2023
Organic 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 D, Cai S, Boyer J, Huang X, Tang C, Liu X, Peng S, Chai J. Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis. Nature Communications 2023, 14: 29. PMID: 36759512, PMCID: PMC9911648, DOI: 10.1038/s41467-022-34606-w.Peer-Reviewed Original ResearchConceptsPrimary biliary cholangitisPrimary biliary cholangitis patientsBiliary cholangitisEtiology of primary biliary cholangitisScRNA-seqPathogenic targetsSeverity of diseaseSingle-cell RNA sequencingAMA-M2PBC patientsAutoantibody levelsPolymeric immunoglobulin receptorMemory BMultiplex immunofluorescenceCholangiocyte injuryPlasma cellsAutoimmune diseasesRNAscope analysisCholangiocytesImmunoglobulin receptorBile formationPatientsTherapeutic interventionsMultiplexed IFRNA sequencingRunt-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 polymorphismsAccumulation
2021
Bile 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 inhibitor
2019
Inflammasome Is Activated in the Liver of Cholestatic Patients and Aggravates Hepatic Injury in Bile Duct–Ligated Mouse
Cai SY, Ge M, Mennone A, Hoque R, Ouyang X, Boyer JL. Inflammasome Is Activated in the Liver of Cholestatic Patients and Aggravates Hepatic Injury in Bile Duct–Ligated Mouse. Cellular And Molecular Gastroenterology And Hepatology 2019, 9: 679-688. PMID: 31887435, PMCID: PMC7160576, DOI: 10.1016/j.jcmgh.2019.12.008.Peer-Reviewed Original ResearchConceptsWT BDL miceCholestatic liver injuryBDL liversBDL miceBile duct ligationBile acidsLiver injuryCholestatic patientsIL-1βM2 anti-inflammatory macrophagesPrimary sclerosing cholangitisPlasma IL-1βLiver hydroxyproline contentLiver of patientsPrimary biliary cholangitisHealthy control subjectsCD206-positive cellsAnti-inflammatory macrophagesIL-1β inductionEndogenous bile acidsCaspase-1 cleavageProcaspase-1 cleavageMouse hepatocytesSclerosing cholangitisLiver histology
2018
Solute Carrier Organic Anion Transporter Family Member 3A1 Is a Bile Acid Efflux Transporter in Cholestasis
Pan Q, Zhang X, Zhang L, Cheng Y, Zhao N, Li F, Zhou X, Chen S, Li J, Xu S, Huang D, Chen Y, Li L, Wang H, Chen W, Cai SY, Boyer JL, Chai J. Solute Carrier Organic Anion Transporter Family Member 3A1 Is a Bile Acid Efflux Transporter in Cholestasis. Gastroenterology 2018, 155: 1578-1592.e16. PMID: 30063921, PMCID: PMC6221191, DOI: 10.1053/j.gastro.2018.07.031.Peer-Reviewed Original ResearchConceptsBile duct ligationLiver tissueBile acidsHepatic levelsHepatoma cell lineFibroblast growth factor 19Cholestatic liver tissuesEfflux transportersCholic acid dietDevelopment of cholestasisGrowth factor 19Sprague-Dawley ratsShorter survival timeBile acid homeostasisHealthy liver tissueReal-time quantitative polymerase chain reactionNuclear factor κBCell linesQuantitative polymerase chain reactionHuman primary hepatocytesMessenger RNALiver injuryCa dietControl miceC57BL/6J miceCenicriviroc, a cytokine receptor antagonist, potentiates all‐trans retinoic acid in reducing liver injury in cholestatic rodents
Yu D, Cai S, Mennone A, Vig P, Boyer JL. Cenicriviroc, a cytokine receptor antagonist, potentiates all‐trans retinoic acid in reducing liver injury in cholestatic rodents. Liver International 2018, 38: 1128-1138. PMID: 29356312, PMCID: PMC6032984, DOI: 10.1111/liv.13698.Peer-Reviewed Original ResearchConceptsBile acid pool sizeTrans retinoic acidAcid pool sizePlasma liver enzymesLiver injurySuperior therapeutic effectLiver necrosisLiver enzymesT cellsTherapeutic effectRetinoic acidAntagonist of CCR2Hepatic inflammatory cellsCholestatic liver injuryBile duct proliferationBody weight ratioCholestatic liver diseasePro-inflammatory cytokinesCytokine receptor antagonistsHepatic hydroxyproline contentExpression of cytokinesDuct-ligated ratsBile acid synthesisHepatic infiltrationLiver disease
2017
Mechanisms of bile acid mediated inflammation in the liver
Li M, Cai SY, Boyer JL. Mechanisms of bile acid mediated inflammation in the liver. Molecular Aspects Of Medicine 2017, 56: 45-53. PMID: 28606651, PMCID: PMC5662014, DOI: 10.1016/j.mam.2017.06.001.Peer-Reviewed Original ResearchConceptsLiver injuryBile acidsCholestatic animal modelsCauses of cholestasisCholestatic liver injuryInnate immune cellsBiliary injuryNeutrophil recruitmentBile flowImmune cellsEffective therapyInflammatory responseAnimal modelsMolecular mediatorsCholestasisInjuryNovel targetLiverElevated levelsPathological processesMolecular mechanismsHepatocytesInflammationPatientsPathogenesisBile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response
Cai SY, Ouyang X, Chen Y, Soroka CJ, Wang J, Mennone A, Wang Y, Mehal WZ, Jain D, Boyer JL. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2017, 2: e90780. PMID: 28289714, PMCID: PMC5333973, DOI: 10.1172/jci.insight.90780.Peer-Reviewed Original ResearchConceptsLiver injuryInflammatory responseBile acid-induced liver injuryCholestatic liver injuryInflammatory liver injuryProinflammatory cytokine expressionCholestatic liver diseaseBile duct ligationVivo mouse modelHepatic infiltrationInflammatory injurySerum aminotransferasesLiver diseaseCholestatic patientsCytokine expressionChemokine inductionPathophysiologic concentrationsNeutrophil chemotaxisDuct ligationPathophysiologic levelsMouse modelNew therapiesInnate immunityInjuryPeriportal areas
2016
Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid–fed mouse model of cholestasis
Kulkarni SR, Soroka CJ, Hagey LR, Boyer JL. Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid–fed mouse model of cholestasis. Hepatology 2016, 64: 2151-2164. PMID: 27639250, PMCID: PMC5115990, DOI: 10.1002/hep.28826.Peer-Reviewed Original ResearchConceptsCholestatic liver injuryLiver injurySRT1720 administrationSIRT1 expressionCa dietMouse modelFibroblast growth factor 15Proliferator-activated receptor gamma coactivator 1Multidrug resistance-associated protein 2Peroxisome proliferator-activated receptor gamma coactivator 1Hepatic BA compositionHepatic BA synthesisGrowth factor 15Receptor gamma coactivator 1Resistance-associated protein 2Plasma alanine aminotransferasePlasma BA concentrationsCultured primary human hepatocytesNovel therapeutic targetSirtuin 1 activationFarnesoid X receptorMiR-34a expressionSIRT1 messenger RNACytochrome P450 7A1Bile acid sensorCFTR-associated ligand is a negative regulator of Mrp2 expression
Li M, Soroka CJ, Harry K, Boyer JL. CFTR-associated ligand is a negative regulator of Mrp2 expression. American Journal Of Physiology - Cell Physiology 2016, 312: c40-c46. PMID: 27834195, PMCID: PMC5283898, DOI: 10.1152/ajpcell.00100.2016.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsCarrier ProteinsCells, CulturedChlorocebus aethiopsCOS CellsDown-RegulationGene Expression RegulationGolgi Matrix ProteinsHepatocytesHumansMaleMembrane ProteinsMembrane Transport ProteinsMiceMultidrug Resistance-Associated Protein 2Multidrug Resistance-Associated ProteinsRatsRats, Sprague-DawleySignal TransductionConceptsPull-down assaysGST pull-down assaysCOOH-terminal PDZNegative regulatorCotransfected COS-7 cellsGlutathione S-transferase fusion proteinS-transferase fusion proteinATP-binding cassette (ABC) transportersTrans-Golgi networkCystic fibrosis transmembrane conductance regulatorProtein-protein interactionsExchanger regulatory factor 1Fibrosis transmembrane conductance regulatorStreptavidin pull-down assaysTransmembrane conductance regulatorCOS-7 cellsRegulatory factor 1PDZ domainCell surface expressionPosttranscriptional regulationTransmembrane proteinPlasma membraneLLC-PK1 cellsCassette transportersCOS-7
2015
Na+/H+ exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury
Li M, Mennone A, Soroka CJ, Hagey LR, Ouyang X, Weinman EJ, Boyer JL. Na+/H+ exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury. Hepatology 2015, 62: 1227-1236. PMID: 26108984, PMCID: PMC4589453, DOI: 10.1002/hep.27956.Peer-Reviewed Original ResearchConceptsBile duct ligationLiver injuryInflammatory responseICAM-1BDL miceBDL-induced liver injuryNeutrophil-mediated liver injuryTotal bile acid concentrationTumor necrosis factor alphaIntercellular adhesion molecule-1Hepatic neutrophil accumulationAttenuated liver injuryCholestatic liver injuryHepatic inflammatory responseMouse liverSerum alanine aminotransferaseBile acid concentrationsHepatic inflammatory diseasesICAM-1 expressionNecrosis factor alphaAdhesion molecule-1Wild-type miceICAM-1 proteinNew therapeutic targetsMessenger RNA levels
2013
Bile Formation and Secretion
Boyer JL. Bile Formation and Secretion. 2013, 3: 1035-1078. PMID: 23897680, PMCID: PMC4091928, DOI: 10.1002/cphy.c120027.Peer-Reviewed Original ResearchAdult sea lamprey tolerates biliary atresia by altering bile salt composition and renal excretion
Cai S, Lionarons DA, Hagey L, Soroka CJ, Mennone A, Boyer JL. Adult sea lamprey tolerates biliary atresia by altering bile salt composition and renal excretion. Hepatology 2013, 57: 2418-2426. PMID: 23175353, PMCID: PMC3604052, DOI: 10.1002/hep.26161.Peer-Reviewed Original ResearchConceptsRenal excretionBile salt compositionBiliary atresiaBile saltsPlasma bile salt levelsEvidence of necrosisAdult liverBile salt levelsBile salt homeostasisNormal plasma levelsForms of cholestasisBile salt transportersCollection of urineAdult lampreysPredominant bile saltProgressive diseaseExogenous organic anionsBile ductPlasma levelsMajor bile saltsAnimal modelsC27 bile alcoholsCholestasisSalt transportersBile alcohols
2012
A C‐terminal tyrosine‐based motif in the bile salt export pump directs clathrin‐dependent endocytosis
Lam P, Xu S, Soroka CJ, Boyer JL. A C‐terminal tyrosine‐based motif in the bile salt export pump directs clathrin‐dependent endocytosis. Hepatology 2012, 55: 1901-1911. PMID: 22161577, PMCID: PMC3319652, DOI: 10.1002/hep.25523.Peer-Reviewed Original ResearchConceptsTyrosine-based motifNucleotide-binding domainEndocytic motifTransmembrane segmentsCanonical tyrosine-based motifTyrosine-based endocytic motifCytoplasmic nucleotide-binding domainsClathrin-dependent pathwayClathrin-dependent endocytosisRegulation of traffickingBroad substrate specificitySite-directed mutagenesisATP-dependent transportHEK293T cellsCytoplasmic terminiEndocytosis motifCassette proteinSubsequent sequence analysisTerminal tailSubstrate specificityConstitutive internalizationReporter systemSequence analysisBile salt export pumpTerminal end
2011
Ostα depletion protects liver from oral bile acid load
Soroka CJ, Velazquez H, Mennone A, Ballatori N, Boyer JL. Ostα depletion protects liver from oral bile acid load. AJP Gastrointestinal And Liver Physiology 2011, 301: g574-g579. PMID: 21719738, PMCID: PMC3174539, DOI: 10.1152/ajpgi.00141.2011.Peer-Reviewed Original ResearchConceptsExcess bile acidsCholic acid feedingWild-type miceBile acid overloadBile acidsLiver injuryAcid overloadLower serum ALT levelsIntestinal bile acid absorptionAcid feedingBile acid loadSerum ALT levelsBile acid absorptionBile acid lossBile duct ligationEffective therapeutic targetBile acid homeostasisWild-type controlsALT levelsUrinary eliminationIntestinal lossObstructive cholestasisIntestinal functionDuct ligationUrinary clearance
2010
Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct–ligated rats and human hepatic cells
He H, Mennone A, Boyer JL, Cai S. Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct–ligated rats and human hepatic cells. Hepatology 2010, 53: 548-557. PMID: 21274875, PMCID: PMC3069505, DOI: 10.1002/hep.24047.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBile Acids and SaltsBile DuctsCell ProliferationCells, CulturedCholestasis, IntrahepaticCholesterol 7-alpha-HydroxylaseCollagen Type ICollagen Type I, alpha 1 ChainDisease Models, AnimalHepatocytesHumansLigationLiverMaleMatrix Metalloproteinase 2RatsRats, Sprague-DawleySmad2 ProteinTretinoinUrsodeoxycholic AcidConceptsBile duct ligationBile salt pool sizeLX-2 cellsUrsodeoxycholic acidHepatic stellate cellsRetinoic acidLiver fibrosisStellate cellsPhosphate-buffered salineCommon bile duct ligationMale Sprague-Dawley ratsPrimary human hepatic stellate cellsTumor necrosis factor αBile duct-ligated ratsHuman hepatic stellate cellsBile duct proliferationHuman hepatocytesLiver hydroxyproline contentNecrosis factor αSprague-Dawley ratsAcute promyelocytic leukemiaΑ-SMA expressionDuct-ligated ratsSmooth muscle actinMatrix metalloproteinase-2