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Slide SourceLipidsOnlinewww.lipidsonline.orgSitosterolemia:A Rare Genetic Disorder Leads to Insight into an Important Physiological ProcessSitosterolemia:A Rare GeneticSlide SourceLipidsOnlinewww.lipidsonline.orgEvidence for Regulation of Dietary Cholesterol AbsorptionnInterindividual variation in cholesterol absorption ratesnAbsorption rates affected by dietary cholesterol levelsnHigh degree of specificity for sterol absorbed,e.g.,cholesterol sitosterolnGenetic disease in humans,phytosterolemianCholesterol excreted into bile by the liver,but mechanism/transporters not identified Evidence for Regulation of DieSlide SourceLipidsOnlinewww.lipidsonline.orgHow is Cholesterol Absorbed?IntestinalIntestinalcellcellFFAFFAMicellesMicellesBile acidsBile acidsLiverLiverCholesterolCholesterolFFAFFAChylomicronsChylomicronsDigest foodDigest food Cholesteryl esterCholesteryl ester CholesterolCholesterolFFAFFAFree cholesterolFree cholesterolBloodBloodLymphaticLymphaticchannelschannelsVLDLVLDLHow is Cholesterol Absorbed?InSlide SourceLipidsOnlinewww.lipidsonline.orgSterol AbsorptionBosner MS et al.J Lipid Res 1999;40:302-308.Number of Subjects1st2nd3rd4th5th6th7th8th9th 10thDecile Percent Cholesterol AbsorptionSterol AbsorptionBosner MS et Slide SourceLipidsOnlinewww.lipidsonline.orgDietary Sterols:Normal PhysiologyDietary Sterols:Normal PhysiSlide SourceLipidsOnlinewww.lipidsonline.orgHOSitosterolSitosterolHOStigmasterolStigmasterolSterol StructuresHOCholesterolCholesterolHOCampesterolCampesterolHOSitosterolHOStigmasterolSterSlide SourceLipidsOnlinewww.lipidsonline.orgBhattacharyya AK et al.J Clin Invest 1974;53:1033-1043.Sitosterolemia,a.k.a.PhytosterolemianAutosomal recessive,first described in 1974nDiagnostically elevated plasma phytosterolsnRare,130 in Arabidopsis thalianaWhat are ABC Proteins?ATP-bindSlide SourceLipidsOnlinewww.lipidsonline.orgABC Genes and Human DiseasenOncologynChemotherapeutic resistancenPulmonologynCystic fibrosisnCardiology/metabolicnTangier diseasenSitosterolemianEndocrinologynNesidioblastosis(PHHI)nOphthalmologynStargardts macular dystrophynDermatologyPseudoxanthoma elasticumnImmunologyAntigen presentationBare lymphocytenHematologyX-linked sideroblastic anemianNeurologyAdrenoleukodystrophynHepatologyFamilial cholestasisABC Genes and Human DiseaseOncSlide SourceLipidsOnlinewww.lipidsonline.orgnMutations in ABCG5(sterolin-1)and ABCG8(sterolin-2)cause sitosterolemianAffected individuals have high levels of plant sterols,but not always cholesterolnTendon/tuberous xanthomas and accelerated atherosclerosisnMust play a key role in regulating dietary sterol absorption and excretionn?Link between diet and atherosclerosisnDo sterolins prevent the entry of toxic bioactive sterols?Conclusions:ABCG5 and ABCG8Mutations in ABCG5(sterolin-1Slide SourceLipidsOnlinewww.lipidsonline.orgNoncholesterol SterolsEndogenous sterolsnSterol synthesis intermediatesnDesmosterolnLathosterolnCholestenol,etcnMetabolitesnCholestanolnOxysterolsExogenous sterolsnPlant sterolsSitosterolCampesterolBrassicasterolAvenosterol,etc.nYeast sterolsErgosterol,etc.nShellfish sterolsDesmosterolFucosterol,etc.Noncholesterol SterolsEndogenoSlide SourceLipidsOnlinewww.lipidsonline.orgElevated Phytosterols are a Marker of CHDHypercholesterolemicsHypercholesterolemics(n=595)(n=595)HyperphytosterolemicsHyperphytosterolemics(n=21)(n=21)Sitosterol0.2650.628Campesterol0.1640.594Cholesterol261262nSitosterol and campesterol concentrations were higher in subjects with personal or family history of premature CHDn42%of probands kindred had history of premature CHD versus 19%of the cohort(P=0.13)Glueck CJ et al.Metabolism 1991;40:842-848.All values expressed as mg/dlElevated Phytosterols are a MaSlide SourceLipidsOnlinewww.lipidsonline.orgRajaratnam RA et al.J Am Coll Cardiol 2000;35:1185-1191.Sitosterol Concentrations in Postmenopausal Women with CHDnPostmenopausal women with CHD had higher levels of sitosterol and campesterol;results remained significant after adjustment for other risk factorsData are mean(SD)Values expressed as mg/dlCasesCases(n=48)(n=48)ControlsControls(n=61)(n=61)P PSitosterol0.332(0.22)0.271(0.13)0.05Campesterol0.611(0.44)0.493(0.25)0.1Rajaratnam RA et al.J Am CollSlide SourceLipidsOnlinewww.lipidsonline.orgLiverLiverFecal sterolsFecal sterolsBile saltsBile saltsUnabsorbedUnabsorbedcholesterolcholesterolCholCholBileBilesaltssaltsBileBileDuodenal/jejunalDuodenal/jejunalenterocyteenterocyteDietDietLuminalLuminalcholesterolcholesterolBileBilesaltssaltsIlealIlealenterocyteenterocyteSterol permeaseSterol permeaseBileBilesaltssaltsBASBASMicellarMicellarcholesterolcholesterolEzetimibeEzetimibeMechanism of Intestinal-Acting AgentsChylomicronChylomicronLymphChylomicronHepaticHepaticportalportalcirculationcirculationPlant Plant stanolsstanolsABCG5/G8ABCG5/G8IBATIBATSlide developed by The Health Science Center for Continuing Medical Education,New York,NYLiverFecal sterolsBile saltsUSlide SourceLipidsOnlinewww.lipidsonline.orgEzetimibe Significantly Reduces Plasma Sitosterol in Patients with SitosterolemiaSalen G et al.Circulation 2002;106:II-185.Mean%Change from BaselineBaseline 2468Endpointavg of wks6 and 8EndpointlastmeasurePlaceboEzetimibe 10 mgWeekEzetimibe Significantly ReduceSlide SourceLipidsOnlinewww.lipidsonline.orgPlaceboPlaceboEzetimibeEzetimibeEzetimibe Lowers Phytosterols in Patients with Mild HypercholesterolemiaSudhop T et al.Circulation 2002;106:1943-1948.Campesterol(mg/dl)PlaceboPlacebo48%48%EzetimibeEzetimibeSitosterol(mg/dl)41%41%PlaceboEzetimibeEzetimibe LoweSlide SourceLipidsOnlinewww.lipidsonline.orgConclusionsnSpecific mechanisms have evolved to keep noncholesterol sterols out of our bodies(STSL locus)nHighly conserved proteins from fugu to humansnPlant sterol levels may be another indicator of cardiovascular risknNoncholesterol sterols correlate with CHDnPlant sterol levels can be lowered by ezetimibe in both normal and sitosterolemic individualsConclusionsSpecific mechanismsSlide SourceLipidsOnlinewww.lipidsonline.org谷固醇血症：一种罕见的遗传性脂代谢紊乱课件
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