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1、Slide Source LipidsOnline www lipidsonline org Sitosterolemia A Rare Genetic Disorder Leads to Insight into an Important Physiological Process Slide Source LipidsOnline www lipidsonline org Evidence for Regulation of Dietary Cholesterol Absorption nInterindividual variation in cholesterol absorption
2、 rates nAbsorption rates affected by dietary cholesterol levels nHigh degree of specificity for sterol absorbed e g cholesterol sitosterol nGenetic disease in humans phytosterolemia nCholesterol excreted into bile by the liver but mechanism transporters not identified Slide Source LipidsOnline www l
3、ipidsonline org How is Cholesterol Absorbed IntestinalIntestinal cellcell FFAFFA MicellesMicelles Bile acidsBile acids LiverLiver CholesterolCholesterol FFAFFA ChylomicronsChylomicrons Digest foodDigest food CholesterylCholesteryl ester ester CholesterolCholesterol FFAFFA Free cholesterolFree choles
4、terol BloodBlood LymphaticLymphatic channelschannels VLDLVLDL Slide Source LipidsOnline www lipidsonline org Sterol Absorption Bosner MS et al J Lipid Res 1999 40 302 308 Number of Subjects 1st2nd3rd4th5th6th7th8th9th 10th Decile Percent Cholesterol Absorption Slide Source LipidsOnline www lipidsonl
5、ine org Dietary Sterols Normal Physiology Slide Source LipidsOnline www lipidsonline org HO Sitosterol HO Stigmasterol Sterol Structures HO Cholesterol HO Campesterol Slide Source LipidsOnline www lipidsonline org Bhattacharyya AK et al J Clin Invest 1974 53 1033 1043 Sitosterolemia a k a Phytostero
6、lemia nAutosomal recessive first described in 1974 nDiagnostically elevated plasma phytosterols nRare 130 in Arabidopsis thaliana Slide Source LipidsOnline www lipidsonline org ABC Genes and Human Disease nOncology nChemotherapeutic resistance nPulmonology nCystic fibrosis nCardiology metabolic nTan
7、gier disease nSitosterolemia nEndocrinology nNesidioblastosis PHHI nOphthalmology nStargardt s macular dystrophy nDermatology Pseudoxanthoma elasticum nImmunology Antigen presentation Bare lymphocyte nHematology X linked sideroblastic anemia nNeurology Adrenoleukodystrophy nHepatology Familial chole
8、stasis Slide Source LipidsOnline www lipidsonline org nMutations in ABCG5 sterolin 1 and ABCG8 sterolin 2 cause sitosterolemia nAffected individuals have high levels of plant sterols but not always cholesterol nTendon tuberous xanthomas and accelerated atherosclerosis nMust play a key role in regula
9、ting dietary sterol absorption and excretion n Link between diet and atherosclerosis nDo sterolins prevent the entry of toxic bioactive sterols Conclusions ABCG5 and ABCG8 Slide Source LipidsOnline www lipidsonline org Noncholesterol Sterols Endogenous sterols nSterol synthesis intermediates nDesmos
10、terol nLathosterol nCholestenol etc nMetabolites nCholestanol nOxysterols Exogenous sterols nPlant sterols Sitosterol Campesterol Brassicasterol Avenosterol etc nYeast sterols Ergosterol etc nShellfish sterols Desmosterol Fucosterol etc Slide Source LipidsOnline www lipidsonline org Elevated Phytost
11、erols are a Marker of CHD HypercholesterolemicsHypercholesterolemics n 595 n 595 HyperphytosterolemicsHyperphytosterolemics n 21 n 21 Sitosterol 0 2650 628 Campesterol 0 1640 594 Cholesterol 261262 nSitosterol and campesterol concentrations were higher in subjects with personal or family history of
12、premature CHD n42 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 dl Slide Source LipidsOnline www lipidsonline org Rajaratnam RA et al J Am Coll Cardiol 2000 35 1185 1191 Sitosterol Concentrations
13、in Postmenopausal Women with CHD nPostmenopausal women with CHD had higher levels of sitosterol and campesterol results remained significant after adjustment for other risk factors Data are mean SD Values expressed as mg dl CasesCases n 48 n 48 ControlsControls n 61 n 61 P P Sitosterol0 332 0 22 0 2
14、71 0 13 0 05 Campesterol0 611 0 44 0 493 0 25 0 1 Slide Source LipidsOnline www lipidsonline org LiverLiver Fecal sterolsFecal sterols Bile saltsBile salts UnabsorbedUnabsorbed cholesterolcholesterol CholChol BileBile saltssalts BileBile Duodenal Duodenal jejunaljejunal enterocyteenterocyte DietDiet
15、 LuminalLuminal cholesterolcholesterol BileBile saltssalts IlealIleal enterocyteenterocyte Sterol Sterol permeasepermease BileBile saltssalts BASBAS MicellarMicellar cholesterolcholesterol EzetimibeEzetimibe Mechanism of Intestinal Acting Agents ChylomicronChylomicron Lymph Chylomicron HepaticHepati
16、c portalportal circulationcirculation Plant Plant stanolsstanols ABCG5 G8ABCG5 G8 IBATIBAT Slide developed by The Health Science Center for Continuing Medical Education New York NY Slide Source LipidsOnline www lipidsonline org Ezetimibe Significantly Reduces Plasma Sitosterol in Patients with Sitosterolemia Salen G et al Circulation 2002 106 II 185 Mean Change from Baseline Baseline 2468 Endpoint avg of wks 6 and 8 Endpoint last measure Placebo Ezetimibe 10 mg Week Slide Source LipidsOnline www
