胆固醇代谢(ppt文档)
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胆固醇代谢平衡调控
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
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
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
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
• Two molecules of acetate-CoA condense forming acetoacetyl-CoA.
• Acetoacetyl-CoA condenses with acetyl-CoA to yield bhydroxy-bmethylglutaryl-CoA (HMG-CoA)
43.8% 22.3%
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.
蒙娜丽莎患有高胆固醇？
意大ቤተ መጻሕፍቲ ባይዱ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。
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）
• The final step the reduction of HMG-CoA to mevalonate, catalyzed by HMG-CoA reductase.
Stage 2
• Conversion of mevalonate into activated isoprene units
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
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
• 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
• 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.
• 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
• 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
膜上的微结构域
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
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
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
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
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
• Two molecules of acetate-CoA condense forming acetoacetyl-CoA.
• Acetoacetyl-CoA condenses with acetyl-CoA to yield bhydroxy-bmethylglutaryl-CoA (HMG-CoA)
43.8% 22.3%
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.
蒙娜丽莎患有高胆固醇？
意大ቤተ መጻሕፍቲ ባይዱ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。
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）
• The final step the reduction of HMG-CoA to mevalonate, catalyzed by HMG-CoA reductase.
Stage 2
• Conversion of mevalonate into activated isoprene units
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
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
• 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
• 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.
• 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
• 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
膜上的微结构域
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