2025
Liver 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 formTHU-333 Non-invasive tests for liver fibrosis are stable in patients with primary biliary cholangitis with two years of treatment with elafibranor
Mayo M, Levy C, Swain M, Schattenberg J, Heneghan M, Corpechot C, Bowlus C, Vierling J, Antunes N, Cranham V, da Silva H, Raskino C, Kowdley K. THU-333 Non-invasive tests for liver fibrosis are stable in patients with primary biliary cholangitis with two years of treatment with elafibranor. Journal Of Hepatology 2025, 82: s332-s333. DOI: 10.1016/s0168-8278(25)01009-8.Peer-Reviewed Original ResearchFGF21 Signaling Exerts Antifibrotic Properties during Pulmonary Fibrosis.
Ghanem M, Archer G, Justet A, Jaillet M, Vasarmidi E, Mordant P, Castier Y, Mal H, Cazes A, Poté N, Crestani B, Mailleux A. FGF21 Signaling Exerts Antifibrotic Properties during Pulmonary Fibrosis. American Journal Of Respiratory And Critical Care Medicine 2025, 211: 486-498. PMID: 39637324, DOI: 10.1164/rccm.202311-2021oc.Peer-Reviewed Original ResearchConceptsIdiopathic pulmonary fibrosisWild-type littermatesPlasma of patientsPulmonary fibrosisAntifibrotic propertiesIntratracheal injection of bleomycinDevelopment of pulmonary fibrosisDecreased fibrosis markersEffects of FGF21Increased sensitivity to bleomycinInjection of bleomycinPulmonary fibrosis developmentSensitivity to bleomycinDecrease of BaxConcentrations of FGF21Human lung fibroblastsTherapeutic optionsFibrosis markersAntifibrotic effectsControl subjectsInjury scoreIntratracheal injectionLiver fibrosisLung fibrogenesisFibroblast growth factor
2024
Pre-Transplant Liver Fibrosis Predicts Poor Overall Survival Following Hematopoietic Stem Cell Transplantation for Sickle Cell Disease
Maurya P, Liang J, Prior D, Ramachandran S, Deng Y, Krishnamurti L. Pre-Transplant Liver Fibrosis Predicts Poor Overall Survival Following Hematopoietic Stem Cell Transplantation for Sickle Cell Disease. Blood 2024, 144: 2302-2302. DOI: 10.1182/blood-2024-211601.Peer-Reviewed Original ResearchGraft-versus-host diseaseHematopoietic stem cell transplantationOutcome of hematopoietic stem cell transplantationVeno-occlusive diseaseChronic graft-versus-host diseaseCenter for International Blood and Marrow Transplant ResearchSickle cell diseaseEvent free survivalStem cell transplantationOverall survivalPresence of fibrosisPoor overall survivalThrombotic microangiopathyLiver fibrosisLiver biopsyFree survivalCell transplantationClinical trials of hematopoietic stem cell transplantationIncidence of acute graft-versus-host diseasePre-transplantTransfusional hemosiderosisAssociated with event free survivalAcute graft-versus-host diseaseGraft-versus-host disease prophylaxisPost-hematopoietic stem cell transplantationGlycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis
Khanal S, Liu Y, Bamidele A, Wixom A, Washington A, Jalan-Sakrikar N, Cooper S, Vuckovic I, Zhang S, Zhong J, Johnson K, Charlesworth M, Kim I, Yeon Y, Yoon S, Noh Y, Meroueh C, Timbilla A, Yaqoob U, Gao J, Kim Y, Lucien F, Huebert R, Hay N, Simons M, Shah V, Kostallari E. Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis. Science Advances 2024, 10: eadn5228. PMID: 38941469, PMCID: PMC11212729, DOI: 10.1126/sciadv.adn5228.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsLiver fibrosisExtracellular vesiclesEV releaseHistone 3 lysine 9 acetylationExtracellular vesicle releaseIncreased EV releaseFibrotic gene expressionNanosized extracellular vesiclesPromoter regionVesicle releasePotential therapeutic targetGene expressionGenetic inhibitionSpatial transcriptomicsStellate cellsGlycolysisUp-regulatedFibrosisTherapeutic targetPericentral zoneLiverPathwayAmplificationExpressionProtocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis
Hussain N, Ma C, Hirschfield G, Walmsley M, Hanford P, Vesterhus M, Kowdley K, Bergquist A, Ponsioen C, Levy C, Assis D, Schramm C, Bowlus C, Trauner M, Aiyegbusi O, Jairath V, Trivedi P. Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis. BMJ Open 2024, 14: e080143. PMID: 38926149, PMCID: PMC11216047, DOI: 10.1136/bmjopen-2023-080143.Peer-Reviewed Original ResearchConceptsPrimary sclerosing cholangitisClinical trialsSclerosing cholangitisCore outcome setImmune-mediated liver diseasesPrimary sclerosing cholangitis treatmentOutcome measuresEvaluate novel therapiesSlow disease progressionPatient-reported outcome measuresMedical therapyNovel therapiesLiver fibrosisDisease progressionHistological assessmentLiver diseaseInternational two-round Delphi surveyImaging-based biomarkersIntervention trialsTherapyConsensus meetingHealthcare payersCholangitisSemistructured qualitative interviewsTwo-round Delphi surveyLiver Sinusoidal Endothelial Cells Contribute to Portal Hypertension Through Collagen Type IV–Driven Sinusoidal Remodeling
Gan C, Yaqoob U, Lu J, Xie M, Anwar A, Jalan-Sakrikar N, Jerez S, Sehrawat T, Navarro-Corcuera A, Kostallari E, Habash N, Cao S, Shah V. Liver Sinusoidal Endothelial Cells Contribute to Portal Hypertension Through Collagen Type IV–Driven Sinusoidal Remodeling. JCI Insight 2024, 9: e174775. PMID: 38713515, PMCID: PMC11382879, DOI: 10.1172/jci.insight.174775.Peer-Reviewed Original ResearchLiver sinusoidal endothelial cellsPortal hypertensionSinusoidal remodelingSinusoidal endothelial cellsSinusoidal resistanceComplication of liver cirrhosisEndothelial cellsSinusoidal endothelial cells in vitroEnhancer-promoter interactionsEpigenome editing approachesEndothelial cells in vitroChronic liver injuryCells in vitroMouse fibrotic liversCollagen type IVLiver cirrhosisGene mutationsExpression regulationLiver fibrosisLiver injuryEpigenetic repressionLiver diseaseCellular sourceCol4 expressionImmunofluorescence stainingBimekizumab safety in moderate to severe plaque psoriasis: Rates of hepatic events and changes in liver parameters over 2 years in randomized phase 3/3b trials
Lebwohl M, Merola J, Strober B, Armstrong A, Yoshizaki A, Gisondi P, Szilagyi B, Peterson L, de Cuyper D, Cross N, Davies O, Gottlieb A. Bimekizumab safety in moderate to severe plaque psoriasis: Rates of hepatic events and changes in liver parameters over 2 years in randomized phase 3/3b trials. Journal Of The American Academy Of Dermatology 2024, 91: 281-289. PMID: 38588819, DOI: 10.1016/j.jaad.2024.03.041.Peer-Reviewed Original ResearchTreatment-emergent adverse eventsAdverse eventsModerate to severe plaque psoriasisIncidence of transaminase elevationsLiver parametersMarkers of liver fibrosisAlanine aminotransferaseHepatic adverse eventsSevere plaque psoriasisLiver function abnormalitiesChronic alcohol consumptionControl study periodAspartate aminotransferaseStudy periodAPRI scorePlaque psoriasisTransaminase elevationFibrosis riskHepatic eventsFIB-4Hepatic dysfunctionLaboratory elevationsClinical markersFunctional abnormalitiesLiver fibrosis
2023
The evil relationship between liver fibrosis and cardiovascular disease in metabolic dysfunction-associated fatty liver disease (MAFLD): Looking for the culprit
Fabris L, Campello E, Cadamuro M, Simioni P. The evil relationship between liver fibrosis and cardiovascular disease in metabolic dysfunction-associated fatty liver disease (MAFLD): Looking for the culprit. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2023, 1870: 166763. PMID: 37951510, DOI: 10.1016/j.bbadis.2023.166763.Peer-Reviewed Original ResearchMetabolic dysfunction-associated fatty liver diseaseFatty liver diseaseCardiovascular diseaseLiver diseaseInsulin resistanceLiver fibrosisMajor public health problemPublic health problemMAFLD patientsMAFLD progressionCardiometabolic riskMetabolic syndromeOverall mortalityHepatic repairHepatic fibrogenesisHepatic componentGeneral populationTherapeutic targetingHealth problemsTranslational potentialFibrosisDiseaseGenetic factorsRisk profilingStrongest predictorLet-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-β production
Song J, Lv H, Liu B, Hao M, Taylor H, Zhang X, Li D, Huang Y. Let-7 suppresses liver fibrosis by inhibiting hepatocyte apoptosis and TGF-β production. Molecular Metabolism 2023, 78: 101828. PMID: 37898449, PMCID: PMC10641683, DOI: 10.1016/j.molmet.2023.101828.Peer-Reviewed Original ResearchConceptsFas-mediated apoptosisLet-7Hepatocyte apoptosisNegative feedback loopMouse primary hepatocytesLet-7 miRNAsTGF-b signalingSignaling networksApoptosis of hepatocytesTransient transfectionFas expressionInhibiting hepatocyte apoptosisSiRNA knockdownLet-7 expressionLet-7 overexpressionMouse modelApoptosisPrimary hepatocytesSuppressed hepatocyte apoptosisTET3Liver fibrosisFeedback loopExpressionDriver of liver fibrosisAdeno-associated viral vectorsThe Sympathetic Nervous System Promotes Hepatic Lymphangiogenesis, which Is Protective Against Liver Fibrosis
Tanaka M, Jeong J, Thomas C, Zhang X, Zhang P, Saruwatari J, Kondo R, McConnell M, Utsumi T, Iwakiri Y. The Sympathetic Nervous System Promotes Hepatic Lymphangiogenesis, which Is Protective Against Liver Fibrosis. American Journal Of Pathology 2023, 193: 2182-2202. PMID: 37673329, PMCID: PMC10699132, DOI: 10.1016/j.ajpath.2023.08.004.Peer-Reviewed Original ResearchConceptsPartial portal vein ligationNoncirrhotic portal hypertensionCirrhotic patientsVascular endothelial growth factorLiver fibrosisEndothelial growth factorPortal hypertensionSympathetic denervationSympathetic nervesBDL ratsVascular diseaseIdiopathic noncirrhotic portal hypertensionGrowth factorPortal hypertensive patientsPortal vein ligationSympathetic nervous systemMechanisms of lymphangiogenesisCeliac ganglionectomyHypertensive patientsLymphatic vessel numberLiver biopsyLiver cirrhosisVein ligationPPVL ratsHepatic lymphatic vesselsS-nitrosylation of EMMPRIN influences the migration of HSCs and MMP activity in liver fibrosis
Zhu X, Tang Z, Li W, Li X, Iwakiri Y, Liu F. S-nitrosylation of EMMPRIN influences the migration of HSCs and MMP activity in liver fibrosis. Acta Biochimica Et Biophysica Sinica 2023, 55: 1640-1649. PMID: 37700592, PMCID: PMC10577453, DOI: 10.3724/abbs.2023141.Peer-Reviewed Original ResearchConceptsExtracellular matrix metalloproteinase inducerLiver fibrosisLevels of EMMPRINMMP activitySinus epithelial cellsHSC migrationMatrix metalloproteinase inducerNormal control liversActivity of MMP2Matrix metalloproteinase activityS-nitrosylationStellate cell migrationHepatic stellate cell migrationTissue microarrayFibrotic liverFibrosisMouse liver tissueControl liversECM accumulationLiver tissueMetalloproteinase activityEMMPRIN mRNALiver areaEpithelial cellsProtein levelsMechanisms of liver fibrosis in metabolic syndrome
Mehal W. Mechanisms of liver fibrosis in metabolic syndrome. EGastroenterology 2023, 1: e100015. PMID: 37946713, PMCID: PMC10634657, DOI: 10.1136/egastro-2023-100015.Peer-Reviewed Original ResearchNon-alcoholic steatohepatitisLiver fibrosisMetabolic syndromeHepatic stellate cellsHepatocellular injuryImmune systemHSC transdifferentiationGrowth factorChronic hepatocellular injuryInnate immune cellsMetabolite changesInnate immune systemAdaptive immune systemNASH fibrosisHepatocellular damageAntifibrotic strategiesImmune cellsProfibrotic roleT cellsFree fatty acidsStellate cellsViral infectionFibrosisSyndromeEndothelial cellsA Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver
Ding C, Yu Z, Sefik E, Zhou J, Kaffe E, Wang G, Li B, Flavell R, Hu W, Ye Y, Li H. A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver. Nature Aging 2023, 3: 813-828. PMID: 37277640, DOI: 10.1038/s43587-023-00428-8.Peer-Reviewed Original ResearchConceptsAged miceLiver diseaseLiver microenvironmentAge-related liver diseasesYin Yang 1Liver immune microenvironmentRegulatory T cellsTreg-specific deletionPotential therapeutic targetMitochondrial functionYang 1Treg apoptosisTreg homeostasisTreg cellsTreg functionImmune microenvironmentLiver fibrosisMetabolic dysfunctionOptimal mitochondrial functionYoung miceT cellsLiver cancerTherapeutic targetAged liverLong noncoding RNAAbsence of either Ripk3 or Mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis
Mohammed S, Thadathil N, Ohene-Marfo P, Tran A, Van Der Veldt M, Georgescu C, Oh S, Nicklas E, Wang D, Haritha N, Luo W, Janknecht R, Miller B, Wren J, Freeman W, Deepa S. Absence of either Ripk3 or Mlkl reduces incidence of hepatocellular carcinoma independent of liver fibrosis. Molecular Cancer Research 2023, 21: 933-946. PMID: 37204757, PMCID: PMC10472095, DOI: 10.1158/1541-7786.mcr-22-0820.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseProgression of NAFLDHepatocellular carcinomaChronic inflammationLiver fibrosisMale miceMouse modelCholine-deficient high-fat dietFemale wild-type miceOncogenic pathwaysFatty liver diseaseMarkers of inflammationHigh-fat dietLow-fat dietDevelopment of inflammationValid therapeutic targetWild-type miceHepatic inflammationInflammation contributesLiver diseaseWT miceFemale miceSex-specific differencesInflammationTherapeutic targetConstitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome
de Jesus A, Chen G, Yang D, Brdicka T, Ruth N, Bennin D, Cebecauerova D, Malcova H, Freeman H, Martin N, Svojgr K, Passo M, Bhuyan F, Alehashemi S, Rastegar A, Uss K, Kardava L, Marrero B, Duric I, Omoyinmi E, Peldova P, Lee C, Kleiner D, Hadigan C, Hewitt S, Pittaluga S, Carmona-Rivera C, Calvo K, Shah N, Balascakova M, Fink D, Kotalova R, Parackova Z, Peterkova L, Kuzilkova D, Campr V, Sramkova L, Biancotto A, Brooks S, Manes C, Meffre E, Harper R, Kuehn H, Kaplan M, Brogan P, Rosenzweig S, Merchant M, Deng Z, Huttenlocher A, Moir S, Kuhns D, Boehm M, Skvarova Kramarzova K, Goldbach-Mansky R. Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome. Nature Communications 2023, 14: 1502. PMID: 36932076, PMCID: PMC10022554, DOI: 10.1038/s41467-023-36941-y.Peer-Reviewed Original ResearchConceptsCutaneous small vessel vasculitisLyn kinaseSmall vessel vasculitisSystemic inflammationVessel vasculitisSrc family tyrosine kinasesLiver fibrosisActivation of Lyn kinaseIncreased expression of ICAM-1Activated Lyn kinaseExpression of ICAM-1Next-generation sequencingSrc kinase inhibitor dasatinibRegulate microvascular permeabilityTransendothelial migrationMonogenic autoinflammatory diseasesKinase inhibitor dasatinibIncreased neutrophil adhesionB2 integrinsSrc-familyTruncating variantsFibrosis syndromeTNF inhibitionPatients' neutrophilsConstitutive activationInhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis
Luukkonen P, Sakuma I, Gaspar R, Mooring M, Nasiri A, Kahn M, Zhang X, Zhang D, Sammalkorpi H, Penttilä A, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-Järvinen H, Petersen K, Shulman G. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2217543120. PMID: 36669104, PMCID: PMC9942818, DOI: 10.1073/pnas.2217543120.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseLiver fibrosisLiver diseaseCommon chronic liver diseaseChronic liver diseaseFatty liver diseaseRisk of fibrosisDistinct mouse modelsPyrimidine catabolismNonalcoholic steatohepatitisMouse modelTherapeutic targetFibrosisDihydropyrimidine dehydrogenaseHuman liverA variantCommon variantsMetabolomics approachDiseaseMiceInhibitionCatabolismKnockdownSteatohepatitisGimeracil
2022
17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice
Ali Mondal S, Sathiaseelan R, Mann S, Kamal M, Luo W, Saccon T, Isola J, Peelor F, Li T, Freeman W, Miller B, Stout M. 17α-estradiol, a lifespan-extending compound, attenuates liver fibrosis by modulating collagen turnover rates in male mice. AJP Endocrinology And Metabolism 2022, 324: e120-e134. PMID: 36516471, PMCID: PMC9902223, DOI: 10.1152/ajpendo.00256.2022.Peer-Reviewed Original ResearchConceptsLiver fibrosisMale miceCombination hormone replacement therapyMatrix metalloproteinase-2 activityHepatic stellate cell activationChronic liver diseaseHormone replacement therapySubset of womenMetalloproteinase-2 activityStellate cell activationGrowth factor-β1Proinflammatory macrophage activationFibrotic burdenCollagen synthesis ratesChronic treatmentLiver diseaseReplacement therapyCytokine expressionMacrophage contentImmune cellsTGF-β1Estrogen signalingHSC activationFactor-β1Macrophage activationThe Independent Effect of Exercise on Biopsy-Proven Non-Alcoholic Fatty Liver Disease: A Systematic Review
Chen G, Banini B, Do A, Lim J. The Independent Effect of Exercise on Biopsy-Proven Non-Alcoholic Fatty Liver Disease: A Systematic Review. Clinical And Molecular Hepatology 2022, 29: s319-s332. PMID: 36517000, PMCID: PMC10029942, DOI: 10.3350/cmh.2022.0366.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseBiopsy-proven non-alcoholic fatty liver diseaseNon-invasive testsFatty liver diseaseHepatic steatosisLiver fibrosisLiver diseaseHistological endpointsIndependent effectsSystematic reviewNon-randomized interventional studyMagnetic resonance imaging-based techniquesAdditional large RCTsChronic liver diseaseSignificant histological improvementEffects of exerciseClinical outcome endpointsSystematic literature searchHistological improvementExercise interventionHepatocyte ballooningOriginal research studiesLarge RCTsOutcome endpointsInterventional studyReview of existing evidence demonstrates that methotrexate does not cause liver fibrosis
Cheema HI, Haselow D, Dranoff JA. Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis. Journal Of Investigative Medicine 2022, 70: 1452-1460. PMID: 36002175, DOI: 10.1136/jim-2021-002206.Peer-Reviewed Original ResearchConceptsChronic liver diseaseLiver diseaseLiver fibrosisLiver injuryPre-existing chronic liver diseaseNon-alcoholic fatty liver diseaseLong-term methotrexateMeta-analysis portionProgressive liver injurySerial liver biopsiesFatty liver diseaseAdvanced liver fibrosisCare of patientsMetabolic liver diseaseNon-invasive assessmentComprehensive literature searchAssessment of injuryMethotrexate doseAdvanced fibrosisCommon indicationDirect causeLiver biopsyTherapeutic dosesRisk factorsInclusion criteria
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