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
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
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
Digoxin 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
Development 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
An endoplasmic reticulum protein, Nogo‐B, facilitates alcoholic liver disease through regulation of kupffer cell polarization
Park J, Shao M, Kim MY, Baik SK, Cho MY, Utsumi T, Satoh A, Ouyang X, Chung C, Iwakiri Y. An endoplasmic reticulum protein, Nogo‐B, facilitates alcoholic liver disease through regulation of kupffer cell polarization. Hepatology 2017, 65: 1720-1734. PMID: 28090670, PMCID: PMC5397326, DOI: 10.1002/hep.29051.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEndoplasmic Reticulum StressHumansKupffer CellsLiver Diseases, AlcoholicMaleMice, Inbred C57BLMice, KnockoutNogo ProteinsConceptsAlcoholic liver diseasePositive Kupffer cellsKupffer cellsLiver injuryALD patientsLiver diseaseM1 polarizationKO miceM2 polarizationLieber-DeCarli ethanol liquid dietDisease severityM1/M2 polarizationKupffer cell polarizationEthanol liquid dietHepatic triglyceride levelsM2 macrophage polarizationHigher hepatic triglyceride levelsChronic ethanol feedingNew therapeutic targetsER stressAbsence of NogoM2 statusWT miceM1 activationTriglyceride levels
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
Pigment 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 indexeNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases
Di Lorenzo A, Lin MI, Murata T, Landskroner-Eiger S, Schleicher M, Kothiya M, Iwakiri Y, Yu J, Huang PL, Sessa WC. eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases. Journal Of Cell Science 2013, 126: 5541-5552. PMID: 24046447, PMCID: PMC3860306, DOI: 10.1242/jcs.115972.Peer-Reviewed Original ResearchMeSH KeywordsAdherens JunctionsAnimalsAntigens, CDCadherinsCapillary PermeabilityCells, CulturedCSK Tyrosine-Protein KinaseEndothelial CellsEndothelium, VascularGuanine Nucleotide Exchange FactorsHumansMaleMiceMice, Inbred C57BLMice, KnockoutNitric OxideNitric Oxide Synthase Type IIIPhosphorylationProtein Processing, Post-TranslationalProtein TransportSrc-Family KinasesStress FibersT-Lymphoma Invasion and Metastasis-inducing Protein 1Vascular Endothelial Growth Factor AConceptsAdherens junctionsVE-cadherinExchange factor Tiam1Vascular endothelial growth factorStress fiber formationEndothelial NO synthaseEndothelial adherens junctionsVE-cadherin phosphorylationCytoskeletal architectureRho GTPasesCortical actinCytoskeletal remodelingRac GTPaseC-SrcRac guanineRho activationMolecular mechanismsPhysiological roleEndothelial barrier functionFiber formationENOS activationGrowth factorEnhanced activationActivationNitric oxide
2011
Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1
Schmitz JC, Protiva P, Gattu AK, Utsumi T, Iwakiri Y, Neto AG, Quinn M, Cornwell ML, Fitchev P, Lugea A, Crawford SE, Chung C. Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1. American Journal Of Pathology 2011, 179: 2990-2999. PMID: 21964188, PMCID: PMC3260804, DOI: 10.1016/j.ajpath.2011.08.009.Peer-Reviewed Original ResearchConceptsPigment epithelium-derived factorWild-type miceLoss of PEDFPEDF expressionQuantitative real-time PCRFibrotic responseNormal extracellular matrixWild-type animalsReal-time PCRSmooth muscle actin stainingExtracellular matrixIntragastric feeding modelMice fed ethanolPancreatitis responsesEarly fibrotic responseEpithelium-derived factorMuscle actin stainingSirius red stainingExpression levelsThrombospondin-1Actin stainingFibrogenic markersMore fibrosisPEDF overexpressionEthanol diet
2003
Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice
Gratton J, Lin MI, Yu J, Weiss ED, Jiang ZL, Fairchild TA, Iwakiri Y, Groszmann R, Claffey KP, Cheng Y, Sessa WC. Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell 2003, 4: 31-39. PMID: 12892711, DOI: 10.1016/s1535-6108(03)00168-5.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCapillary PermeabilityCarcinoma, HepatocellularCarcinoma, Lewis LungCaveolin 1CaveolinsDisease ProgressionEndothelium, VascularEnzyme InhibitorsLiver Neoplasms, ExperimentalLung NeoplasmsMaleMiceMice, Inbred C57BLMice, KnockoutMice, NudeNeovascularization, PhysiologicNitric Oxide SynthaseNitric Oxide Synthase Type IINitric Oxide Synthase Type IIIPeptide FragmentsVascular Endothelial Growth Factor AConceptsEndothelial nitric oxide synthaseTumor progressionAntitumor actionDelays tumor progressionENOS knockout miceNitric oxide synthaseTumor blood vesselsTumor microvascular permeabilityOxide synthaseMicrovascular permeabilityKnockout miceAntiangiogenic effectsTumor vasculatureCell-permeable peptideMicrovascular hyperpermeabilityNovel targetNormal vasculatureHyperpermeabilityBlood vesselsCavtratinAntitumor therapyProgressionMiceSelective inhibitionVasculature