Xinshou Ouyang, PhD
Assistant ProfessorCards
Appointments
Contact Info
Yale School of Medicine
Department of Medicine (Digestive Diseases), P.O. Box 208019
New Haven, CT 06520-8019
United States
About
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Assistant Professor
Biography
Dr. Ouyang has longstanding interests in the research of immunology, with specific training and demonstrated expertise in key research areas of immunobiology in tissue inflammation. He received Ph.D. from Osaka University in Japan. He completed his postdoctoral training with Dr. Tadamitsu Kishimoto at Osaka University and Dr. Tadatsugu Taniguchi at Tokyo University. Metabolic stress to the liver, in the absence of pathogens, results in sterile inflammatory responses that cause liver injury. This has important implications for clinically significant inflammation in ASH, NASH, fibrosis, and HCC. Dr. Ouyang has focused on identifying the mechanisms and key regulators of post-translational protein modifications and RNA epigenetics for the control of metabolic inflammation in liver diseases. Dr. Ouyang has published in Cell Metabolism, Nature Communication, Science, Journal of Hepatology, Cell Death & Differentiation, Cell Reports, etc..
Positions are available in my lab for motivated graduate students, postdoctoral fellows, and visiting scholars interested in investigating the RNA epigenetics to protein translation machinery in metabolic diseases. Individual career development plans are provided to lab staff members to assist them to succeed
Appointments
Digestive Diseases
Assistant ProfessorPrimary
Other Departments & Organizations
Education & Training
- PhD
- Osaka University (2001)
Research
Overview
Identify molecular pathways and the key metabolic regulators integrating stress and inflammatory responses with liver steatosis and fibrosis.
The development of sterile inflammation after cell death is a ubiquitous response that occurs in all organs. The amplitude of this response, however, varies widely, and the liver is notable for developing exceptionally strong sterile inflammation. This is seen in alcoholic steatohepatitis (ASH), and metabolic syndrome-associated development of non-alcoholic steatohepatitis (NASH). Such a high amplitude of sterile inflammation in the liver has major clinical consequences as NASH is by far the most common liver disease in industrialized countries.
We have demonstrated that HIF-1α pathway activation potentiates and sustains the amplitude of acute inflammatory responses, and is vital for the transition from acute self-limiting to sustained chronic inflammation. These mechanistic insights into the role of the HIF-1α pathway in sterile inflammation may have great clinical relevance due to the ability of cardiac glycosides (CGs) to inhibit HIF-1α activation. Digoxin improves oxidative stress during liver injury through maintaining cellular redox homeostasis, and the suppression of HIF-1α pathway activation and downstream signature genes in the liver. We have further identified pyruvate kinase isoform 2 (PKM2) as a digoxin-binding protein. The active nuclear PKM2 directly interacts with multiple modified chromatin proteins, and digoxin reduces the binding of histones to PKM2.
Delineate the RNA modification, specifically m6A-dependent cellular pathways by metabolic signal (s) that control liver steatosis, inflammation, and fibrosis.
The 'epitranscriptome', a collective term for chemical modifications that influence the structure, metabolism, and functions of RNA, has recently emerged as vitally important for the regulation of gene expression. To date, more than 170 types of RNA modifications have been identified, including 5' cap modification, poly(A) tail, pseudouridine (Ψ), N1-methyladenosine (m1A) and N6,2'-O-dimethyladenosine (m6Am), and N6-methyladenosine (m6A). Among these modifications, m6A is the most abundant internal RNA modification in eukaryotic cells that widely occurs in mRNA and non-coding RNAs (ncRNAs). Myeloid lineage-driven metabolic inflammation is associated with significant changes in post-transcriptional mRNA modification and mRNA pool resulting in marked changes in myeloid cell functional status. We have demonstrated that myeloid lineage-restricted deletion of the m6A "writer" protein Methyltransferase Like 3 (METTL3) prevents age-related and diet-induced development of NAFLD and obesity in mice with improved inflammatory and metabolic phenotypes. Our study indicates that m6A methylation is critical in the control of myeloid cell-directed metabolic programming through the regulation of immune transcripts in NAFLD and obesity.
Identify the enzymatic and spatiotemporal steps in inflammasome activation and provide novel insights and a potential target for therapeutic intervention in chronic inflammation.
Inflammasomes are multiprotein cytosolic complexes that serve as a platform for caspase-1-dependent production of several proinflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18, and constitute a crucial step in the initiation of innate immune responses. Excessive inflammasome activity has been involved in diverse chronic inflammatory diseases, notably including metabolic disorders such as NASH. The NLRP3 inflammasome can be activated by a variety of structurally unrelated molecules ranging from insoluble particulates, endogenous danger signals, and pathogen molecules. A common theme from recent studies supports that reorganization of the intracellular organelle network is necessary for NLRP3 inflammasome activation, including lipid directed NLRP3 localization to mitochondria, microtubule-mediated NLRP3 inflammasome assembly, and NLRP3 interaction with Golgi-localized phosphatidylinositol-4-phosphate in response to diverse stimuli. We investigated the organelle dynamics and molecular requirement for NLRP3 recruitment in live cells. We have demonstrated a comprehensive model of GSK3β signaling mediated NLRP3 activation resulting in distinct NLRP3 trafficking, organelle reorganization, and inflammasome assembly.
The current model of inflammasome activation in macrophages explains the initial steps in acute inflammation but is inadequate to explain how the activity is sustained in chronic inflammation, repair, and fibrosis. We have demonstrated that cAMP/PKA/CREB/HIF-1α pathway is required for sustained inflammasome activation.
Research at a Glance
Yale Co-Authors
Publications Timeline
Wajahat Mehal, MD, DPhil
Arumugam Suyavaran, MSc, PhD
James Lorenzen Boyer, MD, FACEP, FAASLD
Bubu Banini, MD, PhD
Huabing Li, PhD
Yasuko Iwakiri, PhD
Publications
Featured Publications
Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation
Arumugam S, Li B, Boodapati S, Nathanson M, Sun B, Ouyang X, Mehal W. Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation. Hepatology 2023, 78: 1448-1461. PMID: 37013923, PMCID: PMC10804318, DOI: 10.1097/hep.0000000000000388.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsVoltage-dependent anion channelBioenergetic capacityMitochondrial DNATranscriptional upregulationCyclic GMP-AMP synthaseGMP-AMP synthaseTranscriptional regulationBioenergetic organellesFunctional mitochondriaMitochondrial membraneExternal mitochondrial membraneAnabolic pathwaysMitochondrial massAnion channelInterferon genesHSC transdifferentiationSubsequent activationCGAS-STINGTransdifferentiationIRF3 pathwayPathwaySTING pathwayGenesMitochondriaQuiescent HSCsGSK3β mediates the spatiotemporal dynamics of NLRP3 inflammasome activation
Arumugam S, Qin Y, Liang Z, Han SN, Boodapati SLT, Li J, Lu Q, Flavell RA, Mehal WZ, Ouyang X. GSK3β mediates the spatiotemporal dynamics of NLRP3 inflammasome activation. Cell Death & Differentiation 2022, 29: 2060-2069. PMID: 35477991, PMCID: PMC9525599, DOI: 10.1038/s41418-022-00997-y.Peer-Reviewed Original ResearchCitationsMeSH Keywords and ConceptsConceptsInflammasome assemblyGlycogen synthase kinase-3βSynthase kinase-3βOrganelle dynamicsGolgi networkSubcellular machineryGolgi apparatusInflammasome activationMechanistic basisKinase-3βMolecular determinantsSpatiotemporal dynamicsGSK3β activationMitochondriaNLRP3 oligomerizationTGNSubsequent bindingGSK3βNLRP3 inflammasome activationActivationNew avenuesAssemblyStepwise processOrganellesPhosphatidylinositolm6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity
Qin Y, Li B, Arumugam S, Lu Q, Mankash SM, Li J, Sun B, Li J, Flavell RA, Li HB, Ouyang X. m6A mRNA methylation-directed myeloid cell activation controls progression of NAFLD and obesity. Cell Reports 2021, 37: 109968. PMID: 34758326, PMCID: PMC8667589, DOI: 10.1016/j.celrep.2021.109968.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsNon-alcoholic fatty liver diseaseProgression of NAFLDLineage-restricted deletionFatty liver diseaseMultiple mRNA transcriptsMyeloid cell activationDiet-induced developmentMethyladenosine (m<sup>6</sup>A) RNA modificationMRNA metabolismProtein methyltransferaseLiver diseaseRNA modificationsCellular stressMetabolic reprogrammingDDIT4 mRNACell activationObesityDifferential expressionMammalian targetMRNA transcriptsSignificant downregulationCytokine stimulationPathway activityMetabolic phenotypeMRNA levelsTargeting glycogen synthase kinase-3β inhibition alleviates acute myocardial infarction through reduction of NLRP3 inflammasome activation
Wang S, Xu L, Chang C, Yao Y, Su X, Cha X, Komal S, Wang P, Ouyang X, ZHANG L, Han S. Targeting glycogen synthase kinase-3β inhibition alleviates acute myocardial infarction through reduction of NLRP3 inflammasome activation. Journal Of Molecular And Cellular Cardiology 2020, 140: 38-39. DOI: 10.1016/j.yjmcc.2019.11.091.Peer-Reviewed Original ResearchCitationsDigoxin 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 ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsHigh-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 rangeDigoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
Ouyang X, Han SN, Zhang JY, Dioletis E, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Stärkel P, Caballeria J, Pongratz RL, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Garcia-Martinez I, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ. Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. Cell Metabolism 2018, 27: 339-350.e3. PMID: 29414684, PMCID: PMC5806149, DOI: 10.1016/j.cmet.2018.01.007.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsMeSH KeywordsAmino Acid SequenceAnimalsCell NucleusChromatinDigoxinDisease Models, AnimalEndotoxinsHistonesHumansHypoxia-Inducible Factor 1, alpha SubunitInflammationLiverNon-alcoholic Fatty Liver DiseaseOxidation-ReductionProtein BindingPyruvate KinaseTHP-1 CellsTranscription, GeneticTranscriptional ActivationConceptsHIF-1α transactivationSterile inflammationHIF-1α pathway activationNon-alcoholic steatohepatitisKinase M2Major clinical consequencesAbility of digoxinLiver inflammationLiver diseasePyruvate kinase M2Clinical consequencesTherapeutic targetInflammationTissue damageHIF-1αPathway activationDigoxinOxidative stressCardiac glycosidesSteatohepatitisDigoxin bindsNovel roleLiverUbiquitous responseActivationDigoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
Ouyang X, Han SN, Zhang JY, Dioletis E, Nemeth BT, Pacher P, Feng D, Bataller R, Cabezas J, Stärkel P, Caballeria J, Pongratz R, Cai SY, Schnabl B, Hoque R, Chen Y, Yang WH, Garcia-Martinez I, Wang FS, Gao B, Torok NJ, Kibbey RG, Mehal WZ. Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis. Cell Metabolism 2018, 27: 1156. PMID: 29719229, DOI: 10.1016/j.cmet.2018.04.007.Peer-Reviewed Original ResearchCitationsAltmetricThe DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury
Hu B, Jin C, Li HB, Tong J, Ouyang X, Cetinbas NM, Zhu S, Strowig T, Lam FC, Zhao C, Henao-Mejia J, Yilmaz O, Fitzgerald KA, Eisenbarth SC, Elinav E, Flavell RA. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science 2016, 354: 765-768. PMID: 27846608, PMCID: PMC5640175, DOI: 10.1126/science.aaf7532.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsCell deathDNA sensor AIM2New therapeutic targetsCaspase-1-dependent deathIntestinal epithelial cellsBone marrow cellsGastrointestinal syndromeTissue injuryInflammasome activationGastrointestinal tractRadiation-induced cell deathRadiation-induced DNA damageTherapeutic targetAcute exposureBone marrowChemotherapeutic agentsMarrow cellsRadiation exposureAIM2Massive cell deathEpithelial cellsHematopoietic failureDeathMolecular mechanismsDNA damageAdenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway
Ouyang X, Ghani A, Malik A, Wilder T, Colegio OR, Flavell RA, Cronstein BN, Mehal WZ. Adenosine is required for sustained inflammasome activation via the A2A receptor and the HIF-1α pathway. Nature Communications 2013, 4: 2909. PMID: 24352507, PMCID: PMC3895487, DOI: 10.1038/ncomms3909.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsMeSH KeywordsAdenosineAdenosine TriphosphateAnimalsCarrier ProteinsCyclic AMPCyclic AMP Response Element-Binding ProteinCyclic AMP-Dependent Protein KinasesHypoxia-Inducible Factor 1, alpha SubunitInflammasomesInterleukin-1betaLipopolysaccharidesLiverMacrophagesMaleMiceMice, Inbred C57BLNLR Family, Pyrin Domain-Containing 3 ProteinReceptor, Adenosine A2ASignal TransductionConceptsHIF-1α pathwayInflammasome activityInflammasome activationA2A receptorsIL-1β productionIL-1β responseReceptor-mediated signalingLack of responseTolerogenic stateChronic diseasesInflammatory responseInflammasome pathwayPrevious exposureLipopolysaccharideAdenosineReceptorsActivationKey regulatorInitial activationPathwaySignalingResponseInterleukinStimuliDisease
2024
Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population
Ding J, Liu H, Zhang X, Zhao N, Peng Y, Shi J, Chen J, Chi X, Li L, Zhang M, Liu W, Zhang L, Ouyang J, Yuan Q, Liao M, Tan Y, Li M, Xu Z, Tang W, Xie C, Li Y, Pan Q, Xu Y, Cai S, Byrne C, Targher G, Ouyang X, Zhang L, Jiang Z, Zheng M, Sun F, Chai J. Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population. Science Translational Medicine 2024, 16: eadh9940. PMID: 39504356, DOI: 10.1126/scitranslmed.adh9940.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsNonalcoholic fatty liver diseaseWhole-genome sequencingHepatocellular carcinomaMolecular subtypesLiver cirrhosisChinese cohort of patientsInfiltration of M1Risk of liver cirrhosisSerum metabolic analysisClinical diagnosisSubtype of nonalcoholic fatty liver diseaseCohort of patientsDevelopment of liver cirrhosisHepatocellular carcinoma developmentIntegrative multiomic analysisHealth care burdenFatty liver diseaseExpression of CYP1A2Urine specimensTreatment strategiesChinese cohortImpaired outcomeM2 macrophagesIntegrative multiomicsLiver disease
Clinical Trials
Current Trials
Inhibition of Sterile Inflammation by Digoxin
HIC ID2000025289RoleSub InvestigatorPrimary Completion Date07/18/2023Recruiting ParticipantsGenderBothAge18 years - 70 years
Academic Achievements & Community Involvement
honor The Samuel D. Kushlan Junior Faculty Award for Excellence in Clinical Research (2018)
Yale School of Medicine AwardYale University Section of Digestive DiseasesDetails07/13/2018United Stateshonor 7th International ALPD & Cirrhosis Symposium Travelling Award (2012)
International AwardDetails10/27/2012China
News & Links
Media
- Naïve CD4+ T cells activated by the combination of IL-6 and TGF-β in the presence of TCR stimulation induces the expression of RORγt as well as IRF8, which physically interacts with RORγt, and in turn suppresses RORγt-mediated IL-17 transcription. IL-21 also acts in a positive autocrine loop in concert with TGF-β to induce RORγt expression. TH17 lineage development is thus achieved through antagonism of IRF8 and RORγt.
- • Loss of METTL3 in myeloid cells prevents obesity and NAFLD in mice • METTL3 regulates Ddit4 mRNA stability via m6A RNA modification • METTL3 deficiency leads to reduced mTOR and NF-κB pathway activity upon cellular stress • Induction of DDIT4 modulates metabolic adaptation to macrophage effector function
- Using live cell multispectral time-lapse tracking acquisition, we show that: ① The phosphorylation of GSK3b- Y216 occurs in response to diverse stimuli, and results in GSK3b-Y221 binding with cytosol NLRP3 at the sites of K86 and E89; ② The GSK3b/NLRP3 protein complexes translocate cross to the mitochondrial membrane, that are known to tightly associate with dynamic endoplasmic reticulum (ER) membrane; ③ Mitochondria transit to TGN and recruit GSK3b/NLRP3 complexes to TGN; ④ TGN disengage from mitochondria and associate with GSK3b/NLRP3 complexes thought PI4K2A phosphorylation at the sites of S5/9 by GSK3b. ⑤ PI4K2A phosphorylation at TGN directs NLRP3 inflammasome assembly. This model indicates that GSK3b -PI4K2A axis signals direct NLRP3 transit to mitochondria and aggregation on TGN leading to inflammasome assembly, and represents a common molecular-trafficking mechanism essential for NLRP3 inflammasome activation by diverse stimuli.
- • Digoxin protects the liver from a wide range of sterile injury • Digoxin downregulates HIF-1α transcription initiated by sterile injury • Digoxin inhibits the transcription of PKM2-dependent genes • Digoxin binds PKM2 and attenuates the interaction between PKM2 and histones
- Inflammasome pathways are important in chronic diseases; however, it is not known how the signalling is sustained after initiation.Here we report that adenosine is a key regulator of inflammasome activity, increasing the duration of the inflammatory response via the A(2A) receptor. Adenosine does not replace signals provided by stimuli such as LPS or ATP but sustains inflammasome activity via a cAMP/PKA/CREB/HIF-1α pathway.
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- November 16, 2022
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Yale School of Medicine
Department of Medicine (Digestive Diseases), P.O. Box 208019
New Haven, CT 06520-8019
United States