2024
Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice
Boutagy N, Gamez-Mendez A, Fowler J, Zhang H, Chaube B, Esplugues E, Kuo A, Lee S, Horikami D, Zhang J, Citrin K, Singh A, Coon B, Lee M, Suarez Y, Fernandez-Hernando C, Sessa W. Dynamic metabolism of endothelial triglycerides protects against atherosclerosis in mice. Journal Of Clinical Investigation 2024, 134: e170453. PMID: 38175710, PMCID: PMC10866653, DOI: 10.1172/jci170453.Peer-Reviewed Original ResearchIntracellular endothelial cell metabolism in vascular function and dysfunction
Citrin K, Chaube B, Fernández-Hernando C, Suárez Y. Intracellular endothelial cell metabolism in vascular function and dysfunction. Trends In Endocrinology And Metabolism 2024 PMID: 39672762, DOI: 10.1016/j.tem.2024.11.004.Peer-Reviewed Original ResearchFatty acid oxidationEndothelial cellsIntracellular metabolic pathwaysInner lining of blood vesselsVascular functionCell metabolismMetabolic pathwaysEndothelial cell metabolismLipid handlingDesign new therapiesRegulate vascular toneInfluence disease progressionAcid oxidationMetabolic signaturesVascular toneNew therapiesLining of blood vesselsDisease progressionLeukocyte adhesionMetabolic changesVascular diseaseOxidative stressBlood vesselsIncreased permeabilityWound healingmiR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression
Fernández-Tussy P, Cardelo M, Zhang H, Sun J, Price N, Boutagy N, Goedeke L, Cadena-Sandoval M, Xirouchaki C, Brown W, Yang X, Pastor-Rojo O, Haeusler R, Bennett A, Tiganis T, Suárez Y, Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression. JCI Insight 2024, 9: e168476. PMID: 39190492, PMCID: PMC11466198, DOI: 10.1172/jci.insight.168476.Peer-Reviewed Original ResearchMiR-33Regulation of biological processesMitochondrial fatty acid oxidationRegulation of lipid metabolismNon-alcoholic fatty liver diseaseDevelopment of effective therapeuticsFatty acid oxidationLipid synthesisProgression of non-alcoholic fatty liver diseaseMitochondrial functionTarget genesBiological processesComplex diseasesNon-alcoholic steatohepatitisLipid accumulationDeletionDevelopment of non-alcoholic fatty liver diseasePathway activationLipid metabolismProgress to non-alcoholic steatohepatitisAcid oxidationHCC progressionEffective therapeuticsTherapeutic targetHepatocellular carcinomaAbstract 129: Hypercholesterolemia-induced Lxr Signaling In Smc Contributes To Atherosclerotic Lesion Remodeling And Regulates Vascular And Visceral Smc Function
Zhang H, Biwer L, de Urturi D, Fernandez-Tussy P, Jovin D, Huang Y, Zhang X, Esplugues E, Greif D, Suarez Y, Fernandez-Hernando C. Abstract 129: Hypercholesterolemia-induced Lxr Signaling In Smc Contributes To Atherosclerotic Lesion Remodeling And Regulates Vascular And Visceral Smc Function. Arteriosclerosis Thrombosis And Vascular Biology 2024, 44: a129-a129. DOI: 10.1161/atvb.44.suppl_1.129.Peer-Reviewed Original ResearchLiver X receptorTranscription factorsVascular smooth muscle cellsRegulation of lipid metabolismLXR signalingB geneScRNA-seqFate decisionsSignaling eventsSMC functionGene expressionActivation of liver X receptorCell statesLesion remodelingCharacterized miceLipid metabolismLineage tracingPhenotypic switchingX receptorReduced fibrous cap thicknessTranscriptionFeatures of plaque instabilitySmooth muscle cellsLipid absorptionProgression of atherosclerosisFatty 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 cellsmicroRNA-33 controls hunger signaling in hypothalamic AgRP neurons
Price N, Fernández-Tussy P, Varela L, Cardelo M, Shanabrough M, Aryal B, de Cabo R, Suárez Y, Horvath T, Fernández-Hernando C. microRNA-33 controls hunger signaling in hypothalamic AgRP neurons. Nature Communications 2024, 15: 2131. PMID: 38459068, PMCID: PMC10923783, DOI: 10.1038/s41467-024-46427-0.Peer-Reviewed Original ResearchConceptsAgRP neuronsFeeding behaviorFatty acid metabolismNon-coding RNAsMitochondrial biogenesisRegulatory pathwaysTarget genesHypothalamic AgRP neuronsExcessive nutrient intakeCentral regulatorBioenergetic processesAcid metabolismActivation of AgRP neuronsModulate feeding behaviorCentral regulation of feeding behaviorRegulation of feeding behaviorMiR-33Hunger signalsMicroRNA-33Metabolic diseasesAlternative therapeutic approachLoss of miR-33Mouse modelMetabolic dysfunctionRegulationHeterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Ruz-Maldonado I, Gonzalez J, Zhang H, Sun J, Bort A, Kabir I, Kibbey R, Suárez Y, Greif D, Fernández-Hernando C. Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage. Nature Communications 2024, 15: 1247. PMID: 38341404, PMCID: PMC10858916, DOI: 10.1038/s41467-024-45439-0.Peer-Reviewed Original Research
2023
Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis
Chaube B, Citrin K, Sahraei M, Singh A, de Urturi D, Ding W, Pierce R, Raaisa R, Cardone R, Kibbey R, Fernández-Hernando C, Suárez Y. Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis. Nature Communications 2023, 14: 8251. PMID: 38086791, PMCID: PMC10716292, DOI: 10.1038/s41467-023-43900-0.Peer-Reviewed Original Research
2025
Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function
Zhang H, de Urturi D, Fernández-Tussy P, Huang Y, Jovin D, Zhang X, Huang S, Lek M, da Silva Catarino J, Sternak M, Citrin K, Swirski F, Gustafsson J, Greif D, Esplugues E, Biwer L, Suárez Y, Fernández-Hernando C. Hypercholesterolemia-induced LXR signaling in smooth muscle cells contributes to vascular lesion remodeling and visceral function. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2417512122. PMID: 40035761, PMCID: PMC11912459, DOI: 10.1073/pnas.2417512122.Peer-Reviewed Original ResearchConceptsVascular smooth muscle cellsSmooth muscle cellsLiver X receptorLesion remodelingMuscle cellsVascular functionArterial media layerContribution of lipid metabolismPhenotypic switchingRegulate vascular toneMonocyte-derived macrophagesLipid metabolismPhenotypic switching of vascular smooth muscle cellsSwitching of vascular smooth muscle cellsNecrotic core areaRegulate vascular functionFoam cell populationVisceral myopathyBladder remodelingAortic atheromaFibrous cap thicknessRemodeling in vivoLipid malabsorptionVascular toneAbundant cell type
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 SREBP2Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
Singh AK, Chaube B, Zhang X, Sun J, Citrin KM, Canfrán-Duque A, Aryal B, Rotllan N, Varela L, Lee RG, Horvath TL, Price N, Suárez Y, Fernandez-Hernando C. Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice. Journal Of Clinical Investigation 2021, 131 PMID: 34255741, PMCID: PMC8409581, DOI: 10.1172/jci140989.Peer-Reviewed Original ResearchDiet-induced obesityGlucose intoleranceHigh-fat fed conditionsLipoprotein lipaseExcess hepatic lipid accumulationSystemic metabolic dysfunctionRole of ANGPTL4Liver lipid metabolismHepatic lipid accumulationTargeted pharmacologic therapyANGPTL4 gene expressionMetabolic turnover studiesHepatic lipase activityObesity-associated diabetesFatty acidsNovel inhibition strategiesPharmacologic therapyLiver steatosisLiver damageLipoprotein remnantsCholesterol levelsMetabolic dysfunctionHepatic uptakeANGPTL4 deficiencyHL activityKetogenic 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 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 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
Caveolin-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 modelAtherosclerosisInflammationSpecific 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
2018
Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis
Aryal B, Singh AK, Zhang X, Varela L, Rotllan N, Goedeke L, Chaube B, Camporez JP, Vatner DF, Horvath TL, Shulman GI, Suárez Y, Fernández-Hernando C. Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis. JCI Insight 2018, 3: e97918. PMID: 29563332, PMCID: PMC5926923, DOI: 10.1172/jci.insight.97918.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAllelesAngiopoietin-Like Protein 4AnimalsAtherosclerosisBody WeightChemokinesCytokinesDiet, High-FatDiet, WesternFatty AcidsGene Expression ProfilingGene Expression RegulationGene Knockout TechniquesGlucoseInsulinIntegrasesIntercellular Signaling Peptides and ProteinsLipid MetabolismLipoprotein LipaseLipoproteinsLiverMaleMiceMice, Inbred C57BLMice, KnockoutMusclesObesityProprotein Convertase 9TriglyceridesConceptsAngiopoietin-like protein 4High-fat dietEctopic lipid depositionLipid depositionGlucose toleranceLipoprotein lipaseShort-term high-fat dietSevere metabolic abnormalitiesProgression of atherosclerosisMajor risk factorTriacylglycerol-rich lipoproteinsFatty acid uptakeAdipose tissue resultsProatherogenic lipoproteinsCardiometabolic diseasesMetabolic abnormalitiesKO miceRisk factorsWhole body lipidMetabolic disordersGlucose metabolismLPL activityAdipose tissueGenetic ablationRapid clearance
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