2025
Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease
Yang Y, Duan Y, Lang S, Fondevila M, Schöler D, Harberts A, Cabré N, Chen S, Shao Y, Vervier K, Miyamoto Y, Zhang X, Chu H, Yang L, Tan C, Eckmann L, Bosques-Padilla F, Verna E, Abraldes J, Brown R, Vargas V, Altamirano J, Caballería J, Shawcross D, Louvet A, Lucey M, Mathurin P, Garcia-Tsao G, Bataller R, Stärkel P, Lawley T, Schnabl B. Targeted inhibition of pathobiont virulence factor mitigates alcohol-associated liver disease. Cell Host & Microbe 2025, 33: 957-972.e6. PMID: 40441146, PMCID: PMC12162233, DOI: 10.1016/j.chom.2025.05.003.Peer-Reviewed Original ResearchConceptsEthanol-induced liver diseaseAlcohol-associated liver diseaseAlcohol-associated hepatitisLiver diseaseGenome of Escherichia coliE. coliMetagenomic sequencing of fecal samplesInternational cohort of patientsGenetic manipulation of bacteriaGnotobiotic mouse modelOutcomes of patientsManipulation of bacteriaCohort of patientsScavenger receptor MARCOGlobal health burdenVirulence factorsMetagenomic sequencingGut microbiotaGenetic manipulationDisease progressionMouse modelKupffer cellsKpsMBacterial spreadInternational cohortGly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice
Hasan M, Wang H, Luo W, Du Y, Li T. Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury in Mdr2 KO mice. AJP Gastrointestinal And Liver Physiology 2025, 329: g45-g57. PMID: 40418643, PMCID: PMC12178242, DOI: 10.1152/ajpgi.00044.2025.Peer-Reviewed Original ResearchConceptsKO miceBile acid compositionBile acid pool sizeBile acid poolBile acid hydrophobicityHepatic bile acidsHepatobiliary toxicityBile acid metabolismMale miceTherapeutic benefitCholestasis modelMdr2-KO miceDecreased liver injuryBile acidsSerum alkaline phosphataseBile acid absorptionAlkaline phosphataseFecal bile acid excretionAcid compositionDiminished therapeutic efficacyImpaired bile flowAcid metabolismHepatobiliary injuryUnique pharmacokineticsBiliary injuryChanges in the FXR-cistrome and alterations in bile acid physiology in Wilson disease
Wooton-Kee C, Yalamanchili H, Mohamed I, Hassan M, Setchell K, Rivas M, Coskun A, Putluri V, Putluri N, Jalal P, Schilsky M, Moore D. Changes in the FXR-cistrome and alterations in bile acid physiology in Wilson disease. Hepatology Communications 2025, 9: e0707. PMID: 40408300, PMCID: PMC12106221, DOI: 10.1097/hc9.0000000000000707.Peer-Reviewed Original ResearchConceptsWild-type miceFarnesoid X receptorWilson's diseaseNon-parenchymal cellsDistal intergenic regionsLiver bile acid concentrationWD patientsHealthy controlsMetabolic target genesFarnesoid X Receptor RegulationBile salt export pumpIntergenic regionFXR activationAutosomal recessive disorderBile acid homeostasisBile acid physiologyFarnesoid X receptor activationPromoter regionHomeostasis pathwaysBile acid metabolismDecreasing FXR activityTarget genesBile acid profilesMarker genesStress pathwaysMineralocorticoid receptor phase separation modulates cardiac preservation
Lei I, Sicim H, Gao W, Huang W, Noly P, Pergande M, Wilson M, Lee A, Liu L, Abou El Ela A, Jiang M, Saddoughi S, Pober J, Platt J, Cascalho M, Pagani F, Chen Y, Pitt B, Wang Z, Mortensen R, Ge Y, Tang P. Mineralocorticoid receptor phase separation modulates cardiac preservation. Nature Cardiovascular Research 2025, 4: 710-726. PMID: 40389663, DOI: 10.1038/s44161-025-00653-x.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Cycle ProteinsCold IschemiaHeart TransplantationHistone Deacetylase 1HumansKidneyLiverLungMaleMiceMice, Inbred C57BLMineralocorticoid Receptor AntagonistsMyocytes, CardiacNuclear ProteinsOrgan PreservationPhase SeparationReceptors, MineralocorticoidTissue DonorsTranscription FactorsConceptsMineralocorticoid receptorDonor heartsHistone deacetylase 1Bromodomain-containing 4Gold standard treatmentEnd-stage heart failureCold ischemic timeShortage of donor heartsExpressed MRDonor cardiomyocytesHuman donor heartsHeart transplantationStandard treatmentIschemic timeHeart failureCardiac preservationSolid organsPharmacological inhibitionCold preservationPreserving biologyHeartLiver 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, PMCID: PMC12067271, 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 formTranscriptomic 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 analysisThe peptidoglycan of Borrelia burgdorferi can persist in discrete tissues and cause systemic responses consistent with chronic illness
McClune M, Ebohon O, Dressler J, Davis M, Tupik J, Lochhead R, Booth C, Steere A, Jutras B. The peptidoglycan of Borrelia burgdorferi can persist in discrete tissues and cause systemic responses consistent with chronic illness. Science Translational Medicine 2025, 17: eadr2955. PMID: 40267217, PMCID: PMC12207536, DOI: 10.1126/scitranslmed.adr2955.Peer-Reviewed Original ResearchConceptsAcute infectionPeripheral blood mononuclear cellsBlood mononuclear cellsMurine modelPostinfectious complicationsMononuclear cellsMinimal pathologyKupffer cellsPersistent symptomsLyme arthritisPublic health concernLiver occupationLiver accumulationInflamed jointsSecreted protein profileInfectionChronic illnessOrgan-specificPatientsSynovial fluidPathogenic moleculesIn vivo 2H‐MR spectroscopy and imaging of hepatic metabolic formation of trimethylamine‐N‐oxide
Dessau H, Harris T, de Graaf R, Montrazi E, Allouche‐Arnon H, Bar‐Shir A. In vivo 2H‐MR spectroscopy and imaging of hepatic metabolic formation of trimethylamine‐N‐oxide. Magnetic Resonance In Medicine 2025, 94: 521-529. PMID: 40228097, PMCID: PMC12137761, DOI: 10.1002/mrm.30531.Peer-Reviewed Original ResearchType I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria
Marques-da-Silva C, Schmidt-Silva C, Bowers C, Charles-Chess N, Samuel C, Shiau J, Park E, Yuan Z, Kim B, Kyle D, Harty J, MacMicking J, Kurup S. Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria. Cell Host & Microbe 2025, 33: 529-544.e9. PMID: 40168996, DOI: 10.1016/j.chom.2025.03.008.Peer-Reviewed Original ResearchConceptsGuanylate-binding proteinsType I interferonPlasmodium infectionI interferonParasitophorous vacuoleLiver-stage malariaNon-immune cellsInfected host cellsCaspase-1 inflammasomeNADPH oxidase 2Clinical malariaControl malariaLysosomal fusionAntimicrobial programPlasmodium parasitesHost cellsInfected erythrocytesProtective immunityMalariaPlasmodiumGenetic inhibitionCaspase-1Immunization programsImmune circuitsMouse hepatocytesTargeting Polymeric Nanoparticles to Specific Cell Populations in the Liver
Harkins L, Vilarinho S, Saltzman W. Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver. Biochemistry 2025, 64: 1685-1697. PMID: 40127248, DOI: 10.1021/acs.biochem.4c00712.Peer-Reviewed Original ResearchConceptsLiver-resident macrophagesCell-specific targetingCell-specific deliveryAccumulation of nanoparticlesSpecific cell populationsDelivery of drugsConjugation of targeting ligandsTreatment of liver diseasesResident macrophagesKupffer cellsLiver diseaseNP administrationCell populationsConjugated nanoparticlesNP designDiseased liverSpecific deliveryCellular distributionTherapeutic carriersLiverSustained releaseNP characteristicsPolymer nanoparticlesCellsDeliveryHepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk
Bao K, Berger J, Na E, Su Q, Halasz G, Sleeman M, Okamoto H. Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk. Diabetes 2025, 74: 885-897. PMID: 40095004, PMCID: PMC12097458, DOI: 10.2337/db24-0958.Peer-Reviewed Original ResearchConceptsAmino acid catabolismGlucagon receptorControlling amino acid metabolismDownstream effectorsGlucagon receptor blockadeA cellsElevated plasma amino acidsAmino acidsAlpha cell massPlasma amino acidsCatabolism of amino acidsPKA knockdownAmino acid metabolismGlucagon-stimulated hepatic glucose productionCatabolic genesGcgr signalingPancreatic A cellsEPAC2 knockdownGNASHyperplasiaHepatic glucose productionDownstream factorsAcid metabolismCell massEpac2Notch1 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, PMCID: PMC11889166, 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
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