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 vesselsAlcohol-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
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. 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 resistance
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 linesS-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 levelsEncapsulation of an Antioxidant in Redox-Sensitive Self-Assembled Albumin Nanoparticles for the Treatment of Hepatitis
Yasuda K, Maeda H, Kinoshita R, Minayoshi Y, Mizuta Y, Nakamura Y, Imoto S, Nishi K, Yamasaki K, Sakuragi M, Nakamura T, Ikeda-Imafuku M, Iwao Y, Ishima Y, Ishida T, Iwakiri Y, Otagiri M, Watanabe H, Maruyama T. Encapsulation of an Antioxidant in Redox-Sensitive Self-Assembled Albumin Nanoparticles for the Treatment of Hepatitis. ACS Nano 2023, 17: 16668-16681. PMID: 37579503, DOI: 10.1021/acsnano.3c02877.Peer-Reviewed Original ResearchConceptsAlbumin nanoparticlesRedox characteristicsNanoparticlesStable formReactive oxygen speciesAlbumin moleculeIntramolecular disulfide bondsDisulfide bondsIntermolecular disulfide bridgesDisulfide bridgesPreparationNanoantioxidantsBondsNanostructuresOxygen speciesMoleculesEncapsulationHereinNanoscaleAdditivesAntioxidantsSerum conditionsTreatment of hepatitisWaterOverexpression of NgBR inhibits high-fat diet–induced atherosclerosis in ApoE-deficiency mice
Gong K, Wang M, Wang D, Gao Y, Ma L, Yang X, Zhu X, Chen S, Zhang M, Li H, Chen Y, Hu W, Miao Q, Iwakiri Y, Liao C, Duan Y, Han J. Overexpression of NgBR inhibits high-fat diet–induced atherosclerosis in ApoE-deficiency mice. Hepatology Communications 2023, 7: e0048. PMID: 36996002, PMCID: PMC10069848, DOI: 10.1097/hc9.0000000000000048.Peer-Reviewed Original ResearchConceptsNgBR overexpressionScavenger receptor type BIHigh-fat diet-induced atherosclerosisApolipoprotein E deficient miceApoE deficiency miceApoE-/- miceDiet-induced atherosclerosisHigh-fat dietLevels of cholesterolBile acid synthesisCholesterol synthesis genesInflammatory factorsVascular inflammationProtein kinase αSinus lesionsHepatic steatosisAortic rootRisk factorsDeficient miceAtherosclerosis treatmentFree fatty acidsCholesterol metabolismAtherosclerosisAcid synthesisAAV injection
2022
Inhibition of high-fat diet–induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms
Wang X, Yang Y, Zhao D, Zhang S, Chen Y, Chen Y, Feng K, Li X, Han J, Iwakiri Y, Duan Y, Yang X. Inhibition of high-fat diet–induced obesity via reduction of ER-resident protein Nogo occurs through multiple mechanisms. Journal Of Biological Chemistry 2022, 298: 101561. PMID: 34998825, PMCID: PMC8814669, DOI: 10.1016/j.jbc.2022.101561.Peer-Reviewed Original ResearchConceptsHigh-fat dietMetabolic disordersHigh-fat diet-induced obesityBody mass index valuesInhibition of NogoSerum proinflammatory cytokinesDiet-induced obesityInfiltration of macrophagesType 2 diabetesWT littermate control miceLittermate control miceEffects of NogoMass index valuesBrown adipose tissueProtect miceNormal chowControl miceProinflammatory cytokinesInsulin resistanceObesity treatmentRisk factorsLipid profileCardiovascular diseaseProtein NogoObesity
2021
Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH
Maeda H, Ishima Y, Saruwatari J, Mizuta Y, Minayoshi Y, Ichimizu S, Yanagisawa H, Nagasaki T, Yasuda K, Oshiro S, Taura M, McConnell MJ, Oniki K, Sonoda K, Wakayama T, Kinoshita M, Shuto T, Kai H, Tanaka M, Sasaki Y, Iwakiri Y, Otagiri M, Watanabe H, Maruyama T. Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH. Journal Of Controlled Release 2021, 341: 457-474. PMID: 34856227, DOI: 10.1016/j.jconrel.2021.11.039.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntioxidantsHumansKupffer CellsMiceNitric OxideNon-alcoholic Fatty Liver DiseaseConceptsMannose receptor C type 1Treatment of NASHNonalcoholic steatohepatitisKupffer cellsBlood flowNO donorReactive oxygen speciesHepatic blood flowDevelopment of steatohepatitisNASH model miceC type 1Nitric oxide donorOxidative stress-associated pathologiesStress-associated pathologiesCombination therapyHepatoprotective effectModel miceLiver lobeOxide donorType 2Therapeutic potentialType 1Nitric oxidePathological phenotypesSpecific uptake
2020
Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity
Zhang S, Guo F, Yu M, Yang X, Yao Z, Li Q, Wei Z, Feng K, Zeng P, Zhao D, Li X, Zhu Y, Miao QR, Iwakiri Y, Chen Y, Han J, Duan Y. Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity. Journal Of Hepatology 2020, 73: 1482-1495. PMID: 32738448, DOI: 10.1016/j.jhep.2020.07.034.Peer-Reviewed Original ResearchConceptsDiet-induced metabolic disordersHepatic lipid accumulationInsulin sensitivityMetabolic disordersInsulin resistanceNogo expressionNon-alcoholic fatty liver diseaseDiet-induced body weight gainInsulin activityDiet-induced glucose intoleranceLipid accumulationFatty liver diseaseHigh-fructose dietGrowth factor 21Littermate control miceDe novo lipogenesisHigh-carbohydrate dietBody weight gainCarbohydrate-responsive element-binding proteinExpression of ChREBPChREBP activityEndoplasmic reticulum stressMetabolic complicationsGlucose intoleranceLiver disease
2019
O-GlcNAc transferase suppresses necroptosis and liver fibrosis
Zhang B, Li MD, Yin R, Liu Y, Yang Y, Mitchell-Richards KA, Nam JH, Li R, Wang L, Iwakiri Y, Chung D, Robert ME, Ehrlich BE, Bennett AM, Yu J, Nathanson MH, Yang X. O-GlcNAc transferase suppresses necroptosis and liver fibrosis. JCI Insight 2019, 4: e127709. PMID: 31672932, PMCID: PMC6948774, DOI: 10.1172/jci.insight.127709.Peer-Reviewed Original ResearchConceptsReceptor-interacting protein kinase 3Liver fibrosisLiver diseaseHepatocyte necroptosisEthanol-induced liver injuryAlcoholic liver cirrhosisChronic liver diseaseMultiple liver diseasesWeeks of ageProtein expression levelsPortal inflammationLiver cirrhosisLiver injuryBallooning degenerationElevated protein expression levelsSpontaneous genetic modelFibrosisKey suppressorKey mediatorMiceProtein kinase 3CirrhosisExpression levelsGlcNAc levelsMixed lineage kinaseDigoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation
Zhao P, Han SN, Arumugam S, Yousaf MN, Qin Y, Jiang JX, Torok NJ, Chen Y, Mankash MS, Liu J, Li J, Iwakiri Y, Ouyang X. Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation. AJP Gastrointestinal And Liver Physiology 2019, 317: g387-g397. PMID: 31411894, PMCID: PMC6842989, DOI: 10.1152/ajpgi.00054.2019.Peer-Reviewed Original ResearchConceptsHigh-fat dietSignificant clinical applicabilityHuman nonalcoholic steatohepatitisNonalcoholic steatohepatitisOral digoxinLiver injuryCell subsetsPathway activationMouse modelHigh-fat diet mouse modelLiver injury mouse modelHepatocyte mitochondrial dysfunctionClinical applicabilityDiet mouse modelInjury mouse modelDifferential involvementLarge clinical experienceNLRP3 inflammasome activationSignificant protective effectHIF-1α transactivationHepatic oxidative stress responseHypoxia-inducible factorLiver inflammationHFD miceWide dosage rangePoly(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
Integrated analysis of microRNA and mRNA expression profiles in splenomegaly induced by non-cirrhotic portal hypertension in rats
Saruwatari J, Dong C, Utsumi T, Tanaka M, McConnell M, Iwakiri Y. Integrated analysis of microRNA and mRNA expression profiles in splenomegaly induced by non-cirrhotic portal hypertension in rats. Scientific Reports 2018, 8: 17983. PMID: 30573742, PMCID: PMC6301948, DOI: 10.1038/s41598-018-36297-0.Peer-Reviewed Original ResearchConceptsCell proliferationWhole-genome microarray analysisInterferon-mediated antiviral activitySuppression of genesMicroRNA-mRNA networkSignificant differential expressionPotential biological functionsMRNA expression profilesTarget mRNAsBiological functionsExpression profilesMicroarray analysisDifferential expressionInnate immune responseMicroRNAsCellular mechanismsHematopoietic systemIntegrated analysisGenesNew insightsComprehensive profileMRNAProliferationTissue fibrosisImportant roleLymphatics 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
Novel application and serial evaluation of tissue-engineered portal vein grafts in a murine model
Maxfield MW, Stacy MR, Kurobe H, Tara S, Yi T, Cleary MA, Zhuang ZW, Rodriguez-Davalos MI, Emre SH, Iwakiri Y, Shinoka T, Breuer CK. Novel application and serial evaluation of tissue-engineered portal vein grafts in a murine model. Regenerative Medicine 2017, 12: 929-938. PMID: 29215317, PMCID: PMC5827823, DOI: 10.2217/rme-2017-0021.Peer-Reviewed Original Research