2025
Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism
Liu R, Zhang Z, Kyaw A, Grabińska K, Shah H, Shen H. Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism. Nature Metabolism 2025, 7: 1871-1888. PMID: 40925986, PMCID: PMC12460162, DOI: 10.1038/s42255-025-01358-y.Peer-Reviewed Original ResearchConceptsAcyl-CoAMitochondrial acyl-CoACoA-dependent pathwayAcyl-CoA profileCultured human cellsMitochondrial importCoA-dependentCoA poolTCA cycleFatty acid oxidationSpatial regulationSubcellular compartmentsCoA biosynthesisCoA metabolismLipid anabolismCoenzyme ACellular metabolismCatabolic processHuman cellsInborn errorsCoASHImportant processesThioester derivativesAcid oxidationMetabolism2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction
Kaul H, Isermann L, Senft K, Popovic M, Georgomanolis T, Baumann L, Sivanesan P, Pouikli A, Nolte H, Lucic B, Hildebrandt X, Seidel K, Gnad T, Gaedke F, Göbel U, Peters F, Cherevatenko M, Park J, Schauss A, Peltzer N, Brüning J, Kornfeld J, Pfeifer A, Langer T, Lusic M, Wickström S, Frezza C, Trifunovic A. 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction. Nature Metabolism 2025, 7: 1593-1613. PMID: 40750944, PMCID: PMC12373511, DOI: 10.1038/s42255-025-01332-8.Peer-Reviewed Original ResearchConceptsBrown adipose tissueNuclear stiffnessResponse to mitochondrial dysfunctionMitochondrial dysfunctionLipid droplet enlargementD-2HGAccumulation of lipid dropletsProtease ClpPFatty acid oxidationBrown adipocytesCellular homeostasisEpigenetic signaturesCellular metabolismGene expressionOncometabolite D-2-hydroxyglutarateD-2-hydroxyglutarateLipid dropletsMolecular underpinningsLipid accumulationExtrinsic cuesNuclear softeningAcid oxidationAdipose tissueClpPMitochondriaSynergistic toxicity in alcohol-associated liver disease and PFAS exposure
Stem A, Tieghi R, Chatzi V, Kleinstreuer N, Valvi D, Thompson D, Vasiliou V. Synergistic toxicity in alcohol-associated liver disease and PFAS exposure. Toxicological Sciences 2025, kfaf110. PMID: 40737496, DOI: 10.1093/toxsci/kfaf110.Peer-Reviewed Original ResearchAlcohol-associated liver diseaseLiver diseaseChronic ethanol intakeCentral mechanismsHepatotoxic effectsPolyfluoroalkyl substancesHigh-risk populationOxidative stressDysregulated lipid metabolismEthanol intakeLiver functionLiver injuryAcetaldehyde-induced cytotoxicityHepatic functionHepatocellular damageOxidative stress inductionLiver pathologyGlobal morbidityPathogenic pathwaysPolyfluoroalkyl substances exposuresExposure to polyfluoroalkyl substancesFatty acid oxidationHealthcare accessEffects of polyfluoroalkyl substancesMultiple mechanismsUCP2 mediates mitochondrial dynamics to induce AgRP neuronal activity
Jin S, Yoon N, Liu Z, Menale C, Kim J, Diano N, Diano S. UCP2 mediates mitochondrial dynamics to induce AgRP neuronal activity. Molecular Metabolism 2025, 99: 102215. PMID: 40683468, PMCID: PMC12328681, DOI: 10.1016/j.molmet.2025.102215.Peer-Reviewed Original ResearchConceptsDynamin-related protein 1Mitochondrial dynamicsAgRP neuron activityExpression level of uncoupling protein 2AgRP neuronsFeeding behaviorWhole-body energy homeostasisLevel of uncoupling protein 2AgRP neuronal functionMitochondrial fatty acid utilizationMRNA expression levelsWhole-body energy metabolismMitochondrial proteinsMitochondrial fissionMitochondrial morphologyFatty acid oxidationAgouti-related protein (AgRP)-expressing neuronsNeuronal activityFatty acid utilizationHypothalamic AgRP neuronsAcid utilizationEnergy homeostasisUCP2Fasting-induced food intakeEnergy metabolism1686-P: Novel Combination of a Mitochondrial Protonophore (MP) and an Acetyl-CoA Carboxylase 2 (ACC2) Inhibitor Causes Weight Loss and Preserves Lean Mass in Obese Mice
SRODA N, SHARMA M, MURAKAMI E, LOGAN C, WENG S, KIRBY B, MYERS R, SUBRAMANIAN M, SHULMAN G, VIJAYAKUMAR A. 1686-P: Novel Combination of a Mitochondrial Protonophore (MP) and an Acetyl-CoA Carboxylase 2 (ACC2) Inhibitor Causes Weight Loss and Preserves Lean Mass in Obese Mice. Diabetes 2025, 74 DOI: 10.2337/db25-1686-p.Peer-Reviewed Original ResearchLean massMitochondrial protonophoreDIO miceFood intakeFat mass lossReduced lean massWeight lossBody weightAcetyl-CoA carboxylase 2Obesity-associated disordersMale DIO miceFat massSemaglutideDiet-inducedNovel combinationObese miceMetabolic disordersEnhanced fatty acid oxidationMiceFatty acid oxidationEvaluation of combinationsObesityInhibitorsTreated withIntakeEndoplasmic 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 transportTranscriptomic and epigenomic signatures of liver metabolism and insulin sensitivity in aging mice
González J, Scharfman O, Zhu W, Kasamoto J, Gould V, Perry R, Higgins-Chen A. Transcriptomic and epigenomic signatures of liver metabolism and insulin sensitivity in aging mice. Mechanisms Of Ageing And Development 2025, 225: 112068. PMID: 40324540, PMCID: PMC12151592, DOI: 10.1016/j.mad.2025.112068.Peer-Reviewed Original ResearchConceptsDNA methylation modulesHepatic insulin resistanceRNA modulesProtein-protein interaction network analysisMetabolic pathwaysMethylation modulatorsPyruvate carboxylase fluxInteraction network analysisCitrate synthase fluxDNA methylation analysisCanonical metabolic pathwaysLipid metabolic pathwaysDecreased fatty acid oxidationComprehensive phenotypic characterizationMZF-1Fatty acid oxidationEpigenomic signaturesInsulin-stimulated conditionsModule genesNetwork analysisPhenotypic characterizationMitochondrial metabolic defectsInsulin resistanceLiver insulin resistanceMethylation analysis
2024
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts
Goedeke L, Ma Y, Gaspar R, Nasiri A, Lee J, Zhang D, Galsgaard K, Hu X, Zhang J, Guerrera N, Li X, LaMoia T, Hubbard B, Haedersdal S, Wu X, Stack J, Dufour S, Butrico G, Kahn M, Perry R, Cline G, Young L, Shulman G. SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts. Journal Of Clinical Investigation 2024, 134: e176708. PMID: 39680452, PMCID: PMC11645152, DOI: 10.1172/jci176708.Peer-Reviewed Original ResearchConceptsSodium-glucose cotransporter type 2Heart failureKetone oxidationGas chromatography-mass spectrometryFatty acid oxidationLeft ventricular ejection fractionReduced myocardial oxidative stressVentricular ejection fractionKetone supplementationWeeks of treatmentMyocardial oxidative stressDecreased pyruvate oxidationInduce heart failurePlasma glucose levelsIn vivo effectsSGLT2i treatmentEjection fractionAssociated with improvementsAwake ratsSGLT2 inhibitionCardioprotective benefitsLiquid chromatography-tandem mass spectrometryPlasma ketonesRates of ketonizationChromatography-tandem mass spectrometryIntracellular 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, 36: 744-755. PMID: 39672762, PMCID: PMC12159263, 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 healingRenal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease
Srivastava S, Zhou H, Shenoi R, Morris M, Lainez-Mas B, Goedeke L, Rajendran B, Setia O, Aryal B, Kanasaki K, Koya D, Inoki K, Dardik A, Bell T, Fernández-Hernando C, Shulman G, Goodwin J. Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease. Science Advances 2024, 10: eadn6068. PMID: 39630889, PMCID: PMC11616692, DOI: 10.1126/sciadv.adn6068.Peer-Reviewed Original ResearchConceptsAngiopoietin-like 4Diabetic kidney diseaseIntegrin B1Fibrogenic moleculesMutant miceSTING pathway activationIncreased fatty acid oxidationProgressive diabetic kidney diseaseDiabetic kidneyKidney diseaseReduced epithelial-to-mesenchymal transitionEpithelial-to-mesenchymal transitionFatty acid oxidationExpression of pro-inflammatory cytokinesTargeted pharmacological therapiesGene expressionMitochondrial damageEndothelial-to-mesenchymal transitionPro-inflammatory cytokinesPathway activationPharmacological therapyControl miceIntegrinAcid oxidationFibrogenic phenotypemiR-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 carcinomaA metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance
Mertens R, Misra A, Xiao P, Baek S, Rone J, Mangani D, Sivanathan K, Arojojoye A, Awuah S, Lee I, Shi G, Petrova B, Brook J, Anderson A, Flavell R, Kanarek N, Hemberg M, Nowarski R. A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance. Immunity 2024, 57: 2077-2094.e12. PMID: 38906145, DOI: 10.1016/j.immuni.2024.06.001.Peer-Reviewed Original ResearchFatty acid oxidationStimulator of interferon genesMetabolic switchIL-18Immune toleranceIntestinal toleranceRelease of mitochondrial DNAActivation of stimulator of interferon genesSusceptibility to inflammationIL-18 stimulationIL-18 activityMitochondrial DNATolerogenic macrophagesChronic inflammationInterleukin-18Immune stateInflammatory challengeInflammatory responseMetabolic programmingSodium influxMacrophage-derivedImmune functionInterferon genesBistable switchAcid oxidationSpatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity
Parlakgül G, Pang S, Artico L, Min N, Cagampan E, Villa R, Goncalves R, Lee G, Xu C, Hotamışlıgil G, Arruda A. Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity. Nature Communications 2024, 15: 3982. PMID: 38729945, PMCID: PMC11087507, DOI: 10.1038/s41467-024-48272-7.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulumER-mitochondria interactionsSubcellular spatial organizationER-mitochondriaER sheetsNutritional fluctuationsFatty acid oxidationNutrient availabilityHepatic fatty acid oxidationMetabolic flexibilityVolume electron microscopyHepatic ERMitochondriaLiver zonationSpatial organizationAcid oxidationPericentral hepatocytesHepatocytesMolecular architectureRibosomeProtein1ReticulumRemodelingZonationInteractionReducing brain Aβ burden ameliorates high-fat diet-induced fatty liver disease in APP/PS1 mice
Tsay H, Gan Y, Su Y, Sun Y, Yao H, Chen H, Hsu Y, Hsu J, Wang H, Shie F. Reducing brain Aβ burden ameliorates high-fat diet-induced fatty liver disease in APP/PS1 mice. Biomedicine & Pharmacotherapy 2024, 173: 116404. PMID: 38471275, DOI: 10.1016/j.biopha.2024.116404.Peer-Reviewed Original ResearchAPP/PS1 miceAmeliorate fatty liver diseaseAlzheimer's diseaseAD-like pathologyHFD-induced hyperglycemiaAD-related pathologyExpression of genesFatty liver diseaseFatty acid oxidationHFD-induced fatty liverAD therapyLipid accumulationHigh-fat diet-induced fatty liver diseaseAPP/PS1HFD feedingCharacteristics of microgliaExposure to HFDHepatic lipogenesisLiver diseaseDiet-induced fatty liver diseaseAcid oxidationHepatic lipids
2023
Calponin 2 regulates ketogenesis to mitigate acute kidney injury
Gui Y, Palanza Z, Gupta P, Li H, Pan Y, Wang Y, Hargis G, Kreutzer D, Wang Y, Bastacky S, Liu Y, Liu S, Zhou D. Calponin 2 regulates ketogenesis to mitigate acute kidney injury. JCI Insight 2023, 8: e170521. PMID: 37751293, PMCID: PMC10721266, DOI: 10.1172/jci.insight.170521.Peer-Reviewed Original ResearchConceptsAcute kidney injuryEstrogen receptor 2Fatty acid oxidationKidney injuryKidney fibrosisCalponin 2Ketone body β-hydroxybutyrateTubular cell deathBody β-hydroxybutyrateSirtuin 5Endogenous ketogenesisKidney functionReceptor 2Protein posttranslational modificationsRate-limiting enzymeFAO pathwayMitochondrial sirtuin 5Animal kidneysΒ-hydroxybutyrateOrgan performanceCell proliferationSynthase 2FibrosisPosttranslational modificationsInjuryMolecular Mechanism of Fasting-Mimicking Diet in Inhibiting Colorectal Cancer Progression: Implications for Immune Therapy and Metabolic Regulation.
Bush C, Perry R. Molecular Mechanism of Fasting-Mimicking Diet in Inhibiting Colorectal Cancer Progression: Implications for Immune Therapy and Metabolic Regulation. Cancer Research 2023, 83: 3493-3494. PMID: 37908187, DOI: 10.1158/0008-5472.can-23-2257.Commentaries, Editorials and LettersConceptsFasting-mimicking dietColorectal cancer progressionIgA class switchingColorectal cancerCancer progressionB cellsClass switchingFatty acid oxidationAnticancer immunityAntitumor immunityImmune therapyMolecular mechanismsTumor regressionMouse modelCaloric restrictionAnticancer effectsMetabolic reprogrammingProgressionDietCancerAcid oxidationCancer researchImmunityMetabolic regulationCellsMulti-omic analysis reveals metabolic pathways that characterize right-sided colon cancer liver metastasis
Morris M, Jain A, Sun B, Kurbatov V, Muca E, Zeng Z, Jin Y, Roper J, Lu J, Paty P, Johnson C, Khan S. Multi-omic analysis reveals metabolic pathways that characterize right-sided colon cancer liver metastasis. Cancer Letters 2023, 574: 216384. PMID: 37716465, PMCID: PMC10620771, DOI: 10.1016/j.canlet.2023.216384.Peer-Reviewed Original ResearchConceptsLiver metastasesColon cancer liver metastasisCancer liver metastasesSided colon cancerSubset of patientsGrowth factor betaMulti-omics analysisFatty acid oxidationMetastatic diseaseInferior survivalClinical differencesClinical behaviorUntargeted metabolomics analysisTumor behaviorColon cancerBile acidsTumor cell metabolismFactor betaPatientsMetastasisPI3K-AktReactive oxygen speciesMEK-ERKLiquid chromatography-mass spectrometryRCC849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats
VIJAYAKUMAR A, MURAKAMI E, HUSS R, SRODA N, SHIMAZAKI A, KASHIWAGI Y, MYERS R, SUBRAMANIAN M, SHULMAN G. 849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats. Diabetes 2023, 72 DOI: 10.2337/db23-849-p.Peer-Reviewed Original ResearchZucker diabetic fattyZDF ratsInsulin sensitivityAcetyl-CoA carboxylase 2T2D progressionAntidiabetic effectsClamp glucose infusion rateIntramyocellular lipid contentImproved insulin sensitivityHyperinsulinemic-euglycemic clampType 2 diabetesGlucose infusion rateNovel therapeutic approachesΒ-cell failureFatty acid oxidationFortress BiotechCardiac lipidsInsulin resistanceInfusion rateTherapeutic approachesStrong rationaleRatsGilead SciencesJanssen ResearchIMCLThe impact of variance in carnitine palmitoyltransferase-1 expression on breast cancer prognosis is stratified by clinical and anthropometric factors
Liu R, Ospanova S, Perry R. The impact of variance in carnitine palmitoyltransferase-1 expression on breast cancer prognosis is stratified by clinical and anthropometric factors. PLOS ONE 2023, 18: e0281252. PMID: 36735704, PMCID: PMC9897541, DOI: 10.1371/journal.pone.0281252.Peer-Reviewed Original ResearchConceptsBreast cancer prognosisBreast cancerFatty acid metabolismCancer prognosisCarnitine palmitoyltransferase 1 expressionHigh-risk breast cancerPre-menopausal patientsAcid metabolismPatient survival probabilityPositron emission tomography-computed tomography (PET-CT) imagesFatty acid oxidationMenopausal statusAnthropometric factorsPathogenic factorsCPT1A expressionRate-limiting enzymeObesityProtective relationshipCancerSurvival probabilityCancer Imaging ArchivePotential rolePatientsPrognosisAcid oxidation
2022
Maf family transcription factors are required for nutrient uptake in the mouse neonatal gut
Bara A, Chen L, Ma C, Underwood J, Moreci R, Sumigray K, Sun T, Diao Y, Verzi M, Lechler T. Maf family transcription factors are required for nutrient uptake in the mouse neonatal gut. Development 2022, 149 PMID: 36504079, PMCID: PMC10112929, DOI: 10.1242/dev.201251.Peer-Reviewed Original ResearchConceptsNutrient uptakeTranscription factorsMaf family transcription factorsMajor transcriptional changesFamily transcription factorsLoss of Blimp1Transcription factor MafBMaf proteinsCell fateTranscriptional regulatorsTranscriptional changesRNA-seqMaster regulatorEnterocyte genesFatty acid oxidationGene expressionPeroxisome numberAdult intestineMetabolic pathwaysMolecular componentsSubsequent degradationMaf factorsC-MafSimilar defectsIntestinal enterocytes
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