Featured Publications
Long non-coding RNA ACTA2-AS1 promotes ductular reaction by interacting with the p300/ELK1 complex
Navarro-Corcuera A, Sehrawat T, Jalan-Sakrikar N, Gibbons H, Pirius N, Khanal S, Hamdan F, Aseem S, Cao S, Banales J, Kang N, Faubion W, LaRusso N, Shah V, Huebert R. Long non-coding RNA ACTA2-AS1 promotes ductular reaction by interacting with the p300/ELK1 complex. Journal Of Hepatology 2021, 76: 921-933. PMID: 34953958, PMCID: PMC8934273, DOI: 10.1016/j.jhep.2021.12.014.Peer-Reviewed Original ResearchConceptsBile duct ligationDuctular reactionACTA2-AS1KO miceBile duct cellsLPS exposureBiliary diseaseFibrogenic markersInjury modelDuct ligationFibrogenic genesLong non-coding RNAsFl/Cholangiocyte proliferationFibrosisHuman cholangiocytesSGC-CBP30Primary cholangiocytesAbstractTextLiver tissueLAY SUMMARYP300 inhibitorTranscription factorsCholangiocytesDuct cellsMechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension
Hilscher M, Sehrawat T, Arab J, Zeng Z, Gao J, Liu M, Kostallari E, Gao Y, Simonetto D, Yaqoob U, Cao S, Revzin A, Beyder A, Wang R, Kamath P, Kubes P, Shah V. Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension. Gastroenterology 2019, 157: 193-209.e9. PMID: 30872106, PMCID: PMC6581607, DOI: 10.1053/j.gastro.2019.03.013.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCalcium SignalingCapillariesChemokine CXCL1Endothelial CellsExtracellular TrapsHydrolasesHypertension, PortalIn Vitro TechniquesIntegrinsLeukocyte ElastaseLigationLiverMechanotransduction, CellularMiceMice, Inbred C57BLMice, KnockoutNeutrophil InfiltrationPortal PressureProtein-Arginine Deiminase Type 4Receptor, Notch1Stress, MechanicalThrombosisVena Cava, InferiorConceptsLiver sinusoidal endothelial cellsPortal hypertensionBile duct ligationPortal pressureSinusoidal endothelial cellsFormation of NETsPrimary liver sinusoidal endothelial cellsMechanical stretchControl micePeptidyl arginine deiminase type IVTreatment of PHUnderwent bile duct ligationSuprahepatic inferior vena cavaEndothelial cellsLower portal pressureNeutrophil chemoattractant CXCL1Intravital imagingExpression of CXCL1Inferior vena cavaRecruit neutrophilsNeutrophil recruitmentC57BL/6 miceVena cavaLess fibrinSubcutaneous injectionSuper enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis
Liu M, Cao S, He L, Gao J, Arab J, Cui H, Xuan W, Gao Y, Sehrawat T, Hamdan F, Ventura-Cots M, Argemi J, Pomerantz W, Johnsen S, Lee J, Gao F, Ordog T, Mathurin P, Revzin A, Bataller R, Yan H, Shah V. Super enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis. Nature Communications 2021, 12: 4560. PMID: 34315876, PMCID: PMC8316465, DOI: 10.1038/s41467-021-24843-w.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChemokinesCytokinesDisease Models, AnimalEndothelial CellsEnhancer Elements, GeneticEpigenesis, GeneticGene Expression RegulationHepatitis, AlcoholicHistonesHumansLipopolysaccharidesLiverMice, Inbred C57BLNeutrophilsNF-kappa BPromoter Regions, GeneticRNA-SeqSignal TransductionTranscription FactorsTumor Necrosis Factor-alphaConceptsAlcoholic hepatitisLiver sinusoidal endothelial cellsChemokine expressionNeutrophil infiltrationLiver neutrophil infiltrationTNFα/NF-κB signalingNF-κB signalingHuman liver explantsElevated chemokine expressionSinusoidal endothelial cellsCXCL expressionChemokine productionCXCL chemokinesCytokine pathwaysCytokines TNFαInflammatory signalingMurine modelLiver explantsTherapeutic potentialPharmacologic inhibitionExtraterminal (BET) proteinsBET inhibitionHuman liverEndothelial cellsAH treatmentQuantitative assessment of portal hypertension with bi-parametric dual-frequency hepatic MR elastography in mouse models
Li J, Sehrawat T, Chen J, Hilscher M, Glaser K, Arab J, De Assuncao T, Simonetto D, Mounajjed T, Manduca A, Ehman R, Shah V, Yin M. Quantitative assessment of portal hypertension with bi-parametric dual-frequency hepatic MR elastography in mouse models. European Radiology 2020, 31: 2303-2311. PMID: 33026502, PMCID: PMC7981248, DOI: 10.1007/s00330-020-07341-3.Peer-Reviewed Original ResearchConceptsPortal hypertensionPortal pressureHepatic MR elastographyMouse modelHigh diagnostic accuracyDiagnostic accuracyHepatic fibrosisMR elastographyWild-type male miceHypertension mouse modelSignificant portal hypertensionCholestatic liver injuryCholestatic liver diseaseLiver MR elastographySham miceLiver diseaseLiver injuryHepatic congestionLiver fibrosisMale micePreclinical modelsTreatment efficacyFibrosisHypertensionDeLong testHepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12
Arab J, Cabrera D, Sehrawat T, Jalan-Sakrikar N, Verma V, Simonetto D, Cao S, Yaqoob U, Leon J, Freire M, Vargas J, De Assuncao T, Kwon J, Guo Y, Kostallari E, Cai Q, Kisseleva T, Oh Y, Arrese M, Huebert R, Shah V. Hepatic stellate cell activation promotes alcohol-induced steatohepatitis through Igfbp3 and SerpinA12. Journal Of Hepatology 2020, 73: 149-160. PMID: 32087348, PMCID: PMC7305991, DOI: 10.1016/j.jhep.2020.02.005.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsAlcohol-induced steatohepatitisNeuropilin-1HSC activationStellate cellsWild-type HSCsLower hepatic triglyceride contentAlcohol-related liver diseaseHepatic stellate cell activationMarkers of steatosisNRP-1 knockdownParenchymal cell injuryDevelopment of steatohepatitisHepatic triglyceride contentEthanol-induced steatosisStellate cell activationAlcoholic hepatitisLipid droplet formationAlcohol feedingLiver diseaseAlcohol damageLess fibrosisLiver fibrosisRegulation of IGFBP3Less inflammation
2023
Modulating sphingosine 1-phosphate receptor signaling skews intrahepatic leukocytes and attenuates murine nonalcoholic steatohepatitis
Liao C, Barrow F, Venkatesan N, Nakao Y, Mauer A, Fredrickson G, Song M, Sehrawat T, Dasgupta D, Graham R, Revelo X, Malhi H. Modulating sphingosine 1-phosphate receptor signaling skews intrahepatic leukocytes and attenuates murine nonalcoholic steatohepatitis. Frontiers In Immunology 2023, 14: 1130184. PMID: 37153573, PMCID: PMC10160388, DOI: 10.3389/fimmu.2023.1130184.Peer-Reviewed Original ResearchConceptsMurine nonalcoholic steatohepatitisNonalcoholic steatohepatitisLiver injuryHepatic macrophage accumulationT cellsIntrahepatic leukocytesDietary feedingNKT cellsMacrophage accumulationReceptor antagonismLeukocyte populationsB cellsDouble-negative T cellsReceptor-specific modulationNegative T cellsStandard chow dietImmune cell populationsC57BL/6 male miceCirculating MarkersLiver histologyProinflammatory markersNK cellsOral gavageChow dietNASH progressionLoss of CEACAM1 in endothelial cells causes hepatic fibrosis
Muturi H, Ghadieh H, Abdolahipour R, Stankus H, Belew G, Liu J, Jahromi M, Lee A, Singer B, Angeli-Pahim I, Sehrawat T, Malhi H, Verhulst S, van Grunsven L, Zarrinpar A, Duarte S, Najjar S. Loss of CEACAM1 in endothelial cells causes hepatic fibrosis. Metabolism 2023, 144: 155562. PMID: 37088122, PMCID: PMC10330196, DOI: 10.1016/j.metabol.2023.155562.Peer-Reviewed Original ResearchConceptsFl/Hepatic fibrosisEndothelial lossVisceral obesityImmunohistochemical analysisWild-type HSCsEndothelial cellsHepatic fibrosis stageLiver tissue biopsiesHepatic stellate cellsNF-κB signalingLiver endothelial cellsNF-κB targetsLiver transplantAdult patientsBariatric surgerySystemic inflammationInflammatory infiltrationLiver biopsyNASH pathogenesisInsulin resistanceFibrosis stageInsulin sensitivityHepatic fibrogenesisMale mice
2022
Mechanotransduction-induced glycolysis epigenetically regulates a CXCL1-dominant angiocrine signaling program in liver sinusoidal endothelial cells in vitro and in vivo
Greuter T, Yaqoob U, Gan C, Jalan-Sakrikar N, Kostallari E, Lu J, Gao J, Sun L, Liu M, Sehrawat TS, Ibrahim SH, Furuta K, Nozickova K, Huang BQ, Gao B, Simons M, Cao S, Shah VH. Mechanotransduction-induced glycolysis epigenetically regulates a CXCL1-dominant angiocrine signaling program in liver sinusoidal endothelial cells in vitro and in vivo. Journal Of Hepatology 2022, 77: 723-734. PMID: 35421427, PMCID: PMC9391258, DOI: 10.1016/j.jhep.2022.03.029.Peer-Reviewed Original ResearchConceptsFocal adhesionsGlycolytic enzymesIsolated focal adhesionsChromosome conformation captureHistone activation marksChromatin immunoprecipitation analysisConformation captureChIP sequencingActivation marksEpigenetic regulationActin dynamicsHistone acetylationRNA sequencingERT2 miceActin polymerizationEndothelial cellsCXCL1 promoterNovel roleIntegrin β1Druggable targetsInhibition of glycolysisNuclear chromatinGlycolysisAngiocrineEnzyme
2021
Endothelial p300 Promotes Portal Hypertension and Hepatic Fibrosis Through C‐C Motif Chemokine Ligand 2–Mediated Angiocrine Signaling
Gao J, Wei B, Liu M, Hirsova P, Sehrawat T, Cao S, Hu X, Xue F, Yaqoob U, Kang N, Cui H, Pomerantz W, Kostallari E, Shah V. Endothelial p300 Promotes Portal Hypertension and Hepatic Fibrosis Through C‐C Motif Chemokine Ligand 2–Mediated Angiocrine Signaling. Hepatology 2021, 73: 2468-2483. PMID: 33159815, PMCID: PMC8102654, DOI: 10.1002/hep.31617.Peer-Reviewed Original ResearchConceptsLiver sinusoidal endothelial cellsPartial inferior vena cava ligationPortal hypertensionLiver fibrosisLiver injuryMacrophage accumulationCCL2 transcriptionKnockout miceC motif chemokine ligand 2Inferior vena cava ligationP50 knockout miceNuclear factor kappa BVena cava ligationChemokine ligand 2Accumulation of macrophagesPathological inflammatory responsesWild-type miceFactor kappa BSinusoidal endothelial cellsInhibition of p300CCL2 deficiencyPortal pressureLiver diseaseInflammatory cellsCCL2 expression
2020
IRE1A Stimulates Hepatocyte-Derived Extracellular Vesicles That Promote Inflammation in Mice With Steatohepatitis
Dasgupta D, Nakao Y, Mauer A, Thompson J, Sehrawat T, Liao C, Krishnan A, Lucien F, Guo Q, Liu M, Xue F, Fukushima M, Katsumi T, Bansal A, Pandey M, Maiers J, DeGrado T, Ibrahim S, Revzin A, Pavelko K, Barry M, Kaufman R, Malhi H. IRE1A Stimulates Hepatocyte-Derived Extracellular Vesicles That Promote Inflammation in Mice With Steatohepatitis. Gastroenterology 2020, 159: 1487-1503.e17. PMID: 32574624, PMCID: PMC7666601, DOI: 10.1053/j.gastro.2020.06.031.Peer-Reviewed Original ResearchConceptsX-box binding protein 1Release of EVsHepatocyte-derived extracellular vesiclesSerine palmitoyltransferase genesExtracellular vesiclesSerine palmitoyltransferaseChromatin immunoprecipitationCeramide biosynthesisInflammatory Extracellular VesiclesMonocyte-derived macrophagesUnfolded protein responseNonalcoholic steatohepatitisDiet-induced steatohepatitisGene expression analysisPrimary hepatocytesNumber of EVsBinding protein 1Cultured primary hepatocytesNanoparticle-tracking analysisNanoscale flow cytometryIRE1ALiver tissueRate-limiting enzymeProtein responseExpression analysisGIPC-Regulated IGFBP-3 Promotes HSC Migration In Vitro and Portal Hypertension In Vivo Through a β1-Integrin Pathway
Yaqoob U, Luo F, Greuter T, Sakrikar N, Sehrawat T, Lu J, Hu X, Gao J, Kostallari E, Chen J, Arab J, Martin-Mateos R, Cao S, Shah V. GIPC-Regulated IGFBP-3 Promotes HSC Migration In Vitro and Portal Hypertension In Vivo Through a β1-Integrin Pathway. Cellular And Molecular Gastroenterology And Hepatology 2020, 10: 545-559. PMID: 32447051, PMCID: PMC7399184, DOI: 10.1016/j.jcmgh.2020.05.005.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAdaptor Proteins, Signal TransducingAnimalsBiomarkersCell MovementCells, CulturedDisease Models, AnimalEpigenesis, GeneticGene Knockdown TechniquesHepatic Stellate CellsHistonesHumansHypertension, PortalInsulin-Like Growth Factor Binding Protein 3Integrin beta1Liver CirrhosisMiceMice, KnockoutPhosphorylationPrimary Cell CultureSignal TransductionTransforming Growth Factor betaUp-RegulationConceptsHepatic stellate cellsPortal hypertensionIGFBP-3Quantitative polymerase chain reactionWestern blot analysisLiver fibrosisPolymerase chain reactionHSC migrationChromatin immunoprecipitationChronic liver injury modelInsulin-like growth factorActivation targetGrowth factorQuiescent hepatic stellate cellsIGFBP-3 increaseTransport proteinsChronic liver diseaseChain reactionLiver injury modelIntegrin-dependent phosphorylationHistone 3 lysine 27 acetylationGene regulation changesHSC activation markersEnzyme-linked immunosorbent assayEnzyme-linked immunosorbent