胆固醇代谢平衡调控机制和合成

• Two molecules of acetate-CoA condense forming acetoacetylCoA.
• Acetoacetyl-CoA condenses with acetylCoA to yield b-hydroxyb-methylglutaryl-CoA (HMG-CoA)
Nexium Seretide Plavix Aranesp
Company
Pfizer
Indication
Sales to June
07($bn)
Hypercholesterolaemia（高胆固醇血症）
13.5
AstraZeneca
Gastroesophageal reflux（胃食管返流）, gastric ulcers（胃溃疡）
Cholesterol（胆固醇）
一、胆固醇的生物学功能
Membrane Fluidity Bile Acids Hormones、Vitamin D Synapse Hedgehog Modification Signal Transduction ……
哺乳动物细胞模式图
膜上的微结构域
• Cholesterol is an essential molecule but is not required in the diet because all cells can synthesize it from simple precursors
Cholesterol is made from acetyl-CoA in four stages
• The final step the reduction of HMG-CoA to mevalonate, catalyzed by HMG-CoA reductase.
Stage 2
• Conversion of mevalonate into activated isoprene units
Cholesterol and cholesterol derivatives
雌激素
雄激素
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
中国死亡原因统计
22.3%
43.8%
• all of its carbon atoms are provided by a single precursor – acetate
Stage 1
• Three acetate units condense to form a six carbon intermediate, mevalonate
胆固醇代谢平衡调控 机制和合成
提纲
1. 胆固醇的生物学功能 2. 胆固醇相关疾病 3. 胆固醇的生物合成 4. 胆固醇在血液中的运输 5. 家族型高胆固醇血症 6. NPC疾病 7. 胆固醇的降解与清除 8. 胆固醇代谢的负反馈调控机制—SCAP-SREBP途径 9. 胆固醇代谢的负反馈调控机制—HMGCR降解途径 10. 饮食胆固醇吸收的分子途径
正是眼部的脂肪瘤，造成了 蒙娜丽莎这副神秘莫测的表情。 画中的她（或者说达芬奇的这个 模特）正在为自己体内过高的胆 固醇而担忧。
Cholesterol and Diseases
Niemann-Pick Type C Disease
老年痴呆症
胆结石
糖尿病/肥胖症
药品销售排行榜
Name
Lipitor
心脑血管疾病 恶性肿瘤 肺炎、流感 感染性疾病 意外死亡 慢性阻塞性肺病 肝病及肝硬化 糖尿病 肾病 其它
From He J. et al., N Engl J Med, (2005), 353: 1124-1134.
蒙娜丽莎患有wk.baidu.com胆固醇？
意大利帕勒莫大学的病理解 剖学教授弗兰克，研究认为蒙娜 丽莎饮食不健康，患有高胆固醇 症。
2. Cholesterol – to bile 3. Cholesteryl esters – transported and secreted in
lipoprotein particles to other tissues that use cholesterol or are stored in the liver
• Isoprene containing molecules are important intermediates in cholesterol biosynthesis
Stage 3
• Polymerization of six 5-carbon isoprene units to form the 30-carbon linear structure of squalene.
Stage 4
• 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
• Much of cholesterol synthesis takes place in the liver
• Most is exported
Cholesterol is exported in three forms
1. Bile salts – amphipathic cholesterol derivatives that aid lipid digestion
6.9
GSK
Asthma（哮喘）
6.7
Bristol-Myers Squibb
Atherosclerotic events（动脉粥样硬化症）
5.8
Amgen
Anaemia（贫血症）
5.1
From IMS Health, MIDAS
三、胆固醇的生物合成
Cholesterol is not required in the diet