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1、胆固醇代谢平衡调控,胆固醇的化学结构式,Nobel laureates: 1928 Windans 阐明胆固醇的结构 1964 Bloch & Lynen 阐明胆固醇从头合成途径 1985 Michael S. Brown & Joseph L. Goldstein 发现低密度脂蛋白受体，阐明胆固醇代谢的调节机制,胆固醇的生物学功能,Phospholipid,Modified from Molecular Biology of the Cell, 1994,Saturated,Unsaturated,Fatty Acid,Polar head group,caveolae,胆固醇代谢异常与疾病
2、,Cardiovascular disease,Obesity,Gall-stone,Abnormal of cholesterol metabolism,脂肪肝-Fatty liver,胆固醇代谢平衡,胆固醇代谢平衡调控途径,一.胆固醇合成途径 (负反馈调控),二.胆固醇吸收途径,三.胆固醇外排途径,1. SREBPs转录水平调控,2. 胆固醇合成关键限速酶HMGCR蛋白降解调控,1. 低密度脂蛋白受体（LDLR）介导的胆固醇吸收,2. NPC1L1介导的肝肠内游离胆固醇的吸收,一.胆固醇合成途径,Wang X, Briggs MR, Hua X, Yokoyama C, Goldstein
3、 JL, Brown MS. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. II. Purification and characterization. J Biol Chem. 1993 Jul 5;268(19):14497-504. Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, Goldstein JL, Brown MS. SREBP-1, a basic-helix-loop
4、-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell. 1993 Oct 8;75(1):187-97. Wang X, Sato R, Brown MS, Hua X, Goldstein JL. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994 Apr 8;77(1):53-62.
5、,胆固醇合成负反馈调控: SREBPs-膜结合的转录因子,SREBPs调控的目的基因,胆固醇合成途径限速酶HMGCR,HMGCR,Lanosterol是调节HMGCR的内源分子,Song BL et al, Cell Metab, 2005,HMGCR通过泛素蛋白酶体途径降解,Sever N*, Song BL*, Yabe D* et al., JBC, 2003 Song and Debose-boyd, JBC, 2004,A,C,泛素蛋白酶体途径,甾醇调控HMGCR降解的分子机制,Cao, J., Wang, J., et al., Cell Metab, 2007,二.胆固醇吸收途径
6、,细胞内胆固醇的动态运输平衡,Frederick R. Maxfield and Ira Tabas, Nature, 2005,家族性高胆固醇血症（低密度脂蛋白受体突变） (Familial Hypercholesterolemia, FH),杂合子患者血清总胆固醇较正常人高出12倍 纯合子患者血清总胆固醇较正常人高出68倍,杂合子患者发生率为1/500 纯合子患者发生率为1/1,000,000,杂合子患者男性3040岁时，患CAD， 23% 患者在50岁以前死于CAD，50% 患者在60岁时明显的CAD症状； 纯合子患者十几岁时，有严重的心血管事件甚至死亡,LDLR突变-黄色瘤,FH患者,
7、LDLR突变-眼底脂质渗出,正常人,LDL来源胆固醇在溶酶体中的运输,Hyock Joo Kwon, et al., Cell, 2009,Joanna P. Davies, JBC, 2000,NPC1的拓扑结构,Eugene D. Carstea, et al, Science, 1997,NPC疾病的细胞学表型,NPC疾病 (Niemann-Pick Disease Type C)临床表型,NPC is one of several inherited diseases of cholesterol metabolism. Symptom: 1) Enlarged liver and s
8、pleen 2) Progressive loss of motor skills, learning problems, feeding difficulties, dementia, and seizures 3) Progressive central nervous system degeneration The majority (95%) of the patients have been classified as npc1.,NPC1L1在胆固醇吸收过程中发挥重要作用,Scott W. Altmann, et al, Science, 2004,A,B,C,Xie et al.
9、, JLR, 2012,NPC1L1介导的胆固醇在小肠中的吸收过程,NPC1L1的拓扑结构,Wang, J., Chu, B.B., et, al., JLR, 2009,NPC1L1在细胞内循环转运与介导胆固醇吸收的分子机制,Wang and Song, 2012, BBA Xie et al., 2012, JLR Ge et al., 2011, PNAS Xie et al., 2011, JBC Zhang et al., 2011, JBC Chu et al., 2009, JBC Wang et al., 2009, JLR Ge et al., 2008, Cell Metabolism,谢 谢！,
