2025
An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis
El Bounkari O, Zan C, Yang B, Ebert S, Wagner J, Bugar E, Kramer N, Bourilhon P, Kontos C, Zarwel M, Sinitski D, Milic J, Jansen Y, Kempf W, Sachs N, Maegdefessel L, Ji H, Gokce O, Riols F, Haid M, Gerra S, Hoffmann A, Brandhofer M, Avdic M, Bucala R, Megens R, Willemsen N, Messerer D, Schulz C, Bartelt A, Harm T, Rath D, Döring Y, Gawaz M, Weber C, Kapurniotu A, Bernhagen J. An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis. Nature Communications 2025, 16: 2297. PMID: 40055309, DOI: 10.1038/s41467-025-57540-z.Peer-Reviewed Original ResearchConceptsApoE-/- miceHyperlipidemic apoE-/- miceCoronary artery diseaseDecreased plasma lipid levelsPlasma lipid levelsHepatic lipid accumulationAtherogenic chemokinesFoam-cell formationFLIM-FRET microscopyArtery diseasePlasma concentrationsVascular inflammationInflammatory conditionsMetabolic dysfunctionAtherosclerotic patientsLipid accumulationAdvanced atherosclerosisMyocardial infarctionLipid levelsSuppressed hepatic lipid accumulationAdvanced atherogenesisCarotid plaquesDisease severityIschemic strokeChemokinesDeuterium MRS for In Vivo Measurement of Lipogenesis in the Liver
Gursan A, de Graaf R, Thomas M, Prompers J, De Feyter H. Deuterium MRS for In Vivo Measurement of Lipogenesis in the Liver. NMR In Biomedicine 2025, 38: e70014. PMID: 39994887, DOI: 10.1002/nbm.70014.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDeuteriumLipogenesisLiverMagnetic Resonance SpectroscopyMaleRatsRats, Sprague-DawleyConceptsH-MRSHepatic DNLMRS dataLiver tissueMeasurement of lipogenesisDietary interventionLiver lipidsHepatic de novo lipogenesisLow density lipoproteinDetection of deuteriumGold standard measureMetabolic diseasesIncreased hepatic DNLLiverDensity lipoproteinDrinking waterDeuterium labelingIn vivo measurementsNMR dataExcised liver tissueTissueDeuteriumMRSMethylene resonancesDeuterated waterLipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation
Liu J, Shen Y, Liu J, Xu D, Chang C, Wang J, Zhou J, Haffty B, Zhang L, Bargonetti J, De S, Hu W, Feng Z. Lipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation. Nature Communications 2025, 16: 1762. PMID: 39971971, PMCID: PMC11839913, DOI: 10.1038/s41467-025-57099-9.Peer-Reviewed Original ResearchConceptsGain-of-functionTumor suppressive function of p53Mutp53 accumulationAccumulate to high levelsFunction of p53Mutant p53 accumulationTumor suppressive functionMutant p53Subcutaneous xenograft tumor modelMutp53Promote tumorigenesisP53 accumulationPalmitoylationPotential therapeutic strategyXenograft tumor modelFASNTumor modelTumor organoidsTransgenic miceTherapeutic strategiesP53
2024
Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression
Asantewaa G, Tuttle E, Ward N, Kang Y, Kim Y, Kavanagh M, Girnius N, Chen Y, Rodriguez K, Hecht F, Zocchi M, Smorodintsev-Schiller L, Scales T, Taylor K, Alimohammadi F, Duncan R, Sechrist Z, Agostini-Vulaj D, Schafer X, Chang H, Smith Z, O’Connor T, Whelan S, Selfors L, Crowdis J, Gray G, Bronson R, Brenner D, Rufini A, Dirksen R, Hezel A, Huber A, Munger J, Cravatt B, Vasiliou V, Cole C, DeNicola G, Harris I. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression. Nature Communications 2024, 15: 6152. PMID: 39034312, PMCID: PMC11271484, DOI: 10.1038/s41467-024-50454-2.Peer-Reviewed Original ResearchConceptsGlutamate-cysteine ligase catalytic subunitLipid abundanceLipogenic enzyme expressionAbundance in vivoLipid productionCatalytic subunitRepress Nrf2Transcription factorsNrf2 repressionAdult tissuesSynthesis of GSHEnzyme expressionNon-redundantRedox bufferMouse liverLoss of GSHTriglyceride productionIn vivo modelsAbundanceGlutathione synthesisLiver balanceFat storesOxidative stressLipidDeletion
2023
The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Luukkonen P, Porthan K, Ahlholm N, Rosqvist F, Dufour S, Zhang X, Lehtimäki T, Seppänen W, Orho-Melander M, Hodson L, Petersen K, Shulman G, Yki-Järvinen H. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metabolism 2023, 35: 1887-1896.e5. PMID: 37909034, DOI: 10.1016/j.cmet.2023.10.008.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisHepatic de novo lipogenesisPlasma β-hydroxybutyrate concentrationsΒ-hydroxybutyrate concentrationsLiver diseaseNovo lipogenesisPNPLA3 I148M variantHepatic mitochondrial redox stateMajor genetic risk factorI148M variantFatty liver diseaseGenetic risk factorsHepatic mitochondrial dysfunctionKetogenic dietMixed mealRisk factorsHepatic metabolismHomozygous carriersM carriersMitochondrial dysfunctionCitrate synthase fluxM variantKetogenesisMitochondrial redox stateMitochondrial functionSpatiotemporal Heterogeneity of De Novo Lipogenesis in Fixed and Living Single Cells
Shuster S, Burke M, Davis C. Spatiotemporal Heterogeneity of De Novo Lipogenesis in Fixed and Living Single Cells. The Journal Of Physical Chemistry B 2023, 127: 2918-2926. PMID: 36976708, DOI: 10.1021/acs.jpcb.2c08812.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesCell SurvivalDiabetes Mellitus, Type 2HumansLipogenesisLiverSingle-Cell AnalysisTriglyceridesConceptsDe novo lipogenesisPanc1 pancreatic cancer cellsPancreatic cancer cellsLipid dropletsType II diabetesGlucose metabolismNovo lipogenesisII diabetesLipid droplet morphologyLiver tissueGlucose uptakeCancer cellsAdipocyte cellsHigh rateLipogenesisDNL ratesCritical metabolic processesAdipocytesMajority of lipidsCellsLipidsBetter preservationObesityDiabetesTriglycerides
2022
Complex regulation of fatty liver disease
Ginsberg HN, Mani A. Complex regulation of fatty liver disease. Science 2022, 376: 247-248. PMID: 35420931, PMCID: PMC9619413, DOI: 10.1126/science.abp8276.Peer-Reviewed Original ResearchDyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
Bhat N, Narayanan A, Fathzadeh M, Kahn M, Zhang D, Goedeke L, Neogi A, Cardone RL, Kibbey RG, Fernandez-Hernando C, Ginsberg HN, Jain D, Shulman G, Mani A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. Journal Of Clinical Investigation 2022, 132: e153724. PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/jci153724.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisNonalcoholic steatohepatitisInsulin resistanceHepatic lipogenesisElevated de novo lipogenesisNonalcoholic fatty liver diseaseFatty liver diseaseLiver of patientsHepatic glycogen storageHigh-sucrose dietHepatic insulin resistanceFatty acid uptakeMetabolic syndromeLiver diseaseHepatic steatosisTriacylglycerol secretionNovo lipogenesisHepatic insulinTherapeutic targetImpaired activationAcid uptakeGlycogen storageMouse liverLiverLipogenesis
2021
Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis
Jiang Z, Zhao M, Voilquin L, Jung Y, Aikio MA, Sahai T, Dou FY, Roche AM, Carcamo-Orive I, Knowles JW, Wabitsch M, Appel EA, Maikawa CL, Camporez JP, Shulman GI, Tsai L, Rosen ED, Gardner CD, Spiegelman BM, Svensson KJ. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Cell Metabolism 2021, 33: 1836-1852.e11. PMID: 34348115, PMCID: PMC8429235, DOI: 10.1016/j.cmet.2021.07.010.Peer-Reviewed Original ResearchConceptsFatty liver diseaseAdipose glucose uptakeGlucose toleranceLiver diseaseHepatic steatosisGlucose uptakeDiet-induced obese miceImpaired glucose toleranceInsulin-like growth factor receptorType 2 diabetesHepatic lipid synthesisIsthmin 1Growth factor receptorObese miceInsulin sensitivityTherapeutic dosingMouse modelGlucoregulatory functionGlucose regulationUnmet needTherapeutic potentialDiabetesLipid accumulationPI3K-AktFactor receptorTMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis
Huang D, Xu B, Liu L, Wu L, Zhu Y, Ghanbarpour A, Wang Y, Chen FJ, Lyu J, Hu Y, Kang Y, Zhou W, Wang X, Ding W, Li X, Jiang Z, Chen J, Zhang X, Zhou H, Li JZ, Guo C, Zheng W, Zhang X, Li P, Melia T, Reinisch K, Chen XW. TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis. Cell Metabolism 2021, 33: 1655-1670.e8. PMID: 34015269, DOI: 10.1016/j.cmet.2021.05.006.Peer-Reviewed Original Research
2020
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. Journal Of Experimental Medicine 2020, 218: e20201416. PMID: 33315085, PMCID: PMC7927432, DOI: 10.1084/jem.20201416.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAnimalsDiabetes Mellitus, Type 2Diet, High-FatEnergy MetabolismFatty LiverGene DeletionGene TargetingGluconeogenesisHomeostasisHumansHyperglycemiaInflammationInsulin ResistanceLipogenesisLiverMaleMice, Inbred C57BLMice, KnockoutMitochondriaMitophagyNF-kappa BOxidative StressPhenotypeReactive Oxygen SpeciesSequestosome-1 ProteinSignal TransductionThioredoxinsConceptsHepatic insulin resistanceWhite adipose tissueInsulin resistanceAdipose inflammationType 2 diabetes mellitusLipid metabolic disordersNF-κB inhibitorAdipose-specific deletionWhole-body energy homeostasisAltered fatty acid metabolismFatty acid metabolismT2DM progressionT2DM patientsDiabetes mellitusReactive oxygen species pathwayHepatic steatosisMetabolic disordersNF-κBP62/SQSTM1Adipose tissueHuman adipocytesEnergy homeostasisExcessive mitophagyOxygen species pathwayInflammationHepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease.
Ter Horst KW, Vatner DF, Zhang D, Cline GW, Ackermans MT, Nederveen AJ, Verheij J, Demirkiran A, van Wagensveld BA, Dallinga-Thie GM, Nieuwdorp M, Romijn JA, Shulman GI, Serlie MJ. Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease. Diabetes Care 2020, 44: 489-498. PMID: 33293347, PMCID: PMC7818337, DOI: 10.2337/dc20-1644.Peer-Reviewed Original ResearchMeSH KeywordsDiabetes Mellitus, Type 2HumansInsulinInsulin ResistanceLipogenesisLiverNon-alcoholic Fatty Liver DiseaseConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisFatty liver diseaseBariatric surgeryLiver diseaseImpaired insulin-mediated suppressionGlucose productionHepatic de novo lipogenesisPeripheral glucose metabolismHyperinsulinemic-euglycemic clampType 2 diabetesInsulin-mediated suppressionInsulin-resistant subjectsHepatic insulin resistanceLiver biopsy samplesSuppress glucose productionLipogenic transcription factorsInsulin-mediated regulationObese subjectsInsulin resistanceAcute increaseNovo lipogenesisGlucose metabolismBiopsy samplesParadoxical increaseBoth proliferation and lipogenesis of brown adipocytes contribute to postnatal brown adipose tissue growth in mice
Negron SG, Ercan-Sencicek AG, Freed J, Walters M, Lin Z. Both proliferation and lipogenesis of brown adipocytes contribute to postnatal brown adipose tissue growth in mice. Scientific Reports 2020, 10: 20335. PMID: 33230135, PMCID: PMC7683731, DOI: 10.1038/s41598-020-77362-x.Peer-Reviewed Original ResearchConceptsBrown adipocytesExit cell cycleDevelopmental dynamicsCell cycle activityBrown adipose tissueDifferent growth phasesMolecular mechanismsCell cycleFluorescence-activated cell sorting (FACS) analysisCell sorting (FACS) analysisBAT growthGrowth phaseEssential roleInterscapular BATCycle activityTissue growthDevelopment of BATBrown adipose tissue growthAdipocytesAdipose tissue growthInterscapular brown adipose tissueProliferationGrowthEmbryogenesisLipogenesisReduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity
Zhang S, Guo F, Yu M, Yang X, Yao Z, Li Q, Wei Z, Feng K, Zeng P, Zhao D, Li X, Zhu Y, Miao QR, Iwakiri Y, Chen Y, Han J, Duan Y. Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity. Journal Of Hepatology 2020, 73: 1482-1495. PMID: 32738448, DOI: 10.1016/j.jhep.2020.07.034.Peer-Reviewed Original ResearchConceptsDiet-induced metabolic disordersHepatic lipid accumulationInsulin sensitivityMetabolic disordersInsulin resistanceNogo expressionNon-alcoholic fatty liver diseaseDiet-induced body weight gainInsulin activityDiet-induced glucose intoleranceLipid accumulationFatty liver diseaseHigh-fructose dietGrowth factor 21Littermate control miceDe novo lipogenesisHigh-carbohydrate dietBody weight gainCarbohydrate-responsive element-binding proteinExpression of ChREBPChREBP activityEndoplasmic reticulum stressMetabolic complicationsGlucose intoleranceLiver disease
2019
Glutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis
Chen Y, Manna SK, Golla S, Krausz KW, Cai Y, Garcia-Milian R, Chakraborty T, Chakraborty J, Chatterjee R, Thompson DC, Gonzalez FJ, Vasiliou V. Glutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis. Free Radical Biology And Medicine 2019, 143: 127-139. PMID: 31351176, PMCID: PMC6848780, DOI: 10.1016/j.freeradbiomed.2019.07.025.Peer-Reviewed Original ResearchMeSH KeywordsAcetyl Coenzyme AAlcohol DrinkingAMP-Activated Protein KinasesAnimalsEthanolFatty AcidsFatty LiverGlucuronic AcidGlutamate-Cysteine LigaseGlutamatesGlutathioneHomeostasisLipogenesisLiverMaleMiceMice, Inbred C57BLMice, KnockoutOligonucleotide Array Sequence AnalysisOxidation-ReductionOxidative StressPentose Phosphate PathwayProtective AgentsTranscription, GeneticConceptsGlutamate-cysteine ligase modifier subunit geneProtein kinase pathwayAcetyl-CoA fluxMultiple cellular pathwaysAlcohol-induced steatosisCellular stressNucleotide biosynthesisLiver microarray analysisGlobal profilingSubunit geneCellular pathwaysMetabolic reprogrammingKinase pathwayMicroarray analysisMolecular mechanismsGSH poolCellular responsesMetabolic pathwaysLower GSHMolecular pathwaysMetabolic homeostasisAmino acidsDepletion of glutathioneCritical pathogenic eventGlucuronate pathwayAltered In Vivo Lipid Fluxes and Cell Dynamics in Subcutaneous Adipose Tissues Are Associated With the Unfavorable Pattern of Fat Distribution in Obese Adolescent Girls
Nouws J, Fitch M, Mata M, Santoro N, Galuppo B, Kursawe R, Narayan D, Vash-Margita A, Pierpont B, Shulman GI, Hellerstein M, Caprio S. Altered In Vivo Lipid Fluxes and Cell Dynamics in Subcutaneous Adipose Tissues Are Associated With the Unfavorable Pattern of Fat Distribution in Obese Adolescent Girls. Diabetes 2019, 68: 1168-1177. PMID: 30936147, PMCID: PMC6610014, DOI: 10.2337/db18-1162.Peer-Reviewed Original ResearchConceptsObese adolescent girlsFat distributionFatty liverMetabolic impairmentMature adipocytesAdipose tissueAbdominal fat distributionEctopic fat distributionFemoral adipose tissueType 2 diabetesAdolescent girlsDe novo lipogenesisSubcutaneous adipose tissueVascular cell proliferationUnfavorable phenotypeSubcutaneous abdominalAdipose lipidsInsulin resistanceObese adolescentsUnderlying metabolic alterationsObese girlsHigh riskNovo lipogenesisGluteal depotMetabolic alterationsMitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight
Mancini G, Pirruccio K, Yang X, Blücher M, Rodeheffer M, Horvath TL. Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight. Cell Reports 2019, 26: 2849-2858.e4. PMID: 30865877, PMCID: PMC6876693, DOI: 10.1016/j.celrep.2019.02.039.Peer-Reviewed Original ResearchConceptsKnockout miceBody weightMitochondria-endoplasmic reticulum interactionSystemic metabolic dysregulationImpaired glucose metabolismHigh-fat dietObese human subjectsCalorie-dense foodsMitofusin 2Control miceStandard chowLean controlsMetabolic dysregulationFood intakeAdult miceGlucose metabolismStandard dietAdipose tissueBrown fatGlucose utilizationAdiposityTissue levelsSystemic levelsMiceAdult animalsRegulation of substrate utilization and adiposity by Agrp neurons
Cavalcanti-de-Albuquerque JP, Bober J, Zimmer MR, Dietrich MO. Regulation of substrate utilization and adiposity by Agrp neurons. Nature Communications 2019, 10: 311. PMID: 30659173, PMCID: PMC6338802, DOI: 10.1038/s41467-018-08239-x.Peer-Reviewed Original ResearchConceptsFat mass accumulationAgRP neuronsPositive energy balanceWhole-body substrate utilizationAgRP neuron activationHypothalamic AgRP neuronsPair-feeding conditionsSubstrate utilizationFatty acid synthaseCaloric ingestionFat utilizationNeuronal mechanismsWeight gainNeuronsMetabolic changesMass accumulationKey enzymeAdiposityAcid synthaseEnergy metabolismNeuron activationLipogenesisActivationCarbohydrate utilizationMetabolic efficiency
2018
PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats
Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov V, Church C, Rodeheffer M, Cline G, Geisler J, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2018, 160: 205-219. PMID: 30445425, PMCID: PMC6307100, DOI: 10.1210/en.2018-00630.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, WhiteAdiposityAnimalsDiabetes Mellitus, Type 2Diet, High-FatGlucokinaseHumansInsulinIntracellular Signaling Peptides and ProteinsLipogenesisLiverLiver GlycogenMaleMiceMice, Inbred C57BLOligonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)RatsRats, Sprague-DawleyConceptsHepatic glycogen synthesisAdipose tissueAntisense oligonucleotideType 2 diabetes mellitusWhite adipose tissue massIncreased hepatic gluconeogenesisChow fed ratsHepatic insulin sensitivityMale Sprague-DawleyAdipose tissue massHepatic insulin resistanceWhite adipose tissueHepatic glucose productionDe novo lipogenesisHepatic glucokinase expressionControl antisense oligonucleotideGlycogen synthesisTranscription factor 3HFF ratsDiabetes mellitusHepatic steatosisInsulin resistanceHyperglycemic clampPlasma glucoseInsulin sensitivityRho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Huang H, Lee S, Sousa-Lima I, Kim S, Hwang W, Dagon Y, Yang W, Cho S, Kang M, Seo J, Shibata M, Cho H, Belew G, Bhin J, Desai B, Ryu M, Shong M, Li P, Meng H, Chung B, Hwang D, Kim M, Park K, Macedo M, White M, Jones J, Kim Y. Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. Journal Of Clinical Investigation 2018, 128: 5335-5350. PMID: 30226474, PMCID: PMC6264719, DOI: 10.1172/jci63562.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic lipid accumulationLiver diseaseInsulin resistanceRisk factorsNovo lipogenesisObesity-related metabolic disordersLipid accumulationObesity-induced steatosisChronic liver diseaseObese diabetic miceDiet-induced obesityMajor risk factorSevere hepatic steatosisHigh-fat dietDe novo lipogenesisThermogenic gene expressionRho kinase 1Antidiabetes drugsDiabetic miceHepatic steatosisActivation of AMPKHepatocellular carcinomaMetabolic disorders
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