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1、,Sitosterolemia: A Rare Genetic Disorder Leads to Insight into an Important Physiological Process,Shailesh B. Patel, BM, ChB, FRCP,Evidence for Regulation of Dietary Cholesterol Absorption,Interindividual variation in cholesterol absorption rates Absorption rates affected by dietary cholesterol leve
2、ls High degree of specificity for sterol absorbed, e.g., cholesterol sitosterol Genetic disease in humans, phytosterolemia Cholesterol excreted into bile by the liver, but mechanism/transporters not identified,How is Cholesterol Absorbed?,Intestinal cell,FFA,Micelles,Bile acids,Liver,Cholesterol,FFA
3、,Chylomicrons,Digest food Cholesteryl ester Cholesterol,FFA Free cholesterol,Blood,Lymphatic channels,VLDL,Sterol Absorption,Bosner MS et al. J Lipid Res 1999;40:302-308.,Number of Subjects,1st,2nd,3rd,4th,5th,6th,7th,8th,9th,10th,Decile Percent Cholesterol Absorption,Dietary Sterols: Normal Physiol
4、ogy,HO,Sitosterol,HO,Stigmasterol,Sterol Structures,HO,Cholesterol,HO,Campesterol,Bhattacharyya AK et al. J Clin Invest 1974;53:1033-1043.,Sitosterolemia, a.k.a. Phytosterolemia,Autosomal recessive, first described in 1974 Diagnostically elevated plasma phytosterols Rare, 1:1,000,000 (20 cases in US
5、) Associated with premature atherosclerosis Increased dietary sterol absorption and failure to excrete sterols into bile Need GC or HPLC to make diagnosis,Sitosterolemia,Biochemical abnormalities Increased plasma phytosterols and their metabolites Increased dietary cholesterol and plant sterol absor
6、ption Expanded body pools of both sitosterol and cholesterol Decreased ability to excrete any sterols into bile by the liver,Plasma Sitosterol and Cholesterol in Sitosterolemia,Lee MH et al. Curr Opin Lipidol 2001;12:141-149.,Cholesterol (mg/dl),Plasma Cholesterol,Plasma Sitosterol (mg/dl),Plasma Si
7、tosterol,68,58,48,38,28,18,8,3,2,1,0,Parents,Normal Siblings,Affected Individuals,Normal Controls,Parents,Normal Siblings,Affected Individuals,Normal Controls,Summary of Metabolic Defect,Loss of sterol discrimination, with Reduced bile excretion of sterols Hyperabsorption of all sterols Reduced ster
8、ol turnover Abnormal regulation of cholesterol synthetic pathway Reduced activities of HMG-CoA reductase, synthase, but increased LDL-receptor activity,Sitosterol and Atherosclerosis: Insight from Homozygous Sitosterolemia,Autopsy study of young sitosterolemic patient who had sudden death 20% plant
9、sterol content of atherosclerotic plaque Same proportions of sterols as in LDL,Hypothesis,Primary defect involves a gene product that Regulates cholesterol absorption in the gut Regulates cholesterol excretion in the liver Prevents noncholesterol sterols from being retained by the body Prevents entr
10、y in the intestine Any small amounts that escape the intestine are rapidly excreted by the liver,Genetic Analyses,Assemble pedigrees, confirm diagnosis by plasma sitosterol levels, collect DNA Low-density genome wide-scan performed Initially at 25 cM resolution 1015 cM at conclusion High-density map
11、ping upon localization Positionally clone the disease gene,2100,63,64,62,65,66,67,68,61,72,71,70,69,Families with Sitosterolemia,700,36,37,34,35,38,39,40,41,42,2700,105,104,103,106,107,108,109,Lee MH et al. Curr Opin Lipidol 2001;12:141-149.,55,56,59,60,90,91,94,95,98,99,102,Fine-Mapping of STSL to
12、D2S2294D2S2174,Lee MH et al. Eur J Hum Genet 2001;9:375-384. 2001 Nature Publishing Group. All rights reserved.,Haldane Map Position,Multipoint LOD Score,D2S1346,GATA194B06,D2S2259,D2S4010,D2S2298,D2S4015,D2S2240,D2S2378,D2S123,D2S2153,D2S4009,Lu K et al. Am J Hum Genet 2001;69:278-290. 2001 The Ame
13、rican Society of Human Genetics. All Rights Reserved,Gene Structures of ABCG5 (Sterolin-1) and ABCG8 (Sterolin-2),Centromere,1kb,ABCG8,ABCG5,Telomere,ATG,ATG,372 bp,143 bp,12,13,11,10,89,7,6,5,34,2,1,1,Exon1 ABCG8,Exon1 ABCG5,Expression Patterns of ABCG5 and ABCG8 in Mouse Tissues,kb,6.0 5.0 4.0 3.0
14、 2.5 2.0 1.5,6.0 5.0 4.0 3.0 2.5 2.0 1.5,3.0 2.5 2.0 1.5,ABCG5,ABCG8,-actin,Lee MH et al. Nat Genet 2001;27:79-83. | Lu K et al. Am J Hum Genet 2001;69:278-290. 2001 Nature Publishing Group. All rights reserved.,Mutations in ABCG5 and ABCG8 Cause Sitosterolemia,What are ABC Proteins?,ATP-binding cas
15、sette containing membrane “transporters“ Defined by “Walker“ motifs A and B Subsequently a “C“ motif defined Large family Present in bacteria to mammals 55 genes in Drosophila melanogaster 56 in Caenorhabditis elegans 51 in Homo sapiens 130 in Arabidopsis thaliana,ABC Genes and Human Disease,Oncology Chemotherapeutic resistance Pulmonolog
