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 vesselsInterleukin-7-based identification of liver lymphatic endothelial cells reveals their unique structural features
Yang Y, Jeong J, Su T, Lai S, Zhang P, Garcia-Milian R, Graham M, Liu X, McConnell M, Utsumi T, Pereira J, Iwakiri Y. Interleukin-7-based identification of liver lymphatic endothelial cells reveals their unique structural features. JHEP Reports 2024, 6: 101069. PMID: 38966234, PMCID: PMC11222939, DOI: 10.1016/j.jhepr.2024.101069.Peer-Reviewed Original ResearchCell surface structuresLymphatic endothelial cellsPublished single-cell RNA-sequencingRNA-seq analysisScRNA-seq analysisSingle-cell RNA sequencingLymphatic systemEndothelial cellsInterleukin-7RNA-seqScRNA-seqExpressed genesRNA sequencingTranscriptomic changesLow abundanceI/R liver injuryGenesIsolation protocolLiver cell typesCell typesIsolation methodLiver of miceHuman liver specimensHeterozygous miceMouse liverLymphatics in the liver for translational science
Iwakiri Y. Lymphatics in the liver for translational science. Clinical Liver Disease 2023, 21: 122-124. PMID: 37936952, PMCID: PMC10627586, DOI: 10.1097/cld.0000000000000019.Peer-Reviewed Original ResearchThe 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 profilesInflammationHepatic lymphatic vascular system in health and disease
Jeong J, Tanaka M, Iwakiri Y. Hepatic lymphatic vascular system in health and disease. Journal Of Hepatology 2022, 77: 206-218. PMID: 35157960, PMCID: PMC9870070, DOI: 10.1016/j.jhep.2022.01.025.Peer-Reviewed Original ResearchConceptsLiver diseaseNon-alcoholic fatty liver diseaseLymphatic systemFatty liver diseaseCongenital liver diseasesPotential therapeutic strategyHepatic lymphatic systemLiver transplantationPortal hypertensionMalignant tumorsTherapeutic strategiesDisease pathogenesisHepatic physiologyDiseasePathological conditionsSpecific markersLymphatic vesselsVascular systemLymphatic vascular systemOrgansTissue homeostasisHypertensionTransplantationPathophysiologyPathogenesisCovid‐19 and Liver Injury: Role of Inflammatory Endotheliopathy, Platelet Dysfunction, and Thrombosis
McConnell MJ, Kondo R, Kawaguchi N, Iwakiri Y. Covid‐19 and Liver Injury: Role of Inflammatory Endotheliopathy, Platelet Dysfunction, and Thrombosis. Hepatology Communications 2022, 6: 255-269. PMID: 34658172, PMCID: PMC8652692, DOI: 10.1002/hep4.1843.Peer-Reviewed Original ResearchConceptsLiver injurySARS-CoV-2Severe acute respiratory syndrome coronavirus 2Coronavirus disease 2019 (COVID-19) symptomsAcute respiratory syndrome coronavirus 2Alcohol-related liver diseaseSARS-CoV-2 infectionRespiratory syndrome coronavirus 2Chronic liver failureLiver-related complicationsDirect viral infectionElevated aspartate aminotransferaseSyndrome coronavirus 2COVID-19Pathophysiologic explanationLiver failureLiver diseasePlatelet dysfunctionVascular inflammationInflammatory environmentHepatic effectsAlanine aminotransferaseViral infectionAspartate aminotransferaseHepatic fociLiver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy
McConnell MJ, Kawaguchi N, Kondo R, Sonzogni A, Licini L, Valle C, Bonaffini PA, Sironi S, Alessio MG, Previtali G, Seghezzi M, Zhang X, Lee A, Pine AB, Chun HJ, Zhang X, Fernandez-Hernando C, Qing H, Wang A, Price C, Sun Z, Utsumi T, Hwa J, Strazzabosco M, Iwakiri Y. Liver injury in COVID-19 and IL-6 trans-signaling-induced endotheliopathy. Journal Of Hepatology 2021, 75: 647-658. PMID: 33991637, PMCID: PMC8285256, DOI: 10.1016/j.jhep.2021.04.050.Peer-Reviewed Original ResearchConceptsLiver sinusoidal endothelial cellsLiver injuryInterleukin-6Sinusoidal endothelial cellsAlanine aminotransferaseLiver histologyD-dimerCOVID-19Primary human liver sinusoidal endothelial cellsSARS-CoV-2 infectionHuman liver sinusoidal endothelial cellsEndothelial cellsSoluble glycoprotein 130IL-6 levelsSmall-interfering RNA knockdownJAK inhibitor ruxolitinibFactor VIII activityProinflammatory factorsInflammatory signalsLarge cohortInhibitor ruxolitinibVWF antigenEndotheliopathyPatientsInjuryAlcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease
Yang Y, Sangwung P, Kondo R, Jung Y, McConnell MJ, Jeong J, Utsumi T, Sessa WC, Iwakiri Y. Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease. Journal Of Hepatology 2021, 75: 377-386. PMID: 33675874, PMCID: PMC8292196, DOI: 10.1016/j.jhep.2021.02.028.Peer-Reviewed Original ResearchConceptsEndothelial nitric oxide synthaseAlcohol-induced liver injuryLiver sinusoidal endothelial cellsAlcohol-related liver diseaseLiver injuryLSEC dysfunctionHsp90 acetylationNO productionHistone deacetylase 6Liver diseaseTherapeutic strategiesHeat shock protein 90 (Hsp90) acetylationLiver sinusoidal endothelial dysfunctionSinusoidal endothelial cell dysfunctionMouse liver sinusoidal endothelial cellsEndothelial cell dysfunctionNitric oxide synthaseEthanol-fed miceSinusoidal endothelial dysfunctionPotential therapeutic approachPotential therapeutic strategyNitric oxide productionNew therapeutic strategiesSinusoidal endothelial cellsAcetylation of Hsp90Single-Cell Transcriptomics Reveals Zone-Specific Alterations of Liver Sinusoidal Endothelial Cells in Cirrhosis
Su T, Yang Y, Lai S, Jeong J, Jung Y, McConnell M, Utsumi T, Iwakiri Y. Single-Cell Transcriptomics Reveals Zone-Specific Alterations of Liver Sinusoidal Endothelial Cells in Cirrhosis. Cellular And Molecular Gastroenterology And Hepatology 2020, 11: 1139-1161. PMID: 33340713, PMCID: PMC7903131, DOI: 10.1016/j.jcmgh.2020.12.007.Peer-Reviewed Original ResearchConceptsLiver sinusoidal endothelial cellsCirrhotic miceSinusoidal endothelial cellsLiver cirrhosisEndothelial cellsIntrahepatic vascular resistanceCarbon tetrachloride inhalationNovel therapeutic strategiesNitric oxide productionCirrhotic mouse liverEC populationsVascular resistanceClinical complicationsLiver fibrosisTherapeutic strategiesCirrhosisOxide productionEndocytic receptorMiceAbstractTextZone 3Extracellular matrix genesVascular ECsLymphatic ECsMouse liverEnhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats
Hsu SJ, Zhang C, Jeong J, Lee SI, McConnell M, Utsumi T, Iwakiri Y. Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats. Gastroenterology 2020, 160: 1315-1329.e13. PMID: 33227282, PMCID: PMC7956141, DOI: 10.1053/j.gastro.2020.11.036.Peer-Reviewed Original ResearchConceptsMeningeal lymphatic drainageLymphatic drainageMicroglia activationMotor functionBile duct ligation modelTumor necrosis factor αSerious neurologic complicationsMeningeal lymphatic systemNecrosis factor αDuct ligation modelNew therapeutic strategiesBrain inflammationNeurologic complicationsHepatic encephalopathyLiver cirrhosisLymph nodesRotarod testMotor dysfunctionCirrhotic ratsInterleukin-1βLigation modelInterferon γProinflammatory genesCisterna magnaTherapeutic strategies
2024
Guidelines for the diagnosis and treatment of idiopathic portal hypertension, extrahepatic portal obstruction, and Budd–Chiari syndrome in Japan
Furuichi Y, Kage M, Ohta M, Ohfuji S, Sasaki H, Hidaka H, Yoshida H, Kanto T, Kusano H, Akahoshi T, Obara K, Hashizume M, Kuniyoshi Y, Kawaguchi T, Okubo H, Ishikawa T, Hirooka M, Iwakiri Y, Nio M, Tanaka A. Guidelines for the diagnosis and treatment of idiopathic portal hypertension, extrahepatic portal obstruction, and Budd–Chiari syndrome in Japan. Hepatology Research 2024, 54: 952-969. PMID: 39364631, DOI: 10.1111/hepr.14118.Peer-Reviewed Original ResearchPublisher Correction: Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage
Gong K, Xue C, Feng Z, Pan R, Wang M, Chen S, Chen Y, Guan Y, Dai L, Zhang S, Jiang L, Li L, Wang B, Yin Z, Ma L, Iwakiri Y, Tang J, Liao C, Chen H, Duan Y. Publisher Correction: Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage. Nature Communications 2024, 15: 7902. PMID: 39256382, PMCID: PMC11387603, DOI: 10.1038/s41467-024-52287-5.Peer-Reviewed Original ResearchNogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia
Xue C, Zeng P, Gong K, Li Q, Feng Z, Wang M, Chen S, Yang Y, Li J, Zhang S, Yin Z, Liang Y, Yan T, Yu M, Feng K, Zhao D, Yang X, Zhang X, Ma L, Iwakiri Y, Chen L, Tang X, Chen Y, Chen H, Duan Y. Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia. Cell Reports 2024, 43: 114691. PMID: 39235944, DOI: 10.1016/j.celrep.2024.114691.Peer-Reviewed Original ResearchLow-density lipoprotein receptorNogo-BCholesterol levelsCellular cholesterol levelsCholesterol excretionDecreased cellular cholesterol levelsATP-binding cassette transportersLiver x receptor-aHepatic uptakeLow-density lipoprotein receptor expressionCholesterol metabolic processHepatic cholesterol uptakeNogo-B expressionLowering cholesterol levelsMetabolic processesCassette transportersLipoprotein receptorApolipoprotein ELower cholesterol levelsCholesterol metabolismCholesterol uptakeDecreased cholesterol levelsReduce hypercholesterolemiaMolecular targetsExcretionCarbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation
Yanagisawa H, Maeda H, Noguchi I, Tanaka M, Wada N, Nagasaki T, Kobayashi K, Kanazawa G, Taguchi K, Chuang V, Sakai H, Nakashima H, Kinoshita M, Kitagishi H, Iwakiri Y, Sasaki Y, Tanaka Y, Otagiri M, Watanabe H, Maruyama T. Carbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation. Redox Biology 2024, 76: 103314. PMID: 39163766, PMCID: PMC11381851, DOI: 10.1016/j.redox.2024.103314.Peer-Reviewed Original ResearchAMP-activated protein kinaseKupffer cell activationHeme oxygenase-1Red blood cellsInhibit Kupffer cell activationLiver heme oxygenase-1Suppress Kupffer cell activationCell activationLiver regenerationModel miceBlood cellsFat accumulationActivating AMP-activated protein kinaseAMP-activated protein kinase activationImpaired liver regenerationMethionine-choline deficient dietNonalcoholic fatty liver diseaseRestore liver regenerationFatty liver diseaseReceptor inductionHealthy miceProtein kinase activityPromoting fatty acid oxidationMouse modelLiver diseaseIntestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage
Gong K, Xue C, Feng Z, Pan R, Wang M, Chen S, Chen Y, Guan Y, Dai L, Zhang S, Jiang L, Li L, Wang B, Yin Z, Ma L, Iwakiri Y, Tang J, Liao C, Chen H, Duan Y. Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage. Nature Communications 2024, 15: 6845. PMID: 39122737, PMCID: PMC11315690, DOI: 10.1038/s41467-024-51352-3.Peer-Reviewed Original ResearchConceptsEnteroendocrine cellsEndoplasmic reticulum (ER)-resident proteinGlucagon-like peptide 1Nogo-BEndoplasmic reticulumStimulate insulin secretionPotential therapeutic targetProglucagonGlucagon-like peptide 1 receptorInhibit glucagon secretionRegulatory processesIntestinal tractProglucagon fragmentInsulin secretionCleavageNogo-B knockoutTherapeutic targetPancreatic cellsPeptide 1Glucagon secretionCellsReticulonGolgiReticulon 4BInsulin resistanceSelective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice
Gratton J, Lin M, Yu J, Weiss E, Jiang Z, Fairchild T, Iwakiri Y, Groszmann R, Claffey K, Cheng Y, Sessa W. Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell 2024, 42: 1127. PMID: 38821059, DOI: 10.1016/j.ccell.2024.05.009.Peer-Reviewed Original ResearchUnlocking the Role of Liver Sinusoidal Endothelial Cells: Key Players in Liver Fibrosis
Iwakiri Y. Unlocking the Role of Liver Sinusoidal Endothelial Cells: Key Players in Liver Fibrosis. Clinical And Molecular Hepatology 2024, 30: 673-676. PMID: 38726502, PMCID: PMC11540341, DOI: 10.3350/cmh.2024.0343.Peer-Reviewed Original ResearchChapter 13 Liver Sinusoidal Cells in alcohol-associated liver disease
Iwakiri Y. Chapter 13 Liver Sinusoidal Cells in alcohol-associated liver disease. 2024, 285-291. DOI: 10.1016/b978-0-323-95262-0.00013-9.Peer-Reviewed Original ResearchAlcohol-associated liver diseaseLiver sinusoidal endothelial cellsPathogenesis of alcohol-associated liver diseaseChronic alcohol consumptionSinusoidal endothelial cellsLiver diseaseNormal function of immune cellsEndothelial cellsFunction of immune cellsSinusoidal cellsAlcohol consumptionIntrahepatic vascular toneHepatic stellate cellsEndothelial cell populationLiver sinusoidal cellsLiver cell typesImmune cellsAntigen clearanceVascular toneKupffer cells/macrophagesKupffer cellsStellate cellsCell populationsLiver homeostasisLiver
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