2025
Predicting adenine base editing efficiencies in different cellular contexts by deep learning
Kissling L, Mollaysa A, Janjuha S, Mathis N, Marquart K, Weber Y, Moon W, Lin P, Fan S, Muramatsu H, Vadovics M, Allam A, Pardi N, Tam Y, Krauthammer M, Schwank G. Predicting adenine base editing efficiencies in different cellular contexts by deep learning. Genome Biology 2025, 26: 115. PMID: 40340964, PMCID: PMC12060317, DOI: 10.1186/s13059-025-03586-7.Peer-Reviewed Original ResearchConceptsBase editing efficiencyEditing efficiencyCell linesPathogenic mutationsBase editingPrimary cells in vivoBase editing screensBase editing outcomesCells in vivoHEK293T cellsAdenine base editingIn vivo settingTarget lociT cellsLipid nanoparticlesCellular contextTarget sequenceMRNA deliveryBase pairsOn-target editingBystander effectEditing outcomesBase editorsIn vitro datasetsMurine liverLiver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis
Sakuma I, Gaspar R, Nasiri A, Dufour S, Kahn M, Zheng J, LaMoia T, Guerra M, Taki Y, Kawashima Y, Yimlamai D, Perelis M, Vatner D, Petersen K, Huttasch M, Knebel B, Kahl S, Roden M, Samuel V, Tanaka T, Shulman G. Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2502978122. PMID: 40310463, DOI: 10.1073/pnas.2502978122.Peer-Reviewed Original ResearchConceptsCholine-deficient l-amino acid-defined high-fat dietBempedoic acidLiver fibrosisLiver diseaseL-amino acid-defined high-fat dietAdvanced liver diseaseCholesterol contentHSD17B13 variantsHigh-fat dietTotal liver cholesterol contentTreated miceActivate signaling pathwaysVariant rs738409Liver cholesterol contentLiver lipidsFibrotic responsePromote inflammationTherapeutic approachesSteatotic liver diseaseDietary cholesterol supplementationFibrosisHuman liver samplesI148MAntisense oligonucleotidesProgressive formNotch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice
Gaspar R, Macêdo A, Nakandakari S, Muñoz V, Abud G, Vieira R, de Sousa Neto I, Pavan I, da Silva L, Simabuco F, da Silva A, Salgado W, Marchini J, Nonino C, Cintra D, Ropelle E, Pajvani U, de Freitas E, Pauli J. Notch1 Signalling Is Downregulated by Aerobic Exercise, Leading to Improvement of Hepatic Metabolism in Obese Mice. Liver International 2025, 45: e70068. PMID: 40078075, DOI: 10.1111/liv.70068.Peer-Reviewed Original ResearchConceptsNotch1 signalingAerobic exerciseRegulation of hepatic glucoseObese miceImpact of aerobic exerciseEffects of Notch1 signalingAerobic exercise trainingMTORC1 pathway activationNotch1 pathwayObese individualsTissue of obese miceCross-sectional studyNotch1 mRNA levelsMitochondrial respirationExercise trainingLivers of obese individualsTreadmill runningGluconeogenic enzymesHepG2 cell lineLipid accumulationTraining groupHepatic glucoseHepatic metabolismNotch1 proteinPathway activationAn 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 strokeChemokinesSuppression 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 disordersDeuterium 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 ResearchConceptsH-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 waterDeletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH
Parthasarathy G, Venkatesan N, Sidhu G, Song M, Liao C, Barrow F, Mauer A, Sehrawat T, Nakao Y, Daniel P, Dasgupta D, Pavelko K, Revelo X, Malhi H. Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH. Hepatology Communications 2025, 9: e0613. PMID: 39899672, DOI: 10.1097/hc9.0000000000000613.Peer-Reviewed Original ResearchConceptsMyeloid cellsMonocyte-derived macrophagesHigh-fatLiver injuryProinflammatory monocyte-derived macrophagesReceptor 1Cell-specific knockout miceMass cytometryT cell subsetsSphingosine 1-phosphate receptor 1Cardiometabolic risk factorsS1P receptor 1Accumulation of monocyte-derived macrophagesImmune cell typesWild-typeLiver inflammatory infiltrationGene ontology pathway analysisWild-type controlsDevelopment of steatohepatitisSphingosine 1-phosphateMitogen-activated protein kinase pathwayT cellsIntrahepatic macrophagesInflammatory infiltrateKnockout miceTime-restricted feeding reduces inflammatory markers and downregulates JAG1 and NICD protein levels in the liver of aged mice
Macêdo A, de Sousa Neto I, Antonio G, Gaspar R, de Lima R, Dias L, Vieira R, Muñoz V, Brunelli D, da Silva A, Cintra D, Ropelle E, Pauli J. Time-restricted feeding reduces inflammatory markers and downregulates JAG1 and NICD protein levels in the liver of aged mice. Nutrition 2025, 133: 112691. PMID: 39983606, DOI: 10.1016/j.nut.2025.112691.Peer-Reviewed Original ResearchConceptsRNA-seq datasetsNotch1 intracellular domainMitochondrial respirationTime-restricted feedingAged miceInflammatory markersAd libitum dietIntracellular domainHepatic mitochondrial respirationATP productionLiver mitochondrial respirationCellular longevityLiver of aged miceLibitum dietDisease Activity ScoreCompared to adult animalsNotch1 signalingProtein contentTime-restricted feeding protocolsUpregulation of Notch1Investigated metabolic parametersProtein levelsNotch1Adult miceCollagen fibersThe evolving role of liver biopsy: Current applications and future prospects
Gopal P, Hu X, Robert M, Zhang X. The evolving role of liver biopsy: Current applications and future prospects. Hepatology Communications 2025, 9: e0628. PMID: 39774070, PMCID: PMC11717517, DOI: 10.1097/hc9.0000000000000628.Peer-Reviewed Original ResearchSpatiotemporal dynamics of fetal liver hematopoietic niches
Peixoto M, Soares-da-Silva F, Bonnet V, Zhou Y, Ronteix G, Santos R, Mailhe M, Nogueira G, Feng X, Pereira J, Azzoni E, Anselmi G, de Bruijn M, Perkins A, Baroud C, Pinto-do-Ó P, Cumano A. Spatiotemporal dynamics of fetal liver hematopoietic niches. Journal Of Experimental Medicine 2025, 222: e20240592. PMID: 39775824, PMCID: PMC11706214, DOI: 10.1084/jem.20240592.Peer-Reviewed Original ResearchConceptsFetal liverSource of hematopoietic growth factorsStromal cellsNon-hematopoietic stromal cellsHematopoietic growth factorsCytokine production patternsStromal cell populationsNeighboring stromal cellsEmbryonic hematopoietic cellsFetal hematopoiesisComplex cellular interactionsHematopoietic progenitorsHematopoietic cellsGrowth factorCell populationsFL developmentCellular interactionsCellsDevelopmental changesSignaling networksAcid sphingomyelinase deficiency and Gaucher disease: Underdiagnosed and often treatable causes of hepatomegaly, splenomegaly, and low HDL cholesterol in lean individuals
Mistry P, Cassiman D, Jones S, Lachmann R, Lukina E, Prada C, Wasserstein M, Thurberg B, Foster M, Patel R, Underhill L, Peterschmitt M. Acid sphingomyelinase deficiency and Gaucher disease: Underdiagnosed and often treatable causes of hepatomegaly, splenomegaly, and low HDL cholesterol in lean individuals. Hepatology Communications 2025, 9: e0621. PMID: 39774103, PMCID: PMC11717527, DOI: 10.1097/hc9.0000000000000621.Peer-Reviewed Original ResearchConceptsGaucher disease type 1Acid sphingomyelinase deficiencyHDL cholesterolSphingomyelinase deficiencyDifferential diagnosis of patientsBiomarkers of disease activityLipoprotein phenotypeLower body mass indexMean HDL cholesterolLow HDL cholesterolLiver function testsDiagnosis of patientsBody mass indexModerate hepatosplenomegalySpleen volumeLipid abnormalitiesLow HDLDiagnostic delayIrreversible complicationsLiver volumeLyso-sphingomyelinMultisystemic manifestationsDisease activityLDL cholesterolDifferential diagnosis
2024
Expanding PFAS Identification with Transformation Product Libraries: Nontargeted Analysis Reveals Biotransformation Products in Mice
Liu S, Dukes D, Koelmel J, Stelben P, Finch J, Okeme J, Lowe C, Williams A, Godri D, Rennie E, Parry E, McDonough C, Pollitt K. Expanding PFAS Identification with Transformation Product Libraries: Nontargeted Analysis Reveals Biotransformation Products in Mice. Environmental Science And Technology 2024, 59: 119-131. PMID: 39704186, DOI: 10.1021/acs.est.4c07750.Peer-Reviewed Original ResearchConceptsMass spectral libraryTransformation productsLiquid chromatography-high resolution mass spectrometryProduct libraryPolyfluoroalkyl substancesBiological transformation productsSpectral libraryFragmentation rulesBehavior of PFASPotential transformation productsMass spectrometryToxicity predictionChemical subclassesReaction productsLiver S9 fractionBiotransformation productsEnzymatic reactionsMutagenic toxicityReactionMouse liver S9 fractionBiological systemsS9 fractionDealkylationChemicalSpectrometryStatistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation
Bierman R, Dave J, Greif D, Salzman J. Statistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation. ELife 2024, 12: rp87517. PMID: 39699003, PMCID: PMC11658768, DOI: 10.7554/elife.87517.Peer-Reviewed Original ResearchConceptsSubcellular localizationUntranslated regionAlternative poly-adenylationSubcellular RNA localizationCell-type specific regulationLow-throughput studiesUntranslated region lengthRNA subcellular localizationSingle-cell resolutionSpatial transcriptomics techniquesRNA localizationFunction predictionPoly-adenylationTranscriptomic techniquesCellular functionsMouse brainSpecific regulationStatistical frameworkIsoform expressionMouse liverRegulationMiceUntranslatedLocalizationRNADietary modulation of gut microbiota affects susceptibility to drug-induced liver injury
Pan H, Song D, Wang Z, Yang X, Luo P, Li W, Li Y, Gong M, Zhang C. Dietary modulation of gut microbiota affects susceptibility to drug-induced liver injury. Gut Microbes 2024, 16: 2439534. PMID: 39673542, PMCID: PMC11649229, DOI: 10.1080/19490976.2024.2439534.Peer-Reviewed Original ResearchConceptsGut microbiotaDrug-induced liver injuryIndole-3-lactic acidComposition of human gut microbiotaWestern style dietDietary modulators of gut microbiotaModulation of gut microbiotaHuman gut microbiotaGut microbiota transplantationModulating gut microbiotaSusceptibility to drug-induced liver injuryIncidence of drug-induced liver injuryDietary fiber interventionLiver injuryDiet-induced variationsBile acid metabolismMicrobiotaTranslocation of lipopolysaccharideImprove liver functionSignaling pathwayDietary shiftsMicrobiota transplantationFiber interventionAcid metabolismIntestinal barrierDaily glucose variability is associated with intrahepatic fat content, β cell sensitivity, and biomarkers of glycolysis in youth with obesity
Barbieri E, Bonet J, Fox D, Nelson R, Nelson M, Nelson L, Fernandez C, Van Name M, Samuels S, Caprio S, Sabati M, Galderisi A, Sherr J, Man C, Santoro N. Daily glucose variability is associated with intrahepatic fat content, β cell sensitivity, and biomarkers of glycolysis in youth with obesity. Obesity 2024, 33: 116-124. PMID: 39658509, PMCID: PMC11666407, DOI: 10.1002/oby.24175.Peer-Reviewed Original ResearchConceptsIntrahepatic fat contentDaily glucose variabilityLiver proton density fat fractionProton density fat fractionGlucose variabilityInsulin sensitivityOral glucose tolerance testFat fractionInsulin secretionAssociated with insulin resistanceFirst-phase insulin secretionAssociated with 2-h glucoseGlucose tolerance testGlucose standard deviationMagnetic resonance imagingOral minimal modelCoefficient of variationBasal insulin secretionPediatric obesityPostprandial glucoseTolerance testCell sensitivityInsulin resistanceObesityResonance imagingIntegrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population
Ding J, Liu H, Zhang X, Zhao N, Peng Y, Shi J, Chen J, Chi X, Li L, Zhang M, Liu W, Zhang L, Ouyang J, Yuan Q, Liao M, Tan Y, Li M, Xu Z, Tang W, Xie C, Li Y, Pan Q, Xu Y, Cai S, Byrne C, Targher G, Ouyang X, Zhang L, Jiang Z, Zheng M, Sun F, Chai J. Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population. Science Translational Medicine 2024, 16: eadh9940. PMID: 39504356, DOI: 10.1126/scitranslmed.adh9940.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseWhole-genome sequencingHepatocellular carcinomaMolecular subtypesLiver cirrhosisChinese cohort of patientsInfiltration of M1Risk of liver cirrhosisSerum metabolic analysisClinical diagnosisSubtype of nonalcoholic fatty liver diseaseCohort of patientsDevelopment of liver cirrhosisHepatocellular carcinoma developmentIntegrative multiomic analysisHealth care burdenFatty liver diseaseExpression of CYP1A2Urine specimensTreatment strategiesChinese cohortImpaired outcomeM2 macrophagesIntegrative multiomicsLiver diseaseValidation of a whole slide image management system for metabolic‐associated steatohepatitis for clinical trials
Pulaski H, Mehta S, Manigat L, Kaufman S, Hou H, Nalbantoglu I, Zhang X, Curl E, Taliano R, Kim T, Torbenson M, Glickman J, Resnick M, Patel N, Taylor C, Bedossa P, Montalto M, Beck A, Wack K. Validation of a whole slide image management system for metabolic‐associated steatohepatitis for clinical trials. The Journal Of Pathology Clinical Research 2024, 10: e12395. PMID: 39294925, PMCID: PMC11410674, DOI: 10.1002/2056-4538.12395.Peer-Reviewed Original ResearchConceptsClinical trialsAssessment of disease activityOverall percent agreementLiver biopsyDisease activityPathological assessmentWashout periodHistological assessmentEndpoint assessmentGold standardPercent agreementScoring systemExpert pathologistsSteatohepatitisAverage agreementDigital scoresPathologistsTrialsGene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging
Occean J, Yang N, Sun Y, Dawkins M, Munk R, Belair C, Dar S, Anerillas C, Wang L, Shi C, Dunn C, Bernier M, Price N, Kim J, Cui C, Fan J, Bhattacharyya M, De S, Maragkakis M, de Cabo R, Sidoli S, Sen P. Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging. Nature Communications 2024, 15: 6357. PMID: 39069555, PMCID: PMC11284234, DOI: 10.1038/s41467-024-50725-y.Peer-Reviewed Original ResearchConceptsTissue-specific functionsDNA hydroxymethylationMagnitude of transcriptional changesAlternative splicing eventsMagnitude of gene expression changesTissue-specific genesGene expression changesGene bodiesSplicing eventsDNA methylationModel organismsTranscriptional changesExpression changesGenesAge-related diseasesFunctional roleMouse liverHuman tissuesProlonged quiescenceRestriction functionSplicingDNAMiceAge-related contextSenescenceGlutathione 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 stressLipidDeletionSerologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis
Thorburn D, Leeming D, Barchuk W, Wang Y, Lu X, Malkov V, Ito K, Bowlus C, Levy C, Goodman Z, Karsdal M, Muir A, Xu J. Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis. Hepatology Communications 2024, 8: e0467. PMID: 38967589, PMCID: PMC11227354, DOI: 10.1097/hc9.0000000000000467.Peer-Reviewed Original ResearchConceptsPrimary sclerosing cholangitisELF scoreAdvanced fibrosisFibrosis stageFibrosis progressionClinical eventsSclerosing cholangitisExtracellular matrix remodeling markersRemodeling markersPredictors of disease severityPhase 2b trialBaseline to weekPRO-C3Progression to cirrhosisWilcoxon rank sum testMarker of collagen formationType III procollagenModerate diagnostic abilityDiagnosing fibrosis stagesRank sum testSerum markersNoninvasive predictorPrognostic markerModerate prognosisMedian change
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