2024
miR-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 carcinoma
2023
MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention
Qiu B, Lawan A, Xirouchaki C, Yi J, Robert M, Zhang L, Brown W, Fernández-Hernando C, Yang X, Tiganis T, Bennett A. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention. Nature Communications 2023, 14: 5405. PMID: 37669951, PMCID: PMC10480499, DOI: 10.1038/s41467-023-41145-5.Peer-Reviewed Original Research
2022
Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity
Wang Q, Zhang B, Stutz B, Liu ZW, Horvath TL, Yang X. Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity. Science Advances 2022, 8: eabn8092. PMID: 36044565, PMCID: PMC9432828, DOI: 10.1126/sciadv.abn8092.Peer-Reviewed Original ResearchConceptsVentromedial hypothalamusWhite adipose tissueVMH neuronsAdipose tissueBody weightLipid metabolismRapid weight gainCounterregulatory responsesSympathetic activitySympathetic innervationAdipocyte hypertrophyTissue lipolysisNeuronal excitabilityFood intakePhysical activityObesity phenotypesGenetic ablationWeight gainHomeostatic set pointEnergy expenditureNeuronsInnervationLipolysisSignificant changesCellular sensors
2020
OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance
Yang Y, Li X, Luan HH, Zhang B, Zhang K, Nam JH, Li Z, Fu M, Munk A, Zhang D, Wang S, Liu Y, Albuquerque JP, Ong Q, Li R, Wang Q, Robert ME, Perry RJ, Chung D, Shulman GI, Yang X. OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 16616-16625. PMID: 32601203, PMCID: PMC7368321, DOI: 10.1073/pnas.1916121117.Peer-Reviewed Original ResearchConceptsRibosomal protein S6 kinase beta-1Macrophage proinflammatory activationGlcNAc signalingProinflammatory activationUnexpected roleWhole-body metabolismNutrient fluxesLipid accumulationImmune cell activationGlcNAcHomeostatic mechanismsMetabolic disturbancesBeta 1Cell activationDiet-induced metabolic dysfunctionDiet-induced obese miceActivationWhole-body insulin resistanceMacrophage inflammationGlcNAcylationOGTPeripheral tissuesPhosphorylationEnhanced inflammationInsulin resistanceO-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity
Yang Y, Fu M, Li MD, Zhang K, Zhang B, Wang S, Liu Y, Ni W, Ong Q, Mi J, Yang X. O-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity. Nature Communications 2020, 11: 181. PMID: 31924761, PMCID: PMC6954210, DOI: 10.1038/s41467-019-13914-8.Peer-Reviewed Original ResearchMeSH KeywordsAcetylglucosamineAnimalsCell Line, TumorDietFastingGene DeletionHEK293 CellsHeLa CellsHomeostasisHumansIntra-Abdominal FatLipolysisMaleMiceMice, Inbred C3HMice, Inbred C57BLMice, KnockoutN-AcetylglucosaminyltransferasesObesityPerilipin-1PhosphorylationProtein Processing, Post-TranslationalSignal TransductionConceptsDiet-induced obesityVisceral fatExcessive visceral fat accumulationPerilipin 1Visceral fat accumulationVisceral fat lossTreatment of obesityPrimary risk factorAdipose tissue homeostasisUnhealthy obesityRisk factorsEnhanced lipolysisInhibits lipolysisFat accumulationO-GlcNAcylationFat lossObesityFat lipolysisRelated diseasesLipolysisInducible deletionLipid dropletsHexosamine biosynthetic pathwayFatTissue homeostasis
2019
O-GlcNAc transferase suppresses necroptosis and liver fibrosis
Zhang B, Li MD, Yin R, Liu Y, Yang Y, Mitchell-Richards KA, Nam JH, Li R, Wang L, Iwakiri Y, Chung D, Robert ME, Ehrlich BE, Bennett AM, Yu J, Nathanson MH, Yang X. O-GlcNAc transferase suppresses necroptosis and liver fibrosis. JCI Insight 2019, 4: e127709. PMID: 31672932, PMCID: PMC6948774, DOI: 10.1172/jci.insight.127709.Peer-Reviewed Original ResearchConceptsReceptor-interacting protein kinase 3Liver fibrosisLiver diseaseHepatocyte necroptosisEthanol-induced liver injuryAlcoholic liver cirrhosisChronic liver diseaseMultiple liver diseasesWeeks of ageProtein expression levelsPortal inflammationLiver cirrhosisLiver injuryBallooning degenerationElevated protein expression levelsSpontaneous genetic modelFibrosisKey suppressorKey mediatorMiceProtein kinase 3CirrhosisExpression levelsGlcNAc levelsMixed lineage kinaseO-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth
Singh JP, Qian K, Lee JS, Zhou J, Han X, Zhang B, Ong Q, Ni W, Jiang M, Ruan HB, Li MD, Zhang K, Ding Z, Lee P, Singh K, Wu J, Herzog RI, Kaech S, Wendel HG, Yates JR, Han W, Sherwin RS, Nie Y, Yang X. O-GlcNAcase targets pyruvate kinase M2 to regulate tumor growth. Oncogene 2019, 39: 560-573. PMID: 31501520, PMCID: PMC7107572, DOI: 10.1038/s41388-019-0975-3.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAcetylglucosamineAnimalsAntigens, NeoplasmCarrier ProteinsCell Line, TumorDatasets as TopicDisease ProgressionFemaleGene Expression ProfilingGlycolysisHEK293 CellsHistone AcetyltransferasesHumansHyaluronoglucosaminidaseMaleMembrane ProteinsMiceN-AcetylglucosaminyltransferasesNeoplasm GradingNeoplasm StagingNeoplasmsProtein Processing, Post-TranslationalThyroid HormonesTissue Array AnalysisUp-RegulationXenograft Model Antitumor AssaysConceptsPyruvate kinase M2O-GlcNAcaseAerobic glycolysisO-GlcNAcylationKinase M2Lysine acetyltransferase activityTumor growthMetabolic rheostatAcetyltransferase activityGlcNAc transferaseMolecular basisMetabolic shiftHuman cancersGlycolysisCancer cellsHigh glucose conditionsGlucose availabilityTumor progressionGlucose conditionsExquisite controlGrowthRheostatCausative roleTargetEnzyme
2018
Adipocyte OGT governs diet-induced hyperphagia and obesity
Li MD, Vera NB, Yang Y, Zhang B, Ni W, Ziso-Qejvanaj E, Ding S, Zhang K, Yin R, Wang S, Zhou X, Fang EX, Xu T, Erion DM, Yang X. Adipocyte OGT governs diet-induced hyperphagia and obesity. Nature Communications 2018, 9: 5103. PMID: 30504766, PMCID: PMC6269424, DOI: 10.1038/s41467-018-07461-x.Peer-Reviewed Original ResearchConceptsSerine/threonine residuesN-acetylglucosamine transferaseNutrient cuesThreonine residuesTranscriptional activationO-GlcNAcylationLipid desaturationIntracellular proteinsOGTHigh-fat diet-induced hyperphagiaDevelopment of obesityBaseline food intakeSignaling contributesLipid signalsCB1 signalingBrain axisChronic dysregulationFood intakeMetabolic diseasesPalatable foodPharmacological manipulationHyperphagiaObesityFat sensorSignaling
2017
Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation
Ruan HB, Ma Y, Torres S, Zhang B, Feriod C, Heck RM, Qian K, Fu M, Li X, Nathanson MH, Bennett AM, Nie Y, Ehrlich BE, Yang X. Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes & Development 2017, 31: 1655-1665. PMID: 28903979, PMCID: PMC5647936, DOI: 10.1101/gad.305441.117.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, BiologicalAnimalsAutophagyAutophagy-Related Protein 5Autophagy-Related Protein-1 HomologCalcium SignalingCalcium-Calmodulin-Dependent Protein Kinase Type 2Cells, CulturedGlucagonHEK293 CellsHeLa CellsHumansInositol 1,4,5-Trisphosphate ReceptorsLiverMice, Inbred C57BLN-AcetylglucosaminyltransferasesNutritional Physiological PhenomenaConceptsAMPK-dependent phosphorylationLiver autophagyN-acetylglucosamine transferaseCalmodulin-dependent kinase IICalcium/calmodulin-dependent kinase IIWhole-body homeostasisULK proteinsNutrient homeostasisKinase IICalcium signalingAutophagic fluxGenetic ablationMetabolic adaptationAutophagyStarvationOGTPhosphorylationHomeostasisMouse liverProduction of glucoseKetone bodiesAdaptationSignalingProteinTransferaseProtein O-GlcNAcylation: emerging mechanisms and functions
Yang X, Qian K. Protein O-GlcNAcylation: emerging mechanisms and functions. Nature Reviews Molecular Cell Biology 2017, 18: 452-465. PMID: 28488703, PMCID: PMC5667541, DOI: 10.1038/nrm.2017.22.Peer-Reviewed Original ResearchConceptsPost-translational modificationsO-GlcNAcylationAdaptor proteinGlcNAcylation levelsO-GlcNAc homeostasisTetratricopeptide repeat domainDiverse cellular processesProtein-protein interactionsOptimal cellular functionContext-dependent recruitmentPost-translational levelCell signaling dynamicsUnwanted protein aggregationCellular O-GlcNAcylationSubstrate-specific interactionsSpecific cell typesN-acetylglucosamine moietiesLevels of OGTGlcNAc signalingMitochondrial proteinsSpatiotemporal regulationCellular functionsCellular processesEpigenetic modificationsProtein substratesMetabolic Regulation of Gene Expression by Histone Lysine β‐hydroxybutyrylation
Zhang D, Xie Z, Chung D, Tang Z, Huang H, Dai L, Qi S, Li J, Colak G, Chen Y, Peng C, Ruan H, Wang D, Jensen L, Kwon O, Lee S, Pletcher S, Tan M, Lombard D, White K, Zhao H, Li J, Roeder R, Yang X, Zhao Y. Metabolic Regulation of Gene Expression by Histone Lysine β‐hydroxybutyrylation. The FASEB Journal 2017, 31 DOI: 10.1096/fasebj.31.1_supplement.755.2.Peer-Reviewed Original ResearchKetone bodiesNeuro-protective roleDiabetic ketoacidosisAdjunctive treatmentKetogenic dietBrain tumorsPharmacological effectsNeurodegenerative diseasesPathophysiological statesCultured cell linesMedical FoundationLines of evidenceCell linesEpilepsyΒ-hydroxybutyrylationNIHRNA-seq analysisMetabolic regulationRegulatory roleGene expressionShanghai Municipal ScienceMetabolic pathwaysKetoacidosisDiabetesPatients
2016
Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation
Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, Qi S, Li J, Colak G, Chen Y, Xia C, Peng C, Ruan H, Kirkey M, Wang D, Jensen LM, Kwon OK, Lee S, Pletcher SD, Tan M, Lombard DB, White KP, Zhao H, Li J, Roeder RG, Yang X, Zhao Y. Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Molecular Cell 2016, 62: 194-206. PMID: 27105115, PMCID: PMC5540445, DOI: 10.1016/j.molcel.2016.03.036.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBinding SitesChromatin Assembly and DisassemblyDiabetic KetoacidosisDisease Models, AnimalEnergy MetabolismEpigenesis, GeneticFatty AcidsGene Expression RegulationGlucoseHEK293 CellsHistonesHumansHydroxybutyratesLiverLysineMice, Inbred C57BLPromoter Regions, GeneticProtein Processing, Post-TranslationalStarvationStreptozocinConceptsLysine β-hydroxybutyrylationΒ-hydroxybutyrylationActive gene promotersEpigenetic regulatory marksRNA-seq analysisHistone acetylation sitesChromatin regulationHistone marksChIP-seqAcetylation sitesProtein modificationGene promoterRegulatory marksDiverse functionsGene expressionMetabolic regulationMetabolic pathwaysCultured cellsPathophysiological statesRegulationExpressionNew avenuesKbhbMarksGenes
2014
O-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat
Ruan HB, Dietrich MO, Liu ZW, Zimmer MR, Li MD, Singh JP, Zhang K, Yin R, Wu J, Horvath TL, Yang X. O-GlcNAc Transferase Enables AgRP Neurons to Suppress Browning of White Fat. Cell 2014, 159: 306-317. PMID: 25303527, PMCID: PMC4509746, DOI: 10.1016/j.cell.2014.09.010.Peer-Reviewed Original ResearchConceptsAgRP neuronsFundamental cellular processesWhite fatN-acetylglucosamine (O-GlcNAc) modificationOrexigenic AgRP neuronsVoltage-dependent potassium channelsCellular processesGlcNAc transferaseDynamic physiological processesNuclear proteinsWhite adipose tissue browningPhysiological processesAdipose tissue browningDiet-induced obesityPhysiological relevanceTissue browningGenetic ablationBeige cellsEnergy metabolismInsulin resistanceNeuronal excitabilityPotassium channelsAdipose tissueCentral mechanismsNeurons
2013
O-GlcNAc Signaling Entrains the Circadian Clock by Inhibiting BMAL1/CLOCK Ubiquitination
Li MD, Ruan HB, Hughes ME, Lee JS, Singh JP, Jones SP, Nitabach MN, Yang X. O-GlcNAc Signaling Entrains the Circadian Clock by Inhibiting BMAL1/CLOCK Ubiquitination. Cell Metabolism 2013, 17: 303-310. PMID: 23395176, PMCID: PMC3647362, DOI: 10.1016/j.cmet.2012.12.015.Peer-Reviewed Original ResearchConceptsCircadian clockProtein modificationNutrient-sensing pathwaysO-GlcNAc signalingHexosamine biosynthesis pathwayCovalent protein modificationBiosynthesis pathwayGlcNAc transferaseNutritional signalsClock oscillationsO-GlcNAcylationAberrant circadian rhythmsClock targetsOGT expressionCircadian oscillationsUbiquitinationN-acetylglucosamineNutrient fluxesMetabolic oscillationsBMAL1GenesPathwayCircadian rhythmKey mechanismClock
2012
O-GlcNAc Transferase/Host Cell Factor C1 Complex Regulates Gluconeogenesis by Modulating PGC-1α Stability
Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, Zhao L, Bennett AM, Samuel VT, Wu J, Yates JR, Yang X. O-GlcNAc Transferase/Host Cell Factor C1 Complex Regulates Gluconeogenesis by Modulating PGC-1α Stability. Cell Metabolism 2012, 16: 226-237. PMID: 22883232, PMCID: PMC3480732, DOI: 10.1016/j.cmet.2012.07.006.Peer-Reviewed Original ResearchMeSH KeywordsAnalysis of VarianceAnimalsBlotting, WesternChromatin ImmunoprecipitationChromatography, High Pressure LiquidGluconeogenesisHeat-Shock ProteinsHEK293 CellsHep G2 CellsHost Cell Factor C1HumansHyperglycemiaImmunoprecipitationLiverMiceMice, Inbred C57BLMultiprotein ComplexesN-AcetylglucosaminyltransferasesPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaProteomicsReal-Time Polymerase Chain ReactionTandem Mass SpectrometryTranscription FactorsConceptsHCF-1O-GlcNAcylationPGC-1αHost cell factor C1Hexosamine biosynthetic pathwayN-acetylglucosamine (O-GlcNAc) modificationDeubiquitinase BAP1Proteomic approachGlcNAc transferasePosttranslational modificationsNuclear proteinsBiosynthetic pathwayMaster regulatorKey regulatorFactor C1C1 complexOGTGlucose availabilityRegulatorProteinGluconeogenesisHepatic gluconeogenesisGlucose homeostasisComplexesHepatic knockdown
2008
Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance
Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 2008, 451: 964-969. PMID: 18288188, DOI: 10.1038/nature06668.Peer-Reviewed Original ResearchMeSH KeywordsAcetylglucosamineAnimalsCell MembraneChlorocebus aethiopsCOS CellsInsulinInsulin ResistanceLipid MetabolismLiverMaleMiceMice, Inbred C57BLN-AcetylglucosaminyltransferasesPhosphatidylinositol PhosphatesPhosphatidylinositolsPhosphorylationProtein Structure, TertiaryProtein TransportSecond Messenger SystemsConceptsO-GlcNAcSignal transductionPhosphoinositide-binding domainsPost-translational modificationsO-GlcNAc transferaseHexosamine biosynthetic pathwayInsulin signal transductionInsulin-responsive genesCellular regulationGlcNAc transferaseNutritional cuesNuclear proteinsBiosynthetic pathwayPlasma membraneProtein degradationNutrient sensorMolecular mechanismsN-acetylglucosamineTransductionPathwayTransferaseHepatic overexpressionGlucose fluxDynamic modificationMetabolic status
2006
Nuclear Receptor Expression Links the Circadian Clock to Metabolism
Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, Mangelsdorf DJ, Evans RM. Nuclear Receptor Expression Links the Circadian Clock to Metabolism. Cell 2006, 126: 801-810. PMID: 16923398, DOI: 10.1016/j.cell.2006.06.050.Peer-Reviewed Original ResearchConceptsNuclear receptor expressionReceptor expressionFat-soluble hormoneBrown adipose tissueKey metabolic tissuesPeripheral circadian clocksGlucose metabolismAdipose tissueDietary lipidsThyroid hormonesMetabolic tissuesKey target genesSkeletal muscleOrphan receptorNuclear receptorsEnergy metabolismNovel roleBasal metabolismHormoneMetabolismReceptorsCircadian clockExpression profilesMouse nuclear receptorsCircadian entrainment
2002
Recruitment of O-GlcNAc Transferase to Promoters by Corepressor mSin3A Coupling Protein O-GlcNAcylation to Transcriptional Repression
Yang X, Zhang F, Kudlow JE. Recruitment of O-GlcNAc Transferase to Promoters by Corepressor mSin3A Coupling Protein O-GlcNAcylation to Transcriptional Repression. Cell 2002, 110: 69-80. PMID: 12150998, DOI: 10.1016/s0092-8674(02)00810-3.Peer-Reviewed Original ResearchMeSH KeywordsAnimal Population GroupsAnimalsCOS CellsGene Expression RegulationGene SilencingGenes, ReporterGlycoproteinsHistone DeacetylasesHumansN-AcetylglucosaminyltransferasesPromoter Regions, GeneticRepressor ProteinsSin3 Histone Deacetylase and Corepressor ComplexTranscription FactorsTranscription, GeneticTumor Cells, CulturedConceptsRNA polymerase IIPolymerase IIGlcNAc transferaseHistone deacetylationTranscription factorsN-acetylglucosamine monosaccharidesHistone deacetylase complexO-GlcNAc modificationProtein O-GlcNAcylationDeacetylase complexTranscriptional repressionThreonine residuesPrecise functional rolePosttranslational modificationsO-GlcNAcylationFunctional roleSpecific mannerMSin3AOGTPromoterDeacetylationTransferaseCorepressorTranscriptionRepression