IntestinalFarnesoidXReceptorControlsTransintestinalCholesterolExcretioninMiceJanFrearkdeBoer,1,*MarleenSchonewille,1,*MarijeBoesjes,1,*HenkWolters,1VincentW.Bloks,1TrijnieBos,2TheoH.vanDijk,2AngelikaJurdzinski,1RenzeBoverhof,2JustinaC.Wolters,1JanA.Kuivenhoven,1JanM.vanDeursen,3RonaldP.J.OudeElferink,4AntonioMoschetta,5ClausKremoser,6HenkjanJ.Verkade,1FolkertKuipers,1,2andAlbertK.Groen1,21DepartmentofPediatrics,2DepartmentofLaboratoryMedicine,UniversityofGroningen,UniversityMedicalCenterGroningen,Groningen,TheNetherlands;3DepartmentofPediatricandAdolescentMedicine,DepartmentofBiochemistryandMolecularBiology,MayoClinicCollegeofMedicine,Rochester,Minnesota;4TytgatInstituteforLiverandIntestinalResearch,DepartmentofHepatologyandGastroenterology,AcademicMedicalCenter,UniversityofAmsterdam,Amsterdam,TheNetherlands;5DepartmentofInterdisciplinaryMedicine,UniversityofBari,IRCCSIstitutoTumori“GiovanniPaoloII,”Bari,Italy;6PhenexPharmaceuticalsAG,Heidelberg,GermanySeeCoveringtheCoversynopsisonpage916.BACKGROUND&AIMS:Theroleoftheintestineinthemaintenanceofcholesterolhomeostasisincreasinglyisrecog-nized.Fecalexcretionofcholesterolisthelaststepintheatheroprotectivereversecholesteroltransportpathway,towhichbiliaryandtransintestinalcholesterolexcretion(TICE)contribute.ThemechanismscontrollingthefluxofcholesterolthroughtheTICEpathway,however,arepoorlyunderstood.WeaimedtoidentifymechanismsthatregulateandstimulateTICE.METHODS:WeperformedstudieswithC57Bl/6Jmice,aswellaswithmicewithintestine-specificknockoutofthefarnesoidXreceptor(FXR),micethatexpressanFXRtransgenespecificallyintheintestine,andABCG8-knockoutmice.MicewerefedacontroldietoradietsupplementedwiththeFXRagonistPX20606,withorwithoutthecholesterolabsorptioninhibitorezetimibe.Somemicewithintestine-specificknockoutofFXRweregivendailyinjectionsoffibroblastgrowthfactor(FGF)19.Todeterminefractionalcholesterolabsorption,miceweregivenintravenousinjectionsofcholesterolD5andoralcholes-terolD7.Miceweregiven13C-acetateindrinkingwaterfo...
