2024
Heterogeneity 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
2021
MMAB 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 SREBP2Loss 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
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 clearanceGenetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance
Price NL, Singh AK, Rotllan N, Goedeke L, Wing A, Canfrán-Duque A, Diaz-Ruiz A, Araldi E, Baldán Á, Camporez JP, Suárez Y, Rodeheffer MS, Shulman GI, de Cabo R, Fernández-Hernando C. Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance. Cell Reports 2018, 22: 2133-2145. PMID: 29466739, PMCID: PMC5860817, DOI: 10.1016/j.celrep.2018.01.074.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAdiposityAnimalsCholesterol, HDLCholesterol, LDLEatingEnzyme ActivationGene DeletionGene Expression RegulationGenetic Predisposition to DiseaseGerm CellsInflammation MediatorsInsulin ResistanceLipid MetabolismLiverMice, Inbred C57BLMicroRNAsModels, BiologicalObesityProtein Kinase C-epsilonSterol Regulatory Element Binding Protein 1ConceptsMiR-33Insulin resistanceFood intakeIncreases food intakeAdipose tissue expansionKey metabolic tissuesWild-type animalsPromotes obesityImpaired lipolysisPair feedingCardiovascular diseaseMetabolic dysfunctionTherapeutic modulationAdipose tissueLipid uptakeMiRNA-based therapiesMetabolic tissuesGenetic ablationTissue expansionMiceObesityTherapyDeleterious effectsDiseasePrevious reports
2015
miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice
Goedeke L, Rotllan N, Ramírez CM, Aranda JF, Canfrán-Duque A, Araldi E, Fernández-Hernando A, Langhi C, de Cabo R, Baldán Á, Suárez Y, Fernández-Hernando C. miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice. Atherosclerosis 2015, 243: 499-509. PMID: 26520906, PMCID: PMC4975922, DOI: 10.1016/j.atherosclerosis.2015.09.033.Peer-Reviewed Original ResearchMeSH Keywords3' Untranslated RegionsAdaptor Proteins, Signal TransducingAnimalsATP Binding Cassette Transporter 1BiomarkersChlorocebus aethiopsCholesterolComputational BiologyCOS CellsDatabases, GeneticDiet, High-FatGene Expression RegulationGene Regulatory NetworksHep G2 CellsHumansLiverMacaca mulattaMaleMice, Inbred C57BLMicroRNAsReceptors, LDLTime FactorsTransfectionTriglyceridesConceptsWild-type miceHepatic lipid levelsMiR-27b expressionLipid levelsHepatic lipidsABCA1 expressionMiR-27bWeeks of treatmentExpression of ABCA1Potential therapeutic targetABCA1 protein levelsCellular cholesterol effluxMiR-27b functionsMiR-27b overexpressionMouse hepatic cellsHepatic LDLRHepatic ABCA1Human hepatic Huh7 cellsHepatic cholesterolWestern dietCardiovascular diseaseTherapeutic administrationLDLR expressionTreatment groupsCholesterol effluxMicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels
Goedeke L, Rotllan N, Canfrán-Duque A, Aranda JF, Ramírez CM, Araldi E, Lin CS, Anderson NN, Wagschal A, de Cabo R, Horton JD, Lasunción MA, Näär AM, Suárez Y, Fernández-Hernando C. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nature Medicine 2015, 21: 1280-1289. PMID: 26437365, PMCID: PMC4711995, DOI: 10.1038/nm.3949.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsATP Binding Cassette Transporter 1Cholesterol, HDLCholesterol, LDLGene Expression RegulationHep G2 CellsHepatocytesHigh-Throughput Screening AssaysHumansLiverMiceMicroRNAsReceptors, LDLRNA Processing, Post-TranscriptionalSignal TransductionSterol Regulatory Element Binding Protein 1
2014
Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice
Goedeke L, Salerno A, Ramírez CM, Guo L, Allen RM, Yin X, Langley SR, Esau C, Wanschel A, Fisher EA, Suárez Y, Baldán A, Mayr M, Fernández-Hernando C. Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Molecular Medicine 2014, 6: 1133-1141. PMID: 25038053, PMCID: PMC4197861, DOI: 10.15252/emmm.201404046.Peer-Reviewed Original ResearchConceptsHigh-fat dietFatty acid synthaseMiR-33Chronic inhibitionTriglyceride levelsTherapeutic silencingHigh-density lipoprotein levelsAcetyl-CoA carboxylaseLipid accumulationAtherosclerotic vascular diseaseHepatic lipid accumulationRegression of atherosclerosisModerate hepatic steatosisLiver of miceNon-human primatesLipoprotein levelsHepatic steatosisVascular diseaseLong-term effectsStrong inverse correlationPersistent inhibitionVivo increaseCholesterol transportMiceAdverse effects
2013
A Regulatory Role for MicroRNA 33* in Controlling Lipid Metabolism Gene Expression
Goedeke L, Vales-Lara FM, Fenstermaker M, Cirera-Salinas D, Chamorro-Jorganes A, Ramírez CM, Mattison JA, de Cabo R, Suárez Y, Fernández-Hernando C. A Regulatory Role for MicroRNA 33* in Controlling Lipid Metabolism Gene Expression. Molecular And Cellular Biology 2013, 33: 2339-2352. PMID: 23547260, PMCID: PMC3648071, DOI: 10.1128/mcb.01714-12.Peer-Reviewed Original ResearchConceptsMiR-33Gene expressionRegulatory roleTarget gene networkKey transcriptional regulatorTarget gene expressionMetabolism gene expressionIntronic microRNAsHuman hepatic cellsLipid metabolismSterol regulatory element-binding protein 2Transcriptional regulatorsSister strandsGene networksLipid metabolism gene expressionSteady-state levelsHost genesFatty acid metabolismFatty acid oxidationKey enzymeLipid homeostasisPassenger strandMicroRNA-33Functional roleProtein 2
2011
The Role of MicroRNAs in Cholesterol Efflux and Hepatic Lipid Metabolism
Moore KJ, Rayner KJ, Suárez Y, Fernández-Hernando C. The Role of MicroRNAs in Cholesterol Efflux and Hepatic Lipid Metabolism. Annual Review Of Nutrition 2011, 31: 49-63. PMID: 21548778, PMCID: PMC3612434, DOI: 10.1146/annurev-nutr-081810-160756.Peer-Reviewed Original ResearchConceptsGene expressionSterol response element-binding proteinMiR-33Fatty acid β-oxidationElement-binding proteinFatty acid homeostasisResponse element-binding proteinRole of microRNAsCholesterol effluxIntronic miRNALipid metabolismRNA bindsPosttranscriptional controlUntranslated regionAbundant miRNABiological processesElegant mechanismMiR-122Lipid homeostasisΒ-oxidationAcid homeostasisCell phenotypeMiRNAsHepatic lipid metabolismMicroRNAsAntagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis
Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, Fernandez-Hernando C, Fisher EA, Moore KJ. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. Journal Of Clinical Investigation 2011, 121: 2921-2931. PMID: 21646721, PMCID: PMC3223840, DOI: 10.1172/jci57275.Peer-Reviewed Original ResearchConceptsABC transporter A1HDL levelsRegression of atherosclerosisCholesterol transportMiR-33MiR-33 inhibitionAtherosclerotic vascular diseasePlasma HDL levelsInflammatory gene expressionReverse cholesterol transportABCA1 levelsAtherosclerosis regressionVascular diseasePlaque macrophagesPlaque stabilityABCA1 expressionAtherosclerotic plaquesMice promotesProtective roleLipid metabolismLDL receptorClinical therapyPlaque sizeAtherosclerosisSREBF2 gene
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 metabolismEfflux