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
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 ResearchMeSH KeywordsAnimalsFemaleHumansLiver CirrhosisMaleMiceMice, KnockoutN-AcetylglucosaminyltransferasesNecroptosisConceptsReceptor-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 kinase
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 ResearchConceptsAlcoholic 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
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
Determination of mesenchymal stem cell fate by pigment epithelium‐derived factor (PEDF) results in increased adiposity and reduced bone mineral content
Gattu AK, Swenson ES, Iwakiri Y, Samuel VT, Troiano N, Berry R, Church CD, Rodeheffer MS, Carpenter TO, Chung C. Determination of mesenchymal stem cell fate by pigment epithelium‐derived factor (PEDF) results in increased adiposity and reduced bone mineral content. The FASEB Journal 2013, 27: 4384-4394. PMID: 23887690, PMCID: PMC3804749, DOI: 10.1096/fj.13-232900.Peer-Reviewed Original ResearchConceptsPigment epithelium-derived factorMesenchymal stem cell fateHuman MSCsMesenchymal stem cell differentiationStem cell fateStem cell differentiationEpithelium-derived factorCell fateOsteogenesis imperfecta type VISignal transductionMSC differentiationNegative regulatorSERPINF1 geneProtein productsOsteoblast differentiationCell differentiationOsteoblast precursorsHuman diseasesPEDF-knockout micePeroxisome proliferator-activated receptorDifferentiation patternsMurine MSCsProliferator-activated receptorAdipocyte markersControl-treated cellsReticulon 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 indexAbsence of Nogo-B (Reticulon 4B) Facilitates Hepatic Stellate Cell Apoptosis and Diminishes Hepatic Fibrosis in Mice
Tashiro K, Satoh A, Utsumi T, Chung C, Iwakiri Y. Absence of Nogo-B (Reticulon 4B) Facilitates Hepatic Stellate Cell Apoptosis and Diminishes Hepatic Fibrosis in Mice. American Journal Of Pathology 2013, 182: 786-795. PMID: 23313137, PMCID: PMC3586693, DOI: 10.1016/j.ajpath.2012.11.032.Peer-Reviewed Original ResearchConceptsHepatic stellate cell apoptosisMF-HSCsStellate cell apoptosisHepatic fibrosisKO miceCell apoptosisHuman hepatic stellate cellsRole of NogoCarbon tetrachloride inhalationCaspase-3B knockout miceHepatic stellate cellsPotential therapeutic strategyApoptosis of HSCsWT miceFibrotic areasLiver fibrosisSelective blockadeExperimental cirrhosisLX2 cellsCirrhotic liverStellate cellsTherapeutic strategiesKnockout miceFibrosiseNOS-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
Reticulon 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
2007
Loss of Akt1 Leads to Severe Atherosclerosis and Occlusive Coronary Artery Disease
Fernández-Hernando C, Ackah E, Yu J, Suárez Y, Murata T, Iwakiri Y, Prendergast J, Miao RQ, Birnbaum MJ, Sessa WC. Loss of Akt1 Leads to Severe Atherosclerosis and Occlusive Coronary Artery Disease. Cell Metabolism 2007, 6: 446-457. PMID: 18054314, PMCID: PMC3621848, DOI: 10.1016/j.cmet.2007.10.007.Peer-Reviewed Original ResearchMeSH KeywordsAcute Coronary SyndromeAnimalsApolipoproteins EApoptosisAtherosclerosisBone Marrow TransplantationCoronary OcclusionDisease Models, AnimalEndothelial CellsFemaleHumansInflammation MediatorsMacrophagesMaleMiceMice, KnockoutNitric Oxide Synthase Type IINitric Oxide Synthase Type IIIProto-Oncogene Proteins c-aktConceptsLoss of Akt1Apolipoprotein E knockout backgroundOcclusive coronary artery diseaseBone marrow transfer experimentsAcute coronary syndromeCoronary artery diseaseLesion expansionCoronary syndromeCoronary atherosclerosisSevere atherosclerosisArtery diseaseInflammatory mediatorsCoronary lesionsVascular protectionVascular originProinflammatory genesENOS phosphorylationCardiovascular systemLesion formationGenetic ablationEndothelial cellsAtherogenesisEnhanced expressionKnockout backgroundVessel wall
2005
Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis
Ackah E, Yu J, Zoellner S, Iwakiri Y, Skurk C, Shibata R, Ouchi N, Easton RM, Galasso G, Birnbaum MJ, Walsh K, Sessa WC. Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis. Journal Of Clinical Investigation 2005, 115: 2119-2127. PMID: 16075056, PMCID: PMC1180542, DOI: 10.1172/jci24726.Peer-Reviewed Original ResearchConceptsSerine-threonine protein kinaseAkt1/protein kinase BαProtein kinase BαProtein kinase BAkt1-/- miceIndividual Akt isoformsLoss of Akt1Substrate phosphorylationCellular functionsAkt substrateProtein kinaseAkt isoformsAkt1 knockout miceGene expressionGenetic lossKinase BBasal phosphorylationCell metabolismPostnatal angiogenesisCellular migrationVivo roleCell migrationAKT1Essential rolePhosphorylation
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
2002
Mice with targeted deletion of eNOS develop hyperdynamic circulation associated with portal hypertension
Iwakiri Y, Cadelina G, Sessa WC, Groszmann RJ. Mice with targeted deletion of eNOS develop hyperdynamic circulation associated with portal hypertension. AJP Gastrointestinal And Liver Physiology 2002, 283: g1074-g1081. PMID: 12381520, DOI: 10.1152/ajpgi.00145.2002.Peer-Reviewed Original ResearchConceptsPartial portal vein ligationEndothelial NO synthaseHyperdynamic circulatory statePortal hypertensive animalsHyperdynamic circulationPortal hypertensionCirculatory stateHypertensive animalsInducible NOSNitric oxideLevels of vasodilatorsPortal vein ligationSham-operated groupSham-operated animalsSystemic vasodilationSplanchnic circulationPeripheral resistanceVein ligationSham animalsNO synthaseKnockout miceGene deletionINOS geneHemodynamic characteristicsMice