2025
Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior
Jin S, Yoon N, Wei M, Worgall T, Rubinelli L, Horvath T, Min W, Diano N, di Lorenzo A, Diano S. Endoplasmic reticulum Nogo drives AgRP neuronal activation and feeding behavior. Cell Metabolism 2025, 37: 1400-1412.e8. PMID: 40334659, PMCID: PMC12136989, DOI: 10.1016/j.cmet.2025.04.005.Peer-Reviewed Original ResearchConceptsAgRP neuron activityNogo-AAgRP neuronsNeuronal activityCeramide levelsNogo-A expressionCellular lipid metabolismIntracellular lipid transportSphingolipid de novo biosynthesisDownregulation of enzymesIncreased ceramide levelsLipid metabolismHigh-fat diet-induced obesityFeeding behaviorAgouti-related proteinControl of feedingControlling lipid metabolismAssociated with brain developmentWhole-body metabolismFatty acid oxidationReticulon 4Food intakeMitochondrial functionSynaptic plasticityLipid transportSuppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases
Rubinelli L, Manzo O, Sungho J, Del Gaudio I, Bareja R, Marino A, Palikhe S, Di Mauro V, Bucci M, Falcone D, Elemento O, Ersoy B, Diano S, Sasset L, Di Lorenzo A. Suppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases. Nature Communications 2025, 16: 1968. PMID: 40000621, PMCID: PMC11862206, DOI: 10.1038/s41467-025-56869-9.Peer-Reviewed Original ResearchConceptsNogo-BEndothelial dysfunctionHFD miceCardiometabolic diseasesSphingolipid signalingDevelopment of therapeutic strategiesBioactive sphingolipidsCeramide degradationSphingosine-1-phosphateHepatic glucose productionIn vivo evidenceEndothelial cellsEndothelial specific deletionCeramideBiosynthesisHigh-fat dietPathological implicationsSphingolipidsGlucose productionHFDIn vivoMale miceMetabolic dysfunctionTherapeutic strategiesMetabolic disorders
2023
CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Hammerschmidt P, Steculorum S, Bandet C, Del Río-Martín A, Steuernagel L, Kohlhaas V, Feldmann M, Varela L, Majcher A, Quatorze Correia M, Klar R, Bauder C, Kaya E, Porniece M, Biglari N, Sieben A, Horvath T, Hornemann T, Brodesser S, Brüning J. CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. Nature Communications 2023, 14: 7824. PMID: 38016943, PMCID: PMC10684560, DOI: 10.1038/s41467-023-42595-7.Peer-Reviewed Original ResearchConceptsMitochondrial stressSpecific ceramide speciesSteroidogenic factor 1Hypothalamic neuronsMitochondrial dynamicsMitochondrial morphologyCeramide synthaseObese miceGlucose homeostasisCeramide speciesCeramide synthesisConditional deletionHypothalamic lipotoxicityCultured hypothalamic neuronsAdverse metabolic effectsFactor 1High-fat dietImpairs glucose homeostasisDiet-induced alterationsCerS6DeletionHomeostasisGlucose toleranceCeramideInsulin sensitivityA defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels
Dutta D, Kanca O, Byeon S, Marcogliese P, Zuo Z, Shridharan R, Park J, Lin G, Ge M, Heimer G, Kohler J, Wheeler M, Kaipparettu B, Pandey A, Bellen H. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels. Nature Metabolism 2023, 5: 1595-1614. PMID: 37653044, PMCID: PMC11151872, DOI: 10.1038/s42255-023-00873-0.Peer-Reviewed Original ResearchConceptsFatty acid synthesisFe-S cluster biogenesisMitochondrial fatty acid synthesisCeramide levelsMost eukaryotic cellsElevated ceramide levelsIron metabolismCluster biogenesisEukaryotic cellsLoss of functionCellular lipidomeEnoyl coenzymeNeurodegenerative phenotypeIron homeostasisHuman-derived fibroblastsMechanistic linkAcid synthesisCeramideMECRMetabolismNeurodegenerationMtFASBiogenesisLast stepMitochondriaExploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14)
Lin G, Tepe B, McGrane G, Tipon R, Croft G, Panwala L, Hope A, Liang A, Zuo Z, Byeon S, Wang L, Pandey A, Bellen H. Exploring therapeutic strategies for infantile neuronal axonal dystrophy (INAD/PARK14). ELife 2023, 12: e82555. PMID: 36645408, PMCID: PMC9889087, DOI: 10.7554/elife.82555.Peer-Reviewed Original ResearchConceptsPatient-derived neural progenitor cellsNeural progenitor cellsPatient-derived neuronsPediatric neurodegenerative disorderRetromer functionMitochondrial morphologyEndolysosomal pathwayMitochondrial defectsProlong lifespanNeurodegenerative phenotypeProgenitor cellsMouse modelRecessive variantsNeurodegenerative disordersGene therapy approachesPathwayInfantile neuroaxonal dystrophyHomologCellsTherapeutic strategiesAzoramidePurkinje cellsFliesPhenotypeMetabolism
2022
Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice
Gaspar R, Lyu K, Hubbard B, Leitner B, Luukkonen P, Hirabara S, Sakuma I, Nasiri A, Zhang D, Kahn M, Cline G, Pauli J, Perry R, Petersen K, Shulman G. Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice. Diabetologia 2022, 66: 567-578. PMID: 36456864, PMCID: PMC11194860, DOI: 10.1007/s00125-022-05838-8.Peer-Reviewed Original ResearchConceptsProtein kinase CsSubcellular compartmentsDistinct subcellular localisationMuscle insulin sensitivityMultiple subcellular compartmentsInsulin receptor kinaseNovel protein kinase CsActivation of PKCεSubcellular localisationPKCθ translocationReceptor kinasePlasma membraneSubcellular distributionTriacylglycerol contentCrucial pathwaysIntramuscular triacylglycerol contentRC miceDiacylglycerolConclusions/interpretationThese resultsPKCεPM compartmentPhosphorylationMuscle triacylglycerol contentSkeletal muscleRecent findingsCharacterization of pulmonary vascular remodeling and MicroRNA-126-targets in COPD-pulmonary hypertension
Goel K, Egersdorf N, Gill A, Cao D, Collum S, Jyothula S, Huang H, Sauler M, Lee P, Majka S, Karmouty-Quintana H, Petrache I. Characterization of pulmonary vascular remodeling and MicroRNA-126-targets in COPD-pulmonary hypertension. Respiratory Research 2022, 23: 349. PMID: 36522710, PMCID: PMC9756782, DOI: 10.1186/s12931-022-02267-4.Peer-Reviewed Original ResearchConceptsSmall pulmonary arteriesChronic cigarette smokingPulmonary vascular remodelingPulmonary hypertensionPulmonary arteryLung microvasculatureVascular remodelingEndothelial cellsCOPD-PHMiR126 expressionChronic obstructive pulmonary disease patientsObstructive pulmonary disease patientsCOPD pulmonary hypertensionPulmonary artery sizePulmonary artery remodelingPulmonary disease patientsPulmonary vascular bedPulmonary arterial wallEndothelial cell marker CD31Microvascular endothelial cellsEndothelial cell markersVessel endothelial cellsNon-COPD lungsLarge vessel endothelial cellsArtery remodeling
2020
IRE1A Stimulates Hepatocyte-Derived Extracellular Vesicles That Promote Inflammation in Mice With Steatohepatitis
Dasgupta D, Nakao Y, Mauer A, Thompson J, Sehrawat T, Liao C, Krishnan A, Lucien F, Guo Q, Liu M, Xue F, Fukushima M, Katsumi T, Bansal A, Pandey M, Maiers J, DeGrado T, Ibrahim S, Revzin A, Pavelko K, Barry M, Kaufman R, Malhi H. IRE1A Stimulates Hepatocyte-Derived Extracellular Vesicles That Promote Inflammation in Mice With Steatohepatitis. Gastroenterology 2020, 159: 1487-1503.e17. PMID: 32574624, PMCID: PMC7666601, DOI: 10.1053/j.gastro.2020.06.031.Peer-Reviewed Original ResearchConceptsX-box binding protein 1Release of EVsHepatocyte-derived extracellular vesiclesSerine palmitoyltransferase genesExtracellular vesiclesSerine palmitoyltransferaseChromatin immunoprecipitationCeramide biosynthesisInflammatory Extracellular VesiclesMonocyte-derived macrophagesUnfolded protein responseNonalcoholic steatohepatitisDiet-induced steatohepatitisGene expression analysisPrimary hepatocytesNumber of EVsBinding protein 1Cultured primary hepatocytesNanoparticle-tracking analysisNanoscale flow cytometryIRE1ALiver tissueRate-limiting enzymeProtein responseExpression analysis
2019
Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides
Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides. New England Journal Of Medicine 2019, 381: 1866-1869. PMID: 31693811, DOI: 10.1056/nejmcibr1910023.Peer-Reviewed Original ResearchMitofusin 1 is required for female fertility and to maintain ovarian follicular reserve
Zhang M, Bener MB, Jiang Z, Wang T, Esencan E, Scott III R, Horvath T, Seli E. Mitofusin 1 is required for female fertility and to maintain ovarian follicular reserve. Cell Death & Disease 2019, 10: 560. PMID: 31332167, PMCID: PMC6646343, DOI: 10.1038/s41419-019-1799-3.Peer-Reviewed Original ResearchConceptsOocyte-granulosa cell communicationDynamic organellesAccumulation of ceramideFemale reproductive agingMitofusin 1Secondary follicle stageMitochondrial dynamicsCell communicationReproductive phenotypesCeramide synthesis inhibitor myriocinDevelopmental arrestApoptotic cell lossMitochondrial dysfunctionTargeted deletionOvarian follicular reserveOocyte maturationFemale fertilityFollicle stageDeletionPhenotypeReproductive agingOocytesCadherinFollicular reserveOrganelles
2018
Sphingolipid biosynthesis induces a conformational change in the murine norovirus receptor and facilitates viral infection
Orchard RC, Wilen CB, Virgin HW. Sphingolipid biosynthesis induces a conformational change in the murine norovirus receptor and facilitates viral infection. Nature Microbiology 2018, 3: 1109-1114. PMID: 30127493, PMCID: PMC6158067, DOI: 10.1038/s41564-018-0221-8.Peer-Reviewed Original ResearchConceptsSerine palmitoyltransferase complexSphingolipid biosynthesisCellular susceptibilityConformational changesLipid biosynthetic enzymesDe novo sphingolipid biosynthesisHost cellular receptorsSerine palmitoyltransferase activityBiosynthetic enzymesBiosynthetic pathwayMurine norovirus infectionMurine norovirusCD300lfCell surfaceBiosynthesisUnappreciated connectionCellular receptorsExtracellular ceramideReceptor conformationViral infectionSurface expressionTarget cell surfaceViral bindingPalmitoyltransferase activityReceptorsPhospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain
Lin G, Lee P, Chen K, Mao D, Tan K, Zuo Z, Lin W, Wang L, Bellen H. Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain. Cell Metabolism 2018, 28: 605-618.e6. PMID: 29909971, DOI: 10.1016/j.cmet.2018.05.019.Peer-Reviewed Original ResearchMeSH Keywordsalpha-SynucleinAnimalsBrainCell Line, TumorCeramidesDrosophilaDrosophila ProteinsFeedback, PhysiologicalFemaleGroup VI Phospholipases A2Group X Phospholipases A2HeLa CellsHumansLysosomesMaleMembrane FluidityMutationNeuronsNuclear ProteinsParkinson DiseaseRNA-Binding ProteinsSphingolipidsVesicular Transport ProteinsConceptsIPLA2-VIAImpairs synaptic transmissionEarly-onset parkinsonismSynaptic transmissionNeuroaxonal dystrophyParkinson's diseaseNeuronal functionBrain tissueNeurodegenerative disordersΑ-synucleinPLA2G6Ceramide levelsProgressive increaseNeurodegenerationLysosomal stressPositive feedback loopRetromer functionPhospholipid compositionCeramideGlycerol phospholipidsParkinsonismVPS35Desipramine
2017
Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway
Charkoftaki G, Jester JV, Thompson DC, Vasiliou V. Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway. The Ocular Surface 2017, 16: 154-162. PMID: 29129753, PMCID: PMC7376578, DOI: 10.1016/j.jtos.2017.11.004.Peer-Reviewed Original ResearchConceptsCorneal damageNM exposureSphingomyelin-ceramide pathwayCorneal stromaIrreversible corneal damageNitrogen mustardAltered lipid profileSulfur mustardCorneal injuryLipid profileCentral corneaCorneal epitheliumRabbit eyesSpecific sphingomyelinsPotent vesicantCorneaOrgan cultureStromaLipidomic analysisExposureMorphological changesDamaging effectsDamageInjuryPathwayHepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans
Horst K, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Zhang D, Samuel VT, Vatner DF, Petersen KF, Shulman GI, Serlie MJ. Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Reports 2017, 19: 1997-2004. PMID: 28591572, PMCID: PMC5469939, DOI: 10.1016/j.celrep.2017.05.035.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic steatosisObese subjectsPKCε activationTissue-specific insulin sensitivityHepatic ceramide contentPeripheral insulin resistanceHepatic lipid accumulationPathogenesis of NAFLDLiver biopsyIntrahepatic triglyceridesLiver fatInsulin sensitivityAdipose tissueTranslational evidenceSteatosisLipid accumulationCeramide contentPKCε translocationSubjectsMolecular mechanismsDiacylglycerol contentHumansActivationMutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma
Boyden LM, Vincent NG, Zhou J, Hu R, Craiglow BG, Bayliss SJ, Rosman IS, Lucky AW, Diaz LA, Goldsmith LA, Paller AS, Lifton RP, Baserga SJ, Choate KA. Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. American Journal Of Human Genetics 2017, 100: 978-984. PMID: 28575652, PMCID: PMC5473720, DOI: 10.1016/j.ajhg.2017.05.003.Peer-Reviewed Original ResearchConceptsYeast complementation studiesNew genetic determinantsCeramide synthesis pathwayKb inversionComplementation studiesRecessive Mendelian disordersCDNA sequencingGenome sequencingCeramide generationMendelian disordersSynthesis pathwayBase changesGenetic determinantsMutationsSequencingExome sequencingRetinoic acidProgressive symmetric erythrokeratodermaEpidermal functionMultiple probandsAlternative pathwayPathwayScaly skinSplicingExonsSTED Imaging of Golgi Dynamics with Cer-SiR: A Two-Component, Photostable, High-Density Lipid Probe for Live Cells
Erdmann RS, Toomre D, Schepartz A. STED Imaging of Golgi Dynamics with Cer-SiR: A Two-Component, Photostable, High-Density Lipid Probe for Live Cells. Methods In Molecular Biology 2017, 1663: 65-78. PMID: 28924659, PMCID: PMC6146391, DOI: 10.1007/978-1-4939-7265-4_6.Peer-Reviewed Original ResearchConceptsLive cellsMembrane-bound proteinsLipid probesGolgi dynamicsCellular functionsGolgi structureCellular organellesGolgi apparatusCeramide lipidsSuper-resolution imagingLabeling strategySTED imagingSTED microscopyCellsPhotostable fluorophoresLipidsGolgiOrganellesTwo-componentBioorthogonal reactionsProbeProteinHigh density
2015
Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity*
Camell CD, Nguyen KY, Jurczak MJ, Christian BE, Shulman GI, Shadel GS, Dixit VD. Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity*. Journal Of Biological Chemistry 2015, 290: 29402-29413. PMID: 26438821, PMCID: PMC4705943, DOI: 10.1074/jbc.m115.680199.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBone Marrow CellsCarrier ProteinsCeramidesDiet, High-FatDisease Models, AnimalFatty AcidsFemaleInflammasomesInflammationInsulin ResistanceLipidsMacrophagesMaleMiceMice, TransgenicMitochondriaNLR Family, Pyrin Domain-Containing 3 ProteinObesityOxidative StressSerine C-PalmitoyltransferaseConceptsDe novo synthesisNovo synthesisOverexpression of catalaseDietary lipid overloadSynthesis machineryTissue homeostasisCell-specific deletionInflammasome activationAdipose tissue homeostasisNLRP3 inflammasome activationMyeloid cell-specific deletionMetabolic pathwaysCeramide synthesisAlternate metabolic pathwaysCaspase-1 cleavageEnergy homeostasisLipid overloadCeramideLipid metabolismInflammasome-dependent mannerOxidative stressDanger signalsFat diet-induced obesityHomeostasisFatty acids
2014
Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload
Elezaby A, Sverdlov AL, Tu VH, Soni K, Luptak I, Qin F, Liesa M, Shirihai OS, Rimer J, Schaffer JE, Colucci WS, Miller EJ. Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload. Journal Of Molecular And Cellular Cardiology 2014, 79: 275-283. PMID: 25497302, PMCID: PMC4301992, DOI: 10.1016/j.yjmcc.2014.12.001.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsCarnitineCatalaseCeramidesCyclic AMP Response Element-Binding ProteinDiglyceridesElectron Transport Complex IIFatty Acid Transport ProteinsGene Expression RegulationHydrogen PeroxideLipidsMiceMitochondria, HeartModels, BiologicalMyocardiumMyocytes, CardiacOrgan SpecificityOxygen ConsumptionPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPhosphorylationPPAR alphaProtein Kinase CProto-Oncogene Proteins c-aktRNA, MessengerSphingomyelinsTranscription FactorsConceptsMetabolic heart diseaseMitochondrial structureMitochondrial fusion genes Mfn1Mitochondrial-targeted catalaseOverexpression of catalaseMitochondrial oxidative stressStructure/functionPhosphorylation of AktToxic metabolite accumulationTranscriptional regulationMitochondrial structure/functionFatty acid uptakeCardiomyocyte lipid accumulationMitochondrial remodelingMetabolite accumulationDiacylglycerol speciesExcess FAATP synthesisMitochondrial functionMitochondrial dysfunctionLipid speciesFA uptakeMitochondrial sizeHydrogen peroxide productionSubunit BSuper‐Resolution Imaging of the Golgi in Live Cells with a Bioorthogonal Ceramide Probe
Erdmann RS, Takakura H, Thompson AD, Rivera‐Molina F, Allgeyer ES, Bewersdorf J, Toomre D, Schepartz A. Super‐Resolution Imaging of the Golgi in Live Cells with a Bioorthogonal Ceramide Probe. Angewandte Chemie International Edition 2014, 53: 10242-10246. PMID: 25081303, PMCID: PMC4593319, DOI: 10.1002/anie.201403349.Peer-Reviewed Original ResearchCeramide-Activated Phosphatase Mediates Fatty Acid–Induced Endothelial VEGF Resistance and Impaired Angiogenesis
Mehra VC, Jackson E, Zhang XM, Jiang XC, Dobrucki LW, Yu J, Bernatchez P, Sinusas AJ, Shulman GI, Sessa WC, Yarovinsky TO, Bender JR. Ceramide-Activated Phosphatase Mediates Fatty Acid–Induced Endothelial VEGF Resistance and Impaired Angiogenesis. American Journal Of Pathology 2014, 184: 1562-1576. PMID: 24606881, PMCID: PMC4005977, DOI: 10.1016/j.ajpath.2014.01.009.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAortaArteriesCattleCeramidesDiet, High-FatEndothelial CellsEnzyme ActivationExtracellular Signal-Regulated MAP KinasesHaploinsufficiencyHindlimbHumansIschemiaMice, Inbred C57BLNeovascularization, PhysiologicNitric OxideNitric Oxide Synthase Type IIIPalmitic AcidPhosphorylationProtein Phosphatase 2Proto-Oncogene Proteins c-aktSerine C-PalmitoyltransferaseSignal TransductionVascular Endothelial Growth Factor AConceptsPP2A inhibitor okadaic acidProtein phosphatase 2AInhibitor okadaic acidVEGF-induced signalingSerine palmitoyltransferase inhibitor myriocinDe novo ceramide synthesisPhosphatase 2AENOS agonistsNovo ceramide synthesisPalmitic acidAngiogenic responsePotential molecular targetsOkadaic acidEndothelial cellsEarly speciesEndothelial cell responsesCord formationVEGFR2 phosphorylationSaturated free fatty acidVEGF resistanceCeramide synthesisResistance mechanismsMolecular targetsVascular homeostasisPhosphorylation
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