《胆固醇代谢》-精选·课件.ppt

* Two sources of cellular cholesterol * * * * * * 筛选潜在的胆固醇吸收抑制剂 0 min 60 min 120 min DMSO C6 NPC1L1 Cholesterol NPC1L1 Cholesterol Compound 6 Inhibits NPC1L1 Endocytosis and Cholesterol Uptake Acknowledgements 合作实验室： 李伯良 教授 熊 缨 博士 杨新颖 老师 李 琴 Thank you! * 胆固醇是个疏水的小分子，这是它的结构式和构象 * * * 大部分人注视达·芬奇的名作《蒙娜丽莎》时，看到的是一位优雅的女士，和她脸上难以捉摸的微笑。维托·弗兰克不这么看，在这位意大利帕勒莫大学病理解剖学教授的眼中，蒙娜丽莎是一位饮食不怎么健康的女性。　　近日，在意大利佛罗伦萨举办的一场欧洲人类病理学大会上，弗兰克教授展现了他令人惊奇的研究结果。在蒙娜丽莎的左眼眼窝处，弗兰克发现了黄斑瘤，这是一种黄色的脂质酸沉积在皮肤下形成的症状。同时，这位教授在蒙娜丽莎的双手上，也发现了一些良性的皮下脂肪瘤的痕迹。　　在弗兰克看来，正是达·芬奇对人物眼部脂肪瘤栩栩如生的重现，造成了蒙娜丽莎这副神秘莫测的表情。弗兰克还根据这位模特显示出的高胆固醇症状推断，她的饮食并不健康，尽管在那个时代，人们还不知“高胆固醇”为何物。大概所有对蒙娜丽莎的种种想象和猜测中，弗兰克的结论恐怕是最不“诗情画意”的一种。 * * * * * * * * * * * * * * * * * * * * * * * * Amino Acid Sequence of the HMG-CoA Reductase Membrane Domain Lysines 89 and 248 are Required for the Sterol-Regulated Ubiquitination and Degradation of HMGCR Strategy for Purifying the E3 of HMG-CoA Reductase E3 Activity Co-immunoprecipitates with Insig-1 in Sterol-Treated Cells Identification of gp78 and VCP as Insig-1-associating proteins Molecular Pathway for Sterol-regulated Degradation of HMGCR Song et al., Mol Cell, 2005 What are other proteins involved in this pathway? Identification of Ufd1 as a gp78 interacting protein IP: Endogenous gp78 IP: Endogenous gp78 Transfect CoIP IP: Flag-Ufd1 A B C Ufd1 is required for the ubiquitination of endogenous HMGCR Ufd1 enhances the E3 activity of gp78 in vitro Dual roles of Ufd1: Enhancing E3 activity and Promoting degradation Cao et al., Cell Metab, 2007 十、饮食胆固醇吸收的分子途径 (HMGCR) De novo Cholesterol Synthesis is a Energy-Consuming Process 18 ? Acetyl-CoA Cholesterol 27 ? NADPH 11 ? O2 18 ? ATP Cholesterol Biosynthesis and Absorption in Human 300-500 mg Dietary Absorption Biosynthesis 600-900 mg ~1000 mg Biliary re-absorption Dietary Cholesterol Absorption by Intestinal Enterocytes Cholesterol Ester Hydrolysis Cholesterol Cholesterol Cholesterol Ester Chylomicron Intestinal lumen Lymph ACAT2 ER Enterocyte Tight Junction