2024
PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases
Gallucci G, Hayes C, Boyer J, Barbier O, Assis D, Ghonem N. PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases. Cells 2024, 13: 1296. PMID: 39120326, PMCID: PMC11312002, DOI: 10.3390/cells13151296.Peer-Reviewed Original ResearchPrimary biliary cholangitisPrimary sclerosing cholangitisPeroxisome proliferator-activated receptorCholestatic liver diseaseUrsodeoxycholic acidUridine 5'-diphospho-glucuronosyltransferaseObeticholic acidBile acid metabolismAdjunctive therapyIncomplete response to UDCAProgression of primary biliary cholangitisResponse to UDCALiver diseasePeroxisome proliferator-activated receptor agonistsSecond-line treatmentMarkers of cholestasisImpairment of bile flowTherapeutic targetTreatment of cholestatic liver diseasesRetention of bile acidsAlternative treatment strategiesProgression to fibrosisProliferator-activated receptorsAcid metabolismBiliary cholangitis
2023
Human vascularized bile duct-on-a chip: a multi-cellular micro-physiological system for studying cholestatic liver disease
Du Y, de Jong I, Gupta K, Waisbourd-Zinman O, Har-Zahav A, Soroka C, Boyer J, Llewellyn J, Liu C, Naji A, Polacheck W, Wells R. Human vascularized bile duct-on-a chip: a multi-cellular micro-physiological system for studying cholestatic liver disease. Biofabrication 2023, 16: 015004. PMID: 37820623, PMCID: PMC10587873, DOI: 10.1088/1758-5090/ad0261.Peer-Reviewed Original ResearchConceptsCholestatic liver diseasePrimary sclerosing cholangitisLiver diseaseBile ductBile duct tissuesDuct tissuePeripheral blood mononuclear cellsEndothelial cellsBlood mononuclear cellsNormal bile duct tissuesHuman vascular endothelial cellsVascular endothelial cellsPSC patientsSclerosing cholangitisIL-17ATh17 cellsMononuclear cellsVascular channelsBiliary organoidsCholangiocyte organoidsBlood vesselsCholangiocytesDiseaseFlow of bloodTight junctionsBile Acid Induced Inflammation and the Role of β-Catenin
Boyer J. Bile Acid Induced Inflammation and the Role of β-Catenin. Cellular And Molecular Gastroenterology And Hepatology 2023, 16: 1033. PMID: 37690462, PMCID: PMC10685134, DOI: 10.1016/j.jcmgh.2023.08.009.Commentaries, Editorials and LettersOrganic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans
Pan Q, Zhu G, Xu Z, Zhu J, Ouyang J, Tong Y, Zhao N, Zhang X, Cheng Y, Zhang L, Tan Y, Li J, Zhang C, Chen W, Cai S, Boyer J, Chai J. Organic Anion Transporting Polypeptide (OATP) 1B3 is a Significant Transporter for Hepatic Uptake of Conjugated Bile Acids in Humans. Cellular And Molecular Gastroenterology And Hepatology 2023, 16: 223-242. PMID: 37146714, PMCID: PMC10394288, DOI: 10.1016/j.jcmgh.2023.04.007.Peer-Reviewed Original ResearchConceptsBA uptake transportersBile duct ligationHepatic neutrophil infiltrationCholestatic liver injuryProinflammatory cytokine productionCholic acid dietAdaptive protective responseLiver-specific overexpressionWild-type miceConjugated bile acidsUptake transportersPrimary hepatocytesUDCA feedingNeutrophil infiltrationBDL miceLiver injuryCytokine productionBile flowDuct ligationOrganic anion transporting polypeptide (OATP) 1B3Conjugated BAsTransgenic miceHepatic uptakeBile acidsProtective responseUnique DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets for primary biliary cholangitis.
Li X, Li Y, Xiao J, Wang H, Guo Y, Mao X, Shi P, Hou Y, Zhang X, Zhao N, Zheng M, He Y, Ding J, Tan Y, Liao M, Li L, Peng Y, Li X, Pan Q, Xie Q, Li Q, Li J, Li Y, Chen Z, Huang Y, Assis DN, Cai SY, Boyer JL, Huang X, Tang CE, Liu X, Peng S, Chai J. Unique DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets for primary biliary cholangitis. Nat Commun 2023, 14: 29. PMID: 36759512, DOI: 10.1038/s41467-022-34606-w.Peer-Reviewed Original ResearchRunt-related transcription factor-1 ameliorates bile acid–induced hepatic inflammation in cholestasis through JAK/STAT3 signaling
Zhang L, Pan Q, Zhang L, Xia H, Liao J, Zhang X, Zhao N, Xie Q, Liao M, Tan Y, Li Q, Zhu J, Li L, Fan S, Li J, Zhang C, Cai S, Boyer J, Chai J. Runt-related transcription factor-1 ameliorates bile acid–induced hepatic inflammation in cholestasis through JAK/STAT3 signaling. Hepatology 2023, 77: 1866-1881. PMID: 36647589, PMCID: PMC10921919, DOI: 10.1097/hep.0000000000000041.Peer-Reviewed Original ResearchConceptsJAK/STAT3Bile duct ligationInflammatory responseLiver injuryCholestatic patientsTranscription factor 1Duct ligationBile acidsLiver inflammatory responseCholestatic liver injuryHepatic inflammatory responseElevated bile acidsCholic acid dietFactor 1Cholic acid feedingLiver-specific ablationNew therapeutic targetsLiver-specific deletionCholestatic miceHepatic inflammationLiver inflammationInflammatory chemokinesHepatic expressionMouse modelAcid diet
2022
SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface
Zhao N, Zhang X, Ding J, Pan Q, Zheng MH, Liu WY, Luo G, Qu J, Li M, Li L, Cheng Y, Peng Y, Xie Q, Wei Q, Li Q, Zou L, Ouyang X, Cai SY, Boyer JL, Chai J. SEMA7AR148W mutation promotes lipid accumulation and NAFLD progression via increased localization on the hepatocyte surface. JCI Insight 2022, 7: e154113. PMID: 35938531, PMCID: PMC9462498, DOI: 10.1172/jci.insight.154113.Peer-Reviewed Original ResearchConceptsIntegrin β1Lipid accumulationPrimary mouse hepatocytesProtein interactionsLipid droplet accumulationMouse liverFatty acid oxidationHeterozygous mutationsIntegrin β1 proteinPKC-α phosphorylationFA uptakeGenetic determinantsMouse peritoneal macrophagesCell membraneStrong genetic determinantsMutationsMouse hepatocytesDroplet accumulationΒ1 proteinCD36 expressionAcid oxidationPKCTriglyceride synthesisGenetic polymorphismsAccumulationFenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis
Gallucci GM, Alsuwayt B, Auclair AM, Boyer JL, Assis DN, Ghonem NS. Fenofibrate Downregulates NF-κB Signaling to Inhibit Pro-inflammatory Cytokine Secretion in Human THP-1 Macrophages and During Primary Biliary Cholangitis. Inflammation 2022, 45: 2570-2581. PMID: 35838934, PMCID: PMC10853883, DOI: 10.1007/s10753-022-01713-1.Peer-Reviewed Original ResearchConceptsPrimary biliary cholangitisPrimary sclerosing cholangitisAnti-inflammatory mechanismsChronic liver diseaseNF-κB signalingBiliary cholangitisLiver diseaseNF-κB p50IL-1βIL-8Peroxisome proliferator-activated receptor alphaPro-inflammatory cytokine secretionProliferator-activated receptor alphaIncomplete biochemical responseAnti-inflammatory effectsAddition of fenofibratePro-inflammatory cytokinesPPARα-dependent mannerHuman THP-1 macrophagesP65 protein expressionLabel therapeutic optionTHP-1 macrophagesTHP-1 cellsSclerosing cholangitisAdult patientsPrimary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases
Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases. Hepatology 2022, 75: 1012-1013. PMID: 34431119, DOI: 10.1002/hep.32117.Peer-Reviewed Original ResearchEffects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis.
Efe C, Lammert C, Taşçılar K, Dhanasekaran R, Ebik B, Higuera-de la Tijera F, Calışkan AR, Peralta M, Gerussi A, Massoumi H, Catana AM, Purnak T, Rigamonti C, Aldana AJG, Khakoo N, Nazal L, Frager S, Demir N, Irak K, Melekoğlu-Ellik Z, Kacmaz H, Balaban Y, Atay K, Eren F, Alvares-da-Silva MR, Cristoferi L, Urzua Á, Eşkazan T, Magro B, Snijders R, Barutçu S, Lytvyak E, Zazueta GM, Demirezer-Bolat A, Aydın M, Heurgue-Berlot A, De Martin E, Ekin N, Yıldırım S, Yavuz A, Bıyık M, Narro GC, Kıyıcı M, Akyıldız M, Kahramanoğlu-Aksoy E, Vincent M, Carr RM, Günşar F, Reyes EC, Harputluoğlu M, Aloman C, Gatselis NK, Üstündağ Y, Brahm J, Vargas NCE, Güzelbulut F, Garcia SR, Aguirre J, Anders M, Ratusnu N, Hatemi I, Mendizabal M, Floreani A, Fagiuoli S, Silva M, Idilman R, Satapathy SK, Silveira M, Drenth JPH, Dalekos GN, Assis DN, Björnsson E, Boyer JL, Yoshida EM, Invernizzi P, Levy C, Montano-Loza AJ, Schiano TD, Ridruejo E, Wahlin S. Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis. Liver International : Official Journal Of The International Association For The Study Of The Liver 2022, 42: 607-614. PMID: 34846800, DOI: 10.1111/liv.15121.Peer-Reviewed Original Research
2021
Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
Gallucci GM, Trottier J, Hemme C, Assis DN, Boyer JL, Barbier O, Ghonem NS. Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis. Hepatology Communications 2021, 5: 2035-2051. PMID: 34558841, PMCID: PMC8631103, DOI: 10.1002/hep4.1787.Peer-Reviewed Original ResearchConceptsSerum bile acidsSerum alkaline phosphataseBile acidsTreatment responseIncomplete responseTotal serum bile acidsElevated serum alkaline phosphatasePeroxisome proliferator-activated receptor alphaProliferator-activated receptor alphaAlkaline phosphatasePrimary sclerosing cholangitisPrimary biliary cholangitisStandard of careSerum ALP levelsBile acid glucuronidationCytotoxic bile acidsPrimary human hepatocytesBA detoxificationFenofibrate therapySclerosing cholangitisAdult patientsBiliary cholangitisLiver failureCombination therapyImproved outcomesIn Memoriam: Peter J. Meier (1947–2021)
Stieger B, Boyer JL. In Memoriam: Peter J. Meier (1947–2021). Journal Of Hepatology 2021, 75: 761-762. DOI: 10.1016/j.jhep.2021.06.039.Peer-Reviewed Original ResearchOutcome of COVID‐19 in Patients With Autoimmune Hepatitis: An International Multicenter Study
Efe C, Dhanasekaran R, Lammert C, Ebik B, la Tijera F, Aloman C, Calışkan A, Peralta M, Gerussi A, Massoumi H, Catana AM, Torgutalp M, Purnak T, Rigamonti C, Aldana A, Khakoo N, Kacmaz H, Nazal L, Frager S, Demir N, Irak K, Ellik ZM, Balaban Y, Atay K, Eren F, Cristoferi L, Batıbay E, Urzua Á, Snijders R, Kıyıcı M, Akyıldız M, Ekin N, Carr RM, Harputluoğlu M, Hatemi I, Mendizabal M, Silva M, Idilman R, Silveira M, Drenth JPH, Assis DN, Björnsson E, Boyer JL, Invernizzi P, Levy C, Schiano TD, Ridruejo E, Wahlin S. Outcome of COVID‐19 in Patients With Autoimmune Hepatitis: An International Multicenter Study. Hepatology 2021, 73: 2099-2109. PMID: 33713486, PMCID: PMC8250536, DOI: 10.1002/hep.31797.Peer-Reviewed Original ResearchConceptsSevere COVID-19Chronic liver diseaseAutoimmune hepatitisLiver injuryMulticenter studyCOVID-19Causes of CLDPropensity score-matched cohortSevere COVID-19 outcomesContinuation of immunosuppressionMaintenance of immunosuppressionOutcomes of patientsIntensive care admissionUse of antiviralsInternational multicenter studyCOVID-19 outcomesCOVID-19 diagnosisContinued immunosuppressionCare admissionCause mortalityIndependent predictorsMedian ageLiver diseaseMechanical ventilationRetrospective studyRole of Biliary Organoids in Cholestasis Research and Regenerative Medicine
Soroka CJ, Roberts SJ, Boyer JL, Assis DN. Role of Biliary Organoids in Cholestasis Research and Regenerative Medicine. Seminars In Liver Disease 2021, 41: 206-212. PMID: 33957696, DOI: 10.1055/s-0041-1728663.Peer-Reviewed Original ResearchConceptsHuman cholestatic diseasesCholestatic diseaseBiliary organoidsStudy of pathophysiologyCholestasis ResearchBiliary treeDisease stageIndividual patientsTranslational studiesPrimary cholangiocytesPersonalized approachBiliary tissueApplication of organoidsStandardization of terminologyTranslational medicineDiseaseOrganoidsMedicineOrganoid technologyPatientsPathophysiologyThe role of bile acids in cholestatic liver injury
Cai SY, Boyer JL. The role of bile acids in cholestatic liver injury. Annals Of Translational Medicine 2021, 9: 737-737. PMID: 33987435, PMCID: PMC8106037, DOI: 10.21037/atm-20-5110.Peer-Reviewed Original ResearchCholestatic liver injuryBile duct proliferationLiver injuryParenchymal cell deathBile acidsDuct proliferationImmune cellsStellate cellsProliferation of cholangiocytesSphingosine-1-phosphate receptor 2Bile acid receptorCell deathMajor cellular componentLiver inflammationClinical evidenceInflammatory cytokinesLiver fibrosisPathogenic rolePathologic effectsReceptor 2Mitochondrial injuryAcid receptorsClinical disordersInjuryOxidative stressBile formation and secretion: An update
Boyer JL, Soroka CJ. Bile formation and secretion: An update. Journal Of Hepatology 2021, 75: 190-201. PMID: 33617926, DOI: 10.1016/j.jhep.2021.02.011.Peer-Reviewed Original ResearchThe role of the retinoid receptor, RAR/RXR heterodimer, in liver physiology
Li B, Cai SY, Boyer JL. The role of the retinoid receptor, RAR/RXR heterodimer, in liver physiology. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2021, 1867: 166085. PMID: 33497820, PMCID: PMC11152086, DOI: 10.1016/j.bbadis.2021.166085.Peer-Reviewed Original ResearchConceptsRAR/retinoid X receptorRetinoid X receptorRAR/RXR heterodimersRetinoic acid receptorsRXR heterodimersLiver physiologySpecific genesMetabolism of lipidsBiological processesDetailed signalingLiver genesEmbryo developmentFunctional roleHepatic stellate cellsCell proliferationRetinoid receptorsX receptorGenesMechanistic viewHeterodimersPhysiologyCholesterol transportAcid receptorsStellate cellsVitamin A
2020
Hepatic NFAT signaling regulates the expression of inflammatory cytokines in cholestasis
Cai SY, Yu D, Soroka CJ, Wang J, Boyer JL. Hepatic NFAT signaling regulates the expression of inflammatory cytokines in cholestasis. Journal Of Hepatology 2020, 74: 550-559. PMID: 33039404, PMCID: PMC7897288, DOI: 10.1016/j.jhep.2020.09.035.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsATP Binding Cassette Transporter, Subfamily BBile Acids and SaltsCells, CulturedCholangitis, SclerosingCytokinesDisease Models, AnimalFemaleGene Expression RegulationGene Knockdown TechniquesHepatocytesHumansLiverLiver Cirrhosis, BiliaryMiceMice, Inbred C57BLMice, KnockoutNFATC Transcription FactorsPyrazolesSignal TransductionTreatment OutcomeConceptsCholestatic liver injuryLiver injuryInflammatory genesIL-8NFAT activationCholestatic liver tissuesHepatic cytokine expressionReduced liver injurySpecific NFAT inhibitorsHepatic inflammatory responseInduces liver injuryMouse hepatocytesIL-8 expressionActivated T cellsIL-8 promoterElevated tissue levelsGene reporterInflammatory cytokinesCytokine expressionElevated mRNA levelsInflammatory responseCholestatic liverT cellsImmune responseNFAT inhibitorAS055 Co-culture of bile-derived organoids from primary sclerosing cholangitis patients with CD4+ T cells replicates pathogenic, CCL20 dependent biliary-immune interactions
Soroka C, Roberts S, Hohenester S, Boyer J, Assis D. AS055 Co-culture of bile-derived organoids from primary sclerosing cholangitis patients with CD4+ T cells replicates pathogenic, CCL20 dependent biliary-immune interactions. Journal Of Hepatology 2020, 73: s41. DOI: 10.1016/s0168-8278(20)30634-6.Peer-Reviewed Original ResearchFenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol
Ghonem NS, Auclair AM, Hemme CL, Gallucci GM, de la Rosa Rodriguez R, Boyer JL, Assis DN. Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol. Clinical Pharmacology & Therapeutics 2020, 108: 1213-1223. PMID: 32480421, PMCID: PMC7886378, DOI: 10.1002/cpt.1930.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBile Acids and SaltsBiomarkersCholangitis, SclerosingCytokinesDrug Therapy, CombinationFemaleFenofibrateHumansInflammation MediatorsLiverLiver Cirrhosis, BiliaryLiver Function TestsMaleMiddle AgedPPAR alphaPrincipal Component AnalysisRetrospective StudiesTreatment OutcomeUrsodeoxycholic AcidYoung AdultConceptsPrimary sclerosing cholangitisPrimary biliary cholangitisBile acid metabolismSclerosing cholangitisBiliary cholangitisBile acidsAcid metabolismPeroxisome proliferator-activated receptor alphaProliferator-activated receptor alphaRetrospective observational studyBeneficial clinical effectsCholestatic liver diseasePro-inflammatory cytokinesBile acid metabolitesHealthy control subjectsBile acid poolSerum alkaline phosphataseAminotransferase abnormalitiesUrsodiol therapyFenofibrate therapyPartial respondersBile acid precursorsClinical effectsFenofibrate treatmentLiver disease