Novel ENU-Induced Point Mutation in Scavenger Receptor Class B, Member 1, Results in Liver Specific Loss of SCARB1 Protein 英文参考文献.docVIP

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Novel ENU-Induced Point Mutation in Scavenger Receptor Class B, Member 1, Results in Liver Specific Loss of SCARB1 Protein 英文参考文献.doc

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Novel ENU-Induced Point Mutation in Scavenger Receptor Class B, Member 1, Results in Liver Specific Loss of SCARB1 Protein 英文参考文献

NovelENU-InducedPointMutationinScavenger ReceptorClassB,Member1,ResultsinLiverSpecificLoss ofSCARB1Protein IoannisM.Stylianou1,2*,KarenL.Svenson2,SaraK.VanOrman1,YaninaLangle1,JohnS.Millar1 ,Beverly Paigen2,DanielJ.Rader1 1SchoolofMedicine,InstituteforTranslationalMedicineandTherapeutics,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica,2TheJackson Laboratory,BarHarbor,Maine,UnitedStatesofAmerica Abstract Cardiovascular disease (CVD) is the largest cause of premature death in human populations throughout the world. Circulatingplasmalipidlevels,specificallyhighlevelsofLDLorlowlevelsofHDL,arepredictiveofsusceptibilitytoCVD.The scavengerreceptorclassBmember1(SCARB1)istheprimaryreceptorfortheselectiveuptakeofHDLcholesterolbyliver and steroidogenic tissues. Hepatic SCARB1 influences plasma HDL-cholesterol levels and is vital for reverse cholesterol transport.HerewedescribethemappingofanovelN-ethyl-N-nitrosourea(ENU)inducedpointmutationintheScarb1gene identifiedinaC57BL/6Jbackground.Themutationislocatedinahighlyconservedaminoacidintheextracellularloopand leadstotheconversionofanisoleucinetoanasparagine(I179N).HomozygousmutantmiceexpressnormalScarb1mRNA levelsandarefertile.SCARB1proteinlevelsaremarkedlyreducedinliver(,90%),butnotinsteroidogenictissues.Thisleads to,70%increasedplasmaHDLlevelsduetoreducedHDLcholesterylesterselectiveuptake.Pdzk1knockoutmicehave liver-specificreductionofSCARB1proteinasdoesthismutant;however,invitroanalysisofthemutationindicatesthatthe regulation of SCARB1 protein in this mutant is independent of PDZK1. This new Scarb1 model may help further our understanding of post-translational and tissue-specific regulation of SCARB1 that may aid the important clinical goal of raisingfunctionalHDL. Citation:StylianouIM,SvensonKL,VanOrmanSK,LangleY,MillarJS,etal.(2009)NovelENU-InducedPointMutationinScavengerReceptorClassB,Member1, ResultsinLiverSpecificLossofSCARB1Protein.PLoSONE4(8):e6521.doi:10.1371/journal.pone.0006521 Editor:Piet