, Ramírez‐Hidalgo C, Araldi E, Daimiel L, Busto R, Fernández‐Hernando C, Suárez Y. Macrophage deficiency of miR‐21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Molecular Medicine 2017, 9: 1244-1262. PMID: 28674080, PMCID: PMC5582411, DOI: 10.15252/emmm.201607492.Peer-Reviewed Original ResearchConceptsER stress-induced apoptosisPost-translational degradationFoam cell formationMiR-21MiR-21 target genesTarget genesJNK signalingPlaque necrosisAbundant miRNAVascular inflammationAccumulation of lipidsHematopoietic cellsMacrophage apoptosisCell formationAberrant expressionMacrophage deficiencyApoptosisCholesterol effluxProgression of atherosclerosisChronic inflammatory diseasePathophysiological processesInflammatory cellsExpressionInflammatory diseasesCardiovascular disease