Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet‐induced adipose tissue inflammation

[摘要] Inflammasomeactivationinitiatesthedevelopmentofmanyinflammatorydiseases,includingobesityandtype2diabetes.Therefore,agentsthattargetdiscreteactivationstepscouldrepresentveryimportantdrugs.WereportedpreviouslythatILG,achalconefromGlycyrrhizauralensis,inhibitsLPS‐inducedNF‐κBactivation.Here,weshowthatILGpotentlyinhibitstheactivationofNLRP3inflammasome,andtheeffectisindependentofitsinhibitorypotencyonTLR4.TheinhibitoryeffectofILGwasstrongerthanthatofparthenolide,aknowninhibitoroftheNLRP3inflammasome.GL,atriterpenoidfromG.uralensis,hadsimilarinhibitoryeffectsonNLRP3activity,buthighconcentrationsofGLwererequired.Incontrast,activationoftheAIM2inflammasomewasinhibitedbyGLbutnotbyILG.Moreover,GLinhibitedNLRP3‐andAIM2‐activatedASColigomerization,whereasILGinhibitedNLRP3‐activatedASColigomerization.LowconcentrationsofILGwerehighlyeffectiveinIAPP‐inducedIL‐1βproductioncomparedwiththesulfonylureadrugglyburide.InvivoanalysesrevealedthatILGpotentlyattenuatedHFD‐inducedobesity,hypercholesterolemia,andinsulinresistance.Furthermore,ILGtreatmentimprovedHFD‐inducedmacrovesicularsteatosisintheliver.Finally,ILGmarkedlyinhibiteddiet‐inducedadiposetissueinflammationandIL‐1βandcaspase‐1productioninwhiteadiposetissueinexvivoculture.TheseresultssuggestthatILGisapotentialdrugtargetfortreatmentofNLRP3inflammasome‐associatedinflammatorydiseases...

[学科分类] 生理学

[关键词] AIM2;caspase‐1;diabetes;glycyrrhizin;IL‐1βobesity