Featured Publications
An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver
Jeong J, Tanaka M, Yang Y, Arefyev N, DiRito J, Tietjen G, Zhang X, McConnell M, Utsumi T, Iwakiri Y. An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver. AJP Gastrointestinal And Liver Physiology 2023, 325: g379-g390. PMID: 37605828, PMCID: PMC10887843, DOI: 10.1152/ajpgi.00139.2023.Peer-Reviewed Original ResearchThe 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 vesselsThe evolving role of liver sinusoidal endothelial cells in liver health and disease
McConnell M, Kostallari E, Ibrahim S, Iwakiri Y. The evolving role of liver sinusoidal endothelial cells in liver health and disease. Hepatology 2023, 78: 649-669. PMID: 36626620, PMCID: PMC10315420, DOI: 10.1097/hep.0000000000000207.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsLiver diseaseAlcohol-associated liver diseaseEndothelial cellsLiver transplant rejectionIschemia-reperfusion injuryLiver sinusoidal endothelial cellsSinusoidal endothelial cellsPortal hypertensionLiver inflammationMicrovascular thrombosisViral hepatitisReperfusion injuryTransplant rejectionLiver healthLiver pathologyLiver homeostasisLiver regenerationQuiescent phenotypePathological processesUnique populationDiseaseLSECLiver biologyGene expression profilesInflammation
2023
Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/lipid homeostasis
Chen Y, Li Q, Zhao S, Sun L, Yin Z, Wang X, Li X, Iwakiri Y, Han J, Duan Y. Berberine protects mice against type 2 diabetes by promoting PPARγ-FGF21-GLUT2-regulated insulin sensitivity and glucose/lipid homeostasis. Biochemical Pharmacology 2023, 218: 115928. PMID: 37979703, DOI: 10.1016/j.bcp.2023.115928.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin sensitivityGlucose/lipid homeostasisInsulin resistanceLipid metabolismFibroblast growth factor 21Glucose/lipid metabolismFGF21-dependent mannerGlucose transporter 2 expressionLipid homeostasisGrowth factor 21Liver lipid accumulationMechanism of berberineEffects of berberineRole of berberineTransporter 2 expressionExpression of PPARγGlobal knockout miceFunction of berberineMultiple therapeutic actionsRegulation of glucoseT2D treatmentT2D miceDiabetic miceCarcinoma cell lines
2019
Poly(amine-co-ester) nanoparticles for effective Nogo-B knockdown in the liver
Cui J, Piotrowski-Daspit AS, Zhang J, Shao M, Bracaglia LG, Utsumi T, Seo YE, DiRito J, Song E, Wu C, Inada A, Tietjen GT, Pober JS, Iwakiri Y, Saltzman WM. Poly(amine-co-ester) nanoparticles for effective Nogo-B knockdown in the liver. Journal Of Controlled Release 2019, 304: 259-267. PMID: 31054286, PMCID: PMC6613984, DOI: 10.1016/j.jconrel.2019.04.044.Peer-Reviewed Original Research
2018
Lymphatics in the liver
Tanaka M, Iwakiri Y. Lymphatics in the liver. Current Opinion In Immunology 2018, 53: 137-142. PMID: 29772409, PMCID: PMC6986420, DOI: 10.1016/j.coi.2018.04.028.BooksConceptsHepatic lymphatic systemLymphatic systemViral hepatitisLiver diseaseLarge lymphHepatic lymphatic vesselsDiseased liverHepatocellular carcinomaLymphatic endothelial cellsEndothelial cellsLiverLymphatic vesselsPotential roleSignificant increaseDiseaseCurrent knowledgeReview articleOrgansCirrhosisHepatitisLymphCarcinomaLymphaticsDevelopment of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions
Minayoshi Y, Maeda H, Yanagisawa H, Hamasaki K, Mizuta Y, Nishida K, Kinoshita R, Enoki Y, Imafuku T, Chuang VTG, Koga T, Fujiwara Y, Takeya M, Sonoda K, Wakayama T, Taguchi K, Ishima Y, Ishida T, Iwakiri Y, Tanaka M, Sasaki Y, Watanabe H, Otagiri M, Maruyama T. Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions. Drug Delivery 2018, 25: 1055-1065. PMID: 29688069, PMCID: PMC6058604, DOI: 10.1080/10717544.2018.1464083.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnti-Inflammatory AgentsB7-H1 AntigenCell LineHepatitisHumansImmunologic FactorsInterferon alpha-2Interferon Type IInterferon-alphaInterleukin 1 Receptor Antagonist ProteinInterleukin-10Kupffer CellsLiverMaleMannoseMiceMice, Inbred C57BLMice, Inbred ICRRAW 264.7 CellsRecombinant ProteinsSerum AlbuminConceptsKupffer cellsImmunomodulatory actionsTypes of hepatitisHepato-protective effectsTreatment of hepatitisAlbumin fusion technologyIL-10Liver injuryPD-L1IL-1raImmunomodulatory effectsModel miceTherapeutic effectivenessSurvival rateIFNα2bRAW264.7 cellsHepatitisInterferon receptorMRNA levelsSignificant inductionConcanavalin AMenMiceConcept studyCells
2017
Biology of portal hypertension
McConnell M, Iwakiri Y. Biology of portal hypertension. Hepatology International 2017, 12: 11-23. PMID: 29075990, PMCID: PMC7090883, DOI: 10.1007/s12072-017-9826-x.BooksMeSH KeywordsAnimalsAscitesBlood PlateletsEndothelial CellsEsophageal and Gastric VaricesFibrosisGastrointestinal HemorrhageHepatic EncephalopathyHepatic Veno-Occlusive DiseaseHepatorenal SyndromeHumansHypertension, PortalLiverMiceMicrovesselsModels, AnimalNeovascularization, PathologicRenal InsufficiencySplanchnic CirculationThrombosisVascular ResistanceConceptsLiver sinusoidal endothelial cellsPortal hypertensionMicrovascular thrombosisHepatic stellate cell activationHyperdynamic circulatory syndromeSystemic arterial vasodilationChronic liver diseaseIntrahepatic vascular resistanceSinusoidal portal hypertensionPortal hypertension resultsStellate cell activationSinusoidal endothelial cellsVascular biology researchHepatorenal syndromeGastroesophageal varicesVariceal hemorrhageVascular resistanceArterial vasodilationCirculatory syndromeRenal failureHepatic encephalopathyHypertension resultsLiver diseasePortosystemic shuntMesenteric vasculature
2016
Cellular distribution of injected PLGA-nanoparticles in the liver
Park JK, Utsumi T, Seo YE, Deng Y, Satoh A, Saltzman WM, Iwakiri Y. Cellular distribution of injected PLGA-nanoparticles in the liver. Nanomedicine Nanotechnology Biology And Medicine 2016, 12: 1365-1374. PMID: 26961463, PMCID: PMC4889500, DOI: 10.1016/j.nano.2016.01.013.Peer-Reviewed Original ResearchConceptsPLGA nanoparticlesSafety of nanoparticlesUptake of nanoparticlesNanoparticle deliveryLiver sinusoidal endothelial cellsNanoparticle retentionNanoparticlesHepatic stellate cellsSinusoidal endothelial cellsKupffer cellsStellate cellsEndothelial cellsTarget cell typeCell typesClodronate liposomesLiver therapyLiver cellsMajor cellsLiverCell populationsCellular distributionLiposomesCellsHepatocytes
2015
Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a
Wang S, Song K, Srivastava R, Dong C, Go G, Li N, Iwakiri Y, Mani A. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. The FASEB Journal 2015, 29: 3436-3445. PMID: 25917329, PMCID: PMC4511193, DOI: 10.1096/fj.15-271171.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell Line, TumorCell TransdifferentiationFatty LiverHep G2 CellsHepatocytesHumansLiverLow Density Lipoprotein Receptor-Related Protein-6MiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseProtein BindingProtein Kinase CProtein Kinase C-alphaRho-Associated KinasesSignal TransductionTransforming Growth Factor beta1VimentinWnt Signaling PathwayWnt3A ProteinConceptsNonalcoholic fatty liver diseaseFatty liver diseaseNonalcoholic steatohepatitisLiver diseaseLDL receptor-related protein 6NASH-related liver diseaseMetabolic risk factorsChronic liver diseaseEarly-onset atherosclerosisImportant potential therapeutic targetTGF-β1 activityPotential therapeutic targetDisease pathwaysRas homolog family member ASmooth muscle αFamily member ARisk factorsDisease progressionCommon causeLRP6 knockdownTherapeutic targetWnt3a administrationHepatocyte transdifferentiationDiseaseMuscle α
2014
Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension
Mookerjee RP, Mehta G, Balasubramaniyan V, Mohamed Fel Z, Davies N, Sharma V, Iwakiri Y, Jalan R. Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension. Journal Of Hepatology 2014, 62: 325-331. PMID: 25152204, PMCID: PMC4530584, DOI: 10.1016/j.jhep.2014.08.024.Peer-Reviewed Original ResearchConceptsDDAH-1 expressionMean arterial pressurePortal hypertensionENOS activityDDAH-1Farnesoid X receptor (FXR) agonismFXR agonist obeticholic acidPortal pressure reductionAgonist obeticholic acidPortal pressure measurementsHealthy liver tissueArterial pressureENOS inhibitorHuman cirrhosisBDL ratsObeticholic acidSpecific molecular targetsPlasma ALTReceptor agonismSaline controlsCirrhosisCirrhosis ratsHypertensionOA treatmentTranslational studiesVascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions
Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions. Journal Of Hepatology 2014, 61: 912-924. PMID: 24911462, PMCID: PMC4346093, DOI: 10.1016/j.jhep.2014.05.047.BooksConceptsChronic liver diseasePortal hypertensionLiver diseaseLiver fibrosis/cirrhosisVascular cellsMesenteric vascular circulationFibrosis/cirrhosisDynamic vascular changesCollateral vessel formationHepatic stellate cellsSinusoidal endothelial cellsGrowth factor pathwaysGrowth factor βExtrahepatic circulationExtrahepatic vasculatureArterial vasodilationLiver injuryVascular changesVasoactive peptidesHypertensionVascular pathobiologySystemic circulationStellate cellsVascular processesLiver vasculaturePigment Epithelium-Derived Factor (PEDF) Suppresses IL-1β-Mediated c-Jun N-Terminal Kinase (JNK) Activation to Improve Hepatocyte Insulin Signaling
Gattu AK, Birkenfeld AL, Iwakiri Y, Jay S, Saltzman M, Doll J, Protiva P, Samuel VT, Crawford SE, Chung C. Pigment Epithelium-Derived Factor (PEDF) Suppresses IL-1β-Mediated c-Jun N-Terminal Kinase (JNK) Activation to Improve Hepatocyte Insulin Signaling. Endocrinology 2014, 155: 1373-1385. PMID: 24456163, PMCID: PMC5393334, DOI: 10.1210/en.2013-1785.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAnimalsEye ProteinsGene Expression RegulationGlucose Tolerance TestHepatocytesHumansInflammationInsulinInsulin ResistanceInterleukin-1betaJNK Mitogen-Activated Protein KinasesLiverMaleMetabolic SyndromeMetabolomicsMiceMice, Inbred C57BLMice, KnockoutMicrospheresNerve Growth FactorsObesityPalmitic AcidPhenotypeRNA InterferenceSerpinsSignal TransductionSuccinic AcidConceptsPigment epithelium-derived factorKO miceMetabolic syndromeIL-1βC-Jun N-terminal kinase (JNK) activationElevated pigment epithelium-derived factorIL-1β challengeHuman hepatocytesIL-1β expressionHuman metabolic syndromeEpithelium-derived factorPEDF-knockout miceInflammatory markersGlucose intoleranceSerum levelsC-Jun N-terminal kinaseKinase activationAntiinflammatory proteinHepatic insulinKnockout micePigment epitheliumN-terminal kinaseMiceSyndromeMetabolic homeostasis
2013
Reticulon 4B (Nogo‐B) facilitates hepatocyte proliferation and liver regeneration in mice
Gao L, Utsumi T, Tashiro K, Liu B, Zhang D, Swenson ES, Iwakiri Y. Reticulon 4B (Nogo‐B) facilitates hepatocyte proliferation and liver regeneration in mice. Hepatology 2013, 57: 1992-2003. PMID: 23299899, PMCID: PMC3628958, DOI: 10.1002/hep.26235.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationEpidermal Growth FactorHepatectomyHepatocyte Growth FactorHepatocytesInterleukin-6LiverLiver RegenerationMaleMiceMice, Inbred C57BLMice, KnockoutModels, AnimalMyelin ProteinsNogo ProteinsSignal TransductionSTAT3 Transcription FactorTime FactorsTransforming Growth Factor betaConceptsHepatocyte growth factorRole of NogoInterleukin-6Hepatocyte proliferationLiver regenerationEpidermal growth factorReticulon 4BTGF-β1Growth factorKi67 labeling indexB knockout miceHepatic stellate cellsReal-time polymerase chain reactionQuantitative real-time polymerase chain reactionIL-6/signal transducerGrowth factor βTime-dependent mannerRemnant liverKO miceLiver fibrosisPolymerase chain reactionInhibitor of DNAStellate cellsKnockout miceLabeling index
2012
Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure
Huang H, Haq O, Utsumi T, Sethasine S, Abraldes JG, Groszmann RJ, Iwakiri Y. Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure. Journal Of Cellular And Molecular Medicine 2012, 16: 1125-1133. PMID: 21801303, PMCID: PMC3213314, DOI: 10.1111/j.1582-4934.2011.01399.x.Peer-Reviewed Original ResearchConceptsPlasma VEGF levelsPortal pressureVEGF levelsPortal hypertensionIntestinal VEGFDevelopment of cirrhosisFibrosis/cirrhosisAge-matched controlsGroups of ratsEnd of exposureCirrhosisRatsSignificant positive correlationWeeksHypertensionVEGFInhalationPositive correlationDifferent stagesCarbon tetrachlorideLevelsPathologyControl
2011
Endothelial dysfunction in the regulation of cirrhosis and portal hypertension
Iwakiri Y. Endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver International 2011, 32: 199-213. PMID: 21745318, PMCID: PMC3676636, DOI: 10.1111/j.1478-3231.2011.02579.x.BooksConceptsLiver sinusoidal endothelial cellsPortal hypertensionEndothelial dysfunctionArterial vasodilationPortosystemic collateral vesselsProduction of vasodilatorsDevelopment of cirrhosisCollateral vessel formationPathological vascular eventsSinusoidal endothelial cellsExtrahepatic circulationIntrahepatic resistanceOesophageal varicesVascular eventsVascular resistanceVasodilator moleculeCollateral vesselsSinusoidal microcirculationPortal veinHypertensionSystemic circulationBlood flowCirrhosisDysfunctionNitric oxideReticulon 4B (Nogo‐B) is a novel regulator of hepatic fibrosis
Zhang D, Utsumi T, Huang H, Gao L, Sangwung P, Chung C, Shibao K, Okamoto K, Yamaguchi K, Groszmann RJ, Jozsef L, Hao Z, Sessa WC, Iwakiri Y. Reticulon 4B (Nogo‐B) is a novel regulator of hepatic fibrosis. Hepatology 2011, 53: 1306-1315. PMID: 21480333, PMCID: PMC3667398, DOI: 10.1002/hep.24200.Peer-Reviewed Original ResearchConceptsBile duct ligationLiver fibrosisPortal pressureKO micePortal hypertensionReticulon 4BWT mice 4 weeksMice 4 weeksFibrosis/cirrhosisSham-operated controlsB knockout miceHepatic stellate cellsPotential therapeutic targetHuman liver sectionsAbsence of NogoGrowth factor β stimulationMechanism of NogoTGFβ/SMAD2WT miceVascular injuryHepatic fibrosisSham operationCirrhotic liverDuct ligationStellate cells
2008
Vascular biology and pathobiology of the liver: Report of a single‐topic symposium
Iwakiri Y, Grisham M, Shah V. Vascular biology and pathobiology of the liver: Report of a single‐topic symposium. Hepatology 2008, 47: 1754-1763. PMID: 18393322, PMCID: PMC2724750, DOI: 10.1002/hep.22203.BooksConceptsPortal hypertensionVascular biologyIschemia-reperfusion injurySingle Topic ConferenceMajority of morbidityClinical sequelaeIR injurySpecific disease syndromesLiver diseaseVascular syndromesVascular diseaseVascular cell signalingHypertensionDisease syndromeLiver cellsSyndromeMajor vascular defectsLiverVascular defectsInjuryDiseasePathobiologyAmerican AssociationCell signalingCirrhosis
2007
Decreased intrahepatic response to α1‐adrenergic agonists in lipopolysaccharide‐treated rats is located in the sinusoidal area and depends on Kupffer cell function
Lee C, Loureiro‐Silva M, Abraldes JG, Iwakiri Y, Haq O, Groszmann RJ. Decreased intrahepatic response to α1‐adrenergic agonists in lipopolysaccharide‐treated rats is located in the sinusoidal area and depends on Kupffer cell function. Journal Of Gastroenterology And Hepatology 2007, 22: 893-900. PMID: 17498219, DOI: 10.1111/j.1440-1746.2007.04922.x.Peer-Reviewed Original ResearchConceptsLipopolysaccharide-treated ratsKupffer cell functionVascular responsesAdrenergic agonistsKupffer cellsNormal liverSinusoidal areaNitric oxide synthase inhibitorCell functionOxide synthase inhibitorRole of KupfferVascular tone controlNitric oxide overproductionKrebs-Henseleit solutionNitric oxide productionΑ1-adrenergic agonistDose-response curveIntrahepatic responseMicrovascular abnormalitiesSecond doseEndotoxemic ratsLiver perfusionSynthase inhibitorMethoxamineGadolinium chlorideVascular endothelial dysfunction in cirrhosis
Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. Journal Of Hepatology 2007, 46: 927-934. PMID: 17391799, DOI: 10.1016/j.jhep.2007.02.006.BooksConceptsEndothelium-dependent relaxationEndothelial dysfunctionSinusoidal endothelial cellsPortal hypertensionVascular nitric oxide levelsVascular endothelial dysfunctionNitric oxide levelsSEC dysfunctionVascular resistanceEarly key eventSplanchnic circulationLiver cirrhosisVasodilator moleculeLiver microcirculationSystemic circulationOxide levelsCirrhosisDysfunctionEndothelial cellsHypertensionMultiple diseasesKey eventsArteryMicrocirculationDisease