胆固醇代谢-科大英才班.pptVIP

胆固醇代谢平衡调控;提纲;;一、胆固醇的生物学功能;哺乳动物细胞模式图;膜上的微结构域;Cholesterol and cholesterol derivatives ;脂肪酸、糖等提供能量（ATP） 胆固醇并不提供能量;二、胆固醇相关疾病;Cholesterol is the major cause of atherosclerosis;;蒙娜丽莎患有高胆固醇？;胆结石;From IMS Health, MIDAS ;三、胆固醇的生物合成;Cholesterol is not required in the diet;Cholesterol is made from acetyl-CoA in four stages;Stage 1;Two molecules of acetate-CoA condense forming acetoacetyl-CoA. Acetoacetyl-CoA condenses with acetyl-CoA to yield b-hydroxy-b-methylglutaryl-CoA (HMG-CoA);The final step the reduction of HMG-CoA to mevalonate, catalyzed by HMG-CoA reductase.;Stage 2;Stage 3;Cyclization of squalene forms the four rings of the steroid nucleus. Subsequent modifications leads to the final product, cholesterol. ;Most of the cholesterol made in the liver is exported;Cholesterol is exported in three forms;四、胆固醇在血液中的运输;Cholesteryl ester formation;Cholesterol transport: the problem;Cholesterol transport: the solution;Cholesterol esters enter cells by receptor mediated endocytosis;五、家族型高胆固醇血症;家族性高胆固醇血症 (Familial Hypercholesterolemia, FH);LDLR突变----黄色瘤;FH患者;六、 Niemann-Pick type C(NPC) 疾病;正常细胞;;七、胆固醇的降解与清除;Degradation of cholesterol;Steroid hormones are formed from cholesterol;八、胆固醇代谢的负反馈调控机制;;;SREBP—膜结合的转录因子;;Amphotericin B;S2P cDNA to CHO cells;DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL, Espenshade PJ. Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell. 1999 Dec 23;99(7):703-12. Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ. Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell. 2000 Aug 4;102(3):315-23.;Purification Scheme for SCAP-interacting Proteins;Two Insigs: Insig-1 and Insig-2;;九、胆固醇代谢的负反馈调控机制;From He J. et al., N Engl J Med, (2005), 353: 1124-1134. and IMS Health, MIDAS ;HMG-CoA Reductase (HMGCR): the Rate-Limiting Enzyme in Cholesterol Biosynthetic Pathway;Proposed Model for INSIG-mediated Regulation ofHMG C