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Metabolism of lipids Course Content •Digestion and absorption of lipids •Triacylglycerol metabolism •Phospholipid metabolism •Cholesterol metabolism •plasma lipoprotein metabolism Summary •Definition • Classes fats lipids : triacylglycerols, TG cholesterol, Ch cholesteryl ester, CE lipoids phospholipids, PL glucolipids, GL • Function nomenclature Fatty acids: Saturated fatty acids 14〜20C palmitic acid 16C stearic acid 18C Unsaturated fatty acids Linolenic acid 18C three unsaturated bonds Linoleate 18C two unsaturated bonds Arachidonic acid 20C four unsaturated bonds Essential fatty acids required for the growth of mammals and they must be obtained from food. Including linoleate 、 linolenate, arachidonic acid amount unsaturated in plant Section I Digestion and absorption of lipids • digestion: – small intestine:bile、pancreatic lipase、colipase、 phospholipase A2、 cholesteryl esterase – product:2-monoacylglycerol(MG)、FFA、 Cholesterol、lysophospholipid • absorption Chemical Structure of Triacylglycerol Fatty Acid Synthesis • Palmitic acid synthesis • Elongation of FA carbon-chainER – ER --Mitochondrial • Synthesis of Unsaturated FA • Regulation of unsaturated FA Biosynthesis of palmitic Acid • Tissues:liver(major site) 、kidney、 breast、adipose、 lung 、 brain ---Cytosol • Materials:Acetyl-CoA、NADPH+H+、ATP、 HCO3- and Mn2+ • Pathway ---Synthesis of malonyl-CoA ---Synthesis of fatty acid Citrate Pyruvate Cycle malonyl-CoA Synthesis 限速酶 ÒÒ õ£CoAôÈ»¯Ã¸ CH3COSCoA £«HCO3- £«ATP ÉúÎï ËØ¡¢Mn 2+ HOOCCH2COSCoA£«ADP£«Pi ±û¶þõ£CoA ÄûÃÊËá¡¢ ÒìÄûÃÊËá ÒÒ õ£CoAôÈ»¯Ã¸£º Pi (+) ÒȵºËØ µ°°×Á×Ëáø H2O µ¥Ìå ¶à¾Û Ìå (ÎÞ»î ÐÔ ) ³¤ Á´Ö¬õ£CoA (Óлî ÐÔ ) ÒÒ õ£CoAôÈ»¯Ã¸ £¨ Óлî ÐÔ £© ÒÒ õ£CoAôÈ»¯Ã¸ P £¨ ÎÞ»î ÐÔ £© ATP µ°°×¼¤Ã¸ ADP (+) ÒȨ̀ßѪÌÇËØ Enzyme-biotin HCO3 + ATP 1 ADP + Pi Enzyme-biotin-CO2 O ll CH3-C-SCoA acetyl-CoA 2 Enzyme-biotin O - ll O2C-CH2-C-SCoA malonyl-CoA The overall reaction, which is spontaneous, may be summarized as: HCO3- + ATP + acetyl-CoA ADP + Pi + malonyl-CoA Acetyl-CoA Carboxylase, which converts acetyl-CoA to malonyl-CoA, is the committed step of the fatty acid synthesis pathway. The mammalian enzyme is regulated, by phosphorylation allosteric control by local metabolites. Conformational changes associated with regulation: In the active conformation, Acetyl-CoA Carboxylase associates to form multimeric filamentous complexes. Transition to the inactive conformation is associated with dissociation to yield the monomeric form of the enzyme (protomer). Phosphorylated protomer of Acetyl-CoA Carboxylase (inactive) Citrate AMP-Activated Kinase catalyzes phosphorylation of Acetyl-CoA Carboxylase, causing inhibition. Dephosphorylated, e.g., by insulinactivated Protein Phosphatase Palmitoyl-CoA Phosphorylated, e.g., via AMP-activated Kinase when cellular stress or exercise depletes ATP. Dephosphorylated Polymer of Acetyl-CoA Carboxylase (active) Regulation of Acetyl-CoA Carboxylase The decreased production of malonyl-CoA prevents energy-utilizing fatty acid synthesis when cellular energy stores are depleted. (AMP is abundant only when ATP has been extensively dephosphorylated.) Phosphorylated protomer of Acetyl-CoA Carboxylase (inactive) Citrate Dephosphorylated, e.g., by insulinactivated Protein Phosphatase Palmitoyl-CoA Phosphorylated, e.g., via AMP-activated Kinase when cellular stress or exercise depletes ATP. Dephosphorylated Polymer of Acetyl-CoA Carboxylase (active) Regulation of Acetyl-CoA Carboxylase The antagonistic effect of insulin, produced when blood glucose is high, is attributed to activation of Protein Phosphatase. Phosphorylated protomer of Acetyl-CoA Carboxylase (inactive) Citrate Regulation of Acetyl-CoA Carboxylase by local metabolites: Dephosphorylated, e.g., by insulinactivated Protein Phosphatase Palmitoyl-CoA Phosphorylated, e.g., via AMP-activated Kinase when cellular stress or exercise depletes ATP. Dephosphorylated Polymer of Acetyl-CoA Carboxylase (active) Regulation of Acetyl-CoA Carboxylase Palmitoyl-CoA (product of Fatty Acid Synthase) promotes the inactive conformation, diminishing production of malonyl-CoA, the precursor of fatty acid synthesis. This is an example of feedback inhibition. Glucose-6-phosphatase glucose-6-P glucose Gluconeogenesis Glycolysis pyruvate fatty acids acetyl CoA Citrate allosterically activates AcetylCoA Carboxylase. ketone bodies cholesterol citrate oxaloacetate Krebs Cycle [Citrate] is high when there is adequate acetyl-CoA entering Krebs Cycle. Excess acetyl-CoA is then converted via malonyl-CoA to fatty acids for storage. Fatty acid synthesis from acetyl-CoA & malonyl-CoA occurs by a series of reactions that are: in bacteria catalyzed by 6 different enzymes plus a separate acyl carrier protein (ACP) in mammals catalyzed by individual domains of a very large polypeptide that includes an ACP domain. NADPH serves as electron donor in the two reactions involving substrate reduction. The NADPH is produced mainly by the Pentose Phosphate Pathway. Mammalian fatty acid synthase • A dimer of two polypeptides of 240 kDa each • Each polypeptide contains eight domains that represent the seven catalytic centres plus an integral acyl carrier protein (ACP) domain 4′ phosphopantetheine The structure of the mammalian Fatty Acid Synthase protein is summarized above KS = b-Ketoacyl Synthase (Condensing Enzyme)---(Cys) AT =Acyl transferase MT = Malonyl/Acetyl-CoA Transacylase DH = Dehydratase ER = Enoyl Reductase KR = b-Ketoacyl Reductase TE = Thioesterase ACP = Acyl Carrier Protein ---(Pant) 4. Reduction 5. Acyl transfer 3.Dehydration 2.Reduction 1.Condensation • Elongation of FA Carbon-chain – ER – Mitochondria • Synthesis of unsaturated FA – unsaturated FA :软油酸、Oleate、linoleate、 linolenate、arachidonic acid ( Essential FA ) – Essential FA:required for the growth of mammals and they must be obtained from food. Including linoleate、linolenate, arachidonic acid Regulation of FA synthesis – Dietary factors: carbohydrate promotes synthesis – Hormone factors insulin,“store hormone”,increase FA synthesis Glucagon ,“release hormon”,inhibit FA synthesis Important of polyunsaturated fatty acids---prostaglandins (PG)、 thromboxanes (TX)、 leukotrienes (LT) • Chemical structure and nomenclature of PG、 TX、 LT • Synthesis of PG、TX and LT • Physiological functions of PG、TX and LT O OH O O R1 R1 R1 R1 R2 R2 R2 R2 B A O C D OH O R1 R1 R1 O R2 R2 R2 OH O OH E G F COOH O R1 O R2 R2 O OH H H I COOH O CH 3 O OH Thromboxane A2 11 9 7 O 5 3 12 13 14 15 17 19 CH3 20 Leukotriene A4(LTA4) 1 COOH Synthesis of Triglycerides location:liver、adipose tissue and small intestinal materials:glucose、dietary fats pathway:Acylglycerol pathway diacylglycerol pathway Degradation of Triacylglycerols • Lipolysis • Glycerol Metabolism • β-Oxidation • Other oxydation modes of fatty acid • Formation and utilization of Ketone Bodies Lipolysis • Concept • Committed enzyme:hormone-sensitive triglyceride lipase (HSL) • Lipolysis hormones:adrenalin 、glucagon、 ACTH and TSH • Anti-lipolysis hormones:Insulin、PEGE2 and Nicotinic Acid PP i AD P HSL HSL (inactive) (active) Pi P Glycerol metabolism Experimental evidence for β-Oxidation of fatty acid ̼±½Ö¬Ëá ż ̼±½Ö¬Ëá Ææ CH 2CH 2CH 2CH 2CH 2COOH CH 2CH 2CH 2CH 2COOH CH 2CH 2CH 2COOH CH 2CH 2COOH CH 2COOH COOH O CH 2C NHCH 2COOH ÄòËá ±½ÒÒ ËáÑÜÉúÎï ) (±½ÒÒ O C NHCH 2COOH ÂíÄòËá (±½¼×ËáÑÜÉúÎï ) β-Oxidation of fatty acid • 概念:脂肪酸氧化从羧基端β-碳原子开始,每次 释放出一个二碳片段(acetyl-CoA) • Steps:Activation of FAenter into mitochondria β-oxidation TAC(Tricarboxylic acid cycle) Activation of fatty acid — Formation of Acyl-CoA • Location:cytosol O RC OH + HSCoA acyl-CoA Carnitine (Acyl-CoA) (Carnitine) Mitochondrion Carnitine acyltransferase Ⅰ CoAS H Carnitine acyltransferase Ⅱ CoAS H 限速酶 β-Oxidation of fatty acid • location:mitochondrial matrix • 过程:在脂肪酸β-氧化多酶复合体的催化下, 从脂酰基β碳原子开始,dehydrogenation 、加水 hydration、dehydrogenation 、thiolysis四步,生成一分子 比原来少两个碳原子的脂酰CoA(acyl-CoA)及一 分子乙酰CoA(acetyl-CoA) β α FAD (dehydrogenation) FADH H2 O (hydration) NAD+ (dehydrogenation) NADH CoASH H + (thiolysis) O Ö¬·¾Ëá RCH2CH2C Ö¬õ£CoA ºÏ ³Éø Ö¬õ£CoA OH ATP+HSCoA AMP+PPi O RCH2CH2C ¡« SCoA C O Ïß Á£Ìå ÄÚĤ Ö¬õ£CoA RCH2CH2C ¡« SCoA FAD 2¡« P Ö¬õ£CoAÍÑÇâø FADH2 H2O ºôÎü Á´ O ·´ ¦¤2£-Ï©Ö¬õ£CoA ¦Â ¦Á RCH CHC ¡« SCoA 2 ¦¤ £- Ï©Ö¬õ£CoA H2O Ë®»¯Ã¸ OH O ¦Â ¦Á L(+)¦Â£-ôÇÖ¬õ£CoA RCH CH2C ¡«+SCoA L(+)¦Â£- ôÇÖ¬õ£ NAD NADH+H+ CoAÍÑÇâø O O ¦Â ¦Á RC CH2C ¡« SCoA ¦Â£-ͪ Ö¬õ£CoA ¢Ú¼Ó Ë®(hydration) 3¡« P ºôÎü Á´ ¦Â£- ͪ Ö¬õ£CoA HSCoA Áò½âø O O Ö¬õ£CoA RC ¡« SCoA + CH3C ¡« SCoA (ÉÙÁ½ ¸ö̼Ô-×Ó) ¢ÙÍÑÇâ (dehydrogenation) H2O ¢ÛÍÑÇâ(dehydrogenation) ¢ÜÁò½â(thiolysis) ÒÒ õ£CoA 脂肪酸β-Oxidation要点 • 脂肪酸仅需活化一次(cytosol),消耗一个 ATP的两个高能键; • Acyl-CoA由carnitine运入线粒体,限速酶: CAT-Ⅰ; • β-Oxidation(mitochondrion): including dehydrogenation 、hydration 、dehydrogenation 、 thiolysis four repeated steps 脂肪酸氧化的能量生成 • 如软脂酸(C16): – 7次β-氧化,生成8分子乙酰CoA、7分子 FADH2及7分子NADH 即 12 ×8 +2×7+3 ×7=131分子ATP – 脂肪酸活化时消耗2个高能磷酸键 – 净生成131-2=129分子ATP n n • formula:12 × 2 +5 ×(2 -1) –2 • 能量利用率:51.6 ¡Á129 ¡Á100=68% 9791 Difference between synthesis and degradation of palmitic Acid difference synthesis degradation cytosol mitochondria ACP CoA Two carbonfragment reducing equivalents HCO3- and citrate Malonyl-CoA Acytel-CoA NADPH FAD、NAD+ needed Not needed Energy alteration Consume 7ATP+ 14NADPH Form 129ATP location Acyl carrier Difference Between Fatty Acid Synthesis And β-Oxidation Diffference Location Thioester linkage Two carbonfragment Electron carrier HCO3- and cytratre Energy alteration Synthesis β -Oxidation Cytoplasm Mitochondrion ACP CoA Malonyl-CoA Acetyl-CoA NADPH FADH、NADH needed Nod needed Consume 7ATP+ 14NADPH Form 129ATP Other oxydation modes of fatty acid • Oxydation of unsaturated FA • FA oxydation in peroxisomes • Oxydation of propionic acid Formation and utilization of Ketone Bodies • Ketone Bodies:Acetoacetate、 βHydroxybutyrate and Acetone • Ketogenesis • Utilization of Ketone Bodies • Physiology Significance of Ketogenesis • Regulation of Ketogenesis ketone bodies(KB) γ Acetoacetate β α β-hydroxybutyrate Acetone CoASH CoASH 限速酶 CoASH βα NAD+ CO2 NAD H H+ Utilization of Ketone Bodies HSCoA+ATP ÒÒ õ£ÒÒ õ£Áò¼¤Ã¸ AMP+PPi CH2COCH2COOH ÒÒ õ£ÒÒ Ëá CH3COCH2COSCoA ÒÒ õ£ÒÒ õ£CoAÁò½âø COOH CH2 COSCoA çúçêõ£CoAתÁòø CH2 COOH CH2 COOH HSCoA 2CH3COSCoA ±ûͪ CH2 TCAÑ-»· ÌÇÒìÉú ±ûͪ Ëᣨ»òÈéËᣩ ÌÇ Liver Blood Extrahepatic Tissues ① ② Urine ⑥ ③ Citric acid cycle ④ ⑤ Acetone Lungs ⑦ Citric acid cycle Major energy materials provided for tissues Glucose Red Blood Cell + Brain + Muscle Liver FFA KB + +(exercise) +(rest) + + + Concentration of energy materials of the blood in full of eating or hungry (mmol/L) Glucose β-Hydroxybutyrate Acetoacetate Full(of eating) Hungry(5-6 weeks) 5.0 4.49 0.02 6.67 1.17 Three Crucial Steps for Ketogenesis Regulation • Control of free fatty acid(FFA) mobilization from adipose tissue • The activity of carnitine acyltransferase (CAT-1) in liver,which determines the propotion of the fatty acid flux that is oxidized rather than esterified; • Partition of acetyl-CoA between the pathway of ketogenesis and the citric acid cycle 复习题 • 名词解释 – 1、脂肪的动员(lipolysis); – 2、激素敏感性甘油三酯脂肪酶(HSL); – 3、脂解激素; – 4、脂肪酸的β-氧化(β-oxidation); – 5、必需脂酸(essential fatty acid); – 6、酮体(ketone bodies) • 问答 – 1、简述胆汁酸盐的生理作用。 – 2、简述酮体生成的生理意义。 – 3、写出甘油异生为葡萄糖的过程。 – 4、一分子三软脂酰甘油彻底氧化成CO2 和 H2O,产生多少分子ATP?写出代谢途径的 全过程。 测试题 • 1、胆汁酸盐在 脂 类 消 化 中 主 要 作 用: A、 有 使 脂 肪 乳 化 的 作 用 B、 有 促 进 脂 肪 吸 收 的 作 用 C、 有 促 进 胰 脂 酶 活 性 的 作 用 D、 使 水 解 的 脂 类 呈 溶 解 状 态 E、 有 促 进 辅 脂 酶 活 性 的 作 用 (A、B) 测试题 • 2、参 与 脂 肪 酸 氧 化, 以 FAD 为 辅 基的酶催化: (D) A、 还 原 不 饱 和 脂 酰 CoA B、 β-羟 脂 酰 CoA 脱 氢 C、 脂 肪 酸 的 激 活 D、 脂 酰 CoA 脱 氢 E、 β-酮 脂 酰 还 原 测试题 • 3、一分子14 碳的肉豆蔻酸经β-氧化为乙酰CoA A、活化肉豆蔻酸消耗2 分子高能磷酸键 B、肉豆蔻酸需经7次β-氧化才生成7分子乙酰CoA C、生成6 分子FADH2 和6 分子NADH + H+ D、肉毒碱脂酰转移酶Ⅱ是豆蔻酸β-氧化的关键酶 (A、C) 测试题 • 4、对脂酸分解代谢而言下列哪一种叙述是错误的? A、存在于胞液 B、生成CH3CO~CoA C、β氧化的活性形式是RCH2CH2CH2CO~CoA D、一种中间物是RCH2CHOHCH2CO~CoA E、反应进行时NAD+→NADH (A) 测试题 • 5、彻底氧化1分子硬脂酰CoA(18:0) 共需消耗多少分子O2? A、23 B、26 C、30 D、16 E、32 (B) 测试题 • 6、有关酮体的正确叙述是:(A、B、C、D) A、酮体包括丙酮、乙酰乙酸和β-羟丁酸 B、酮体可以从尿中排出 C、饥饿可引起酮体增加 D、糖尿病可引起酮体增加 测试题 • 7、能将酮体氧化成CO2和H2O的组织是 A、心肌 B、红细胞 C、脑 D、肝 (A、C) 本小节要求 •掌握软脂酸合成的原料、限速酶;了解软 脂酸合成过程及合成的调节。 •熟悉前列腺素、血栓噁烷及白三烯合成的 原料。 Section II Phospholipid Metabolism Classification of Phospholipids •phosphoglyceride Phosphatidylcholine (PC) Phosphatidylethanolamine (PE) Phosphatidylserine (PS) Phosphatidylglycerol (PG) Diphosphatidylglycerol (DPG) phosphatidyl inositol(PI) •Sphingomyelin Chemical Structure of Phosphoglyceride O O R2 C CH 2 O O CH CH 2 O C R1 O P O X O- Most phospholipids have a saturated fatty acid on C-1 and an unsaturated fatty acid (Arachidonic Acid )on C2 of the glycerol backbone. Structure of Phospholipid Classification of phosphoglyceride-1 • X-OH X- name Classification of phosphoglyceride-2 X-OH X- name Glycerophospholipid synthesis • Site: liver,kidney,intestine – endoplasmic reticulum, ER • Sources:FA,glycerol,phosphate,nitrogenous base (choline,ethanolamine,serine,inostol,etc), ATP, CTP • CDP- nitrogenous base • CDP-diacylglycerol CDP-choline与CDP- diacylglycerol Diacylglycerol Pathway O CH 2OH ÆÏÌÑÌÇ HO CH 2O תõ£Ã¸ HO CH CH 2O P R1COCoA 3-Á×Ëá¸ÊÓÍ R1 CH CH 2O CoA C P 1-Ö¬õ£-3-Á×Ëá¸ÊÓÍ O O תõ£Ã¸ CH 2O C R1 Á×Ö¬ËáÁ×Ëáø R2 C O CH R2COCoA CoA CH 2O Pi P Á×Ö¬Ëá O O O CH 2O C R1 תõ£Ã¸ R1 C R2 C O CH CH 2OH 1,2-¸ÊÓͶþõ¥ £¨ DG£© O R3COCoA CoA CH 2 O O CH CH 2 O ¸ÊÓÍÈýõ¥ £¨ TG£© C R2 O C R3 Diacylglycerol Pathway—PE, PC CDP- Diacylglycerol Pathway—PI、PS、DPG Synthesis of CDP- nitrogenous base Phosphoglycerol degradation Synthesis and Degradation of Sphingomyelin •Site: brain---ER •Souces:palmitoyl-CoA, Serine,NADPH+H,FAD •Pathway: Degradation of Sphingomyelin • Sphingomyelinase (PLC ) -----Defects in the enzymes result in genetic diseases such as NiemannPick disease 本小节要求 • 熟悉常见甘油磷脂的名称、组成、合成 原料及CTP的作用;了解各种磷脂酶作 用的部位。 作业题 • 1、以下两题任选一题(必做) – 吃的多动的少容易长胖,试从生化角度分析其 原因。 – 从生化角度谈谈你对减肥的认识。 • 2、请用代谢图将糖类与脂类的合成与分解 代谢联系起来。(必做) • 3、简述甘油磷脂合成的原料及辅助因子。 • 4、葡萄糖如何为脂酸合成提供原料? 测试题 • 彻底氧化1分子硬脂酰CoA(18:0)共 需消耗多少分子O2? A、23 B、26 C、30 D、16 E、32 (B) 复习题 • 1、关于脂酸生物合成的途径正确的是: A、不需乙酰CoA B、中间产物是丙二酰CoA C、在线粒体内进行 D、以NADH为还原剂 E、最终产物为十碳以下脂酸 (B) 复习题 • 2、脂酸合成所需的乙酰CoA由 A、胞浆直接提供 B、线粒体合成并转化为柠檬酸转运 到胞浆 C、胞浆的乙酰肉毒碱提供 D、线粒体合成,以乙酰CoA的形式 E、胞浆的乙酰磷酸提供 (B) 复习题 • 3、下列磷脂中哪一个含有胆碱? A、脑磷脂 B、卵磷脂 C、磷脂酸 D、心磷脂 (B) 复习题 • 4、合成卵磷脂时所需的活性胆碱是 A、TDP-胆碱 B、ADP-胆碱 C、UDP-胆碱 D、GDP-胆碱 E、CDP-胆碱 (E) Section IV Cholesterol(Ch) Metabolism Cholesterol Structure RCOO HO Cholesterol(Ch) Cholesterol Ester(CE) 环戊烷多氢菲 Roles of Cholesterol • Membrane component • Steroid synthesis • Bile acid/salt precursor • Vitamin D precursor Sources of Cholesterol Diet De novo synthesis Cholesterol synthesized in extrahepatic tissues Liver cholesterol pool Secretion of HDL and VLDL Free cholesterol In bile Conversion to bile salts/acids Dietary Cholesterol • • • • Animal products – eggs Absorb about 50% Increase intake = decreased absorption Excrete – 1 g/day (bile acids) Dietary Cholesterol • • • • Assume 400 mg intake / day 200 mg is absorbed 1000 mg is excreted 800 mg from de novo synthesis Lowering cholesterol in diet has very little effect on blood cholesterol !!! Cholesterol Synthesis • 80 % in liver, ~10% intestine, ~5% skin Occurs in cytosol • Requires 18Acetyl-CoA、16NADPH、36ATP • Similar to ketogenic pathway Highly regulated Cholesterol Synthesis-1 2 CH3COSCoA 硫解酶 CH3COCH2COSCoA CH3COSCoA HMGCoA合成酶 CH3 HOOCCH2C CH2COSCoA HMGCoA OH NADPH+H 限速酶 HMGCoA还原酶 CoA + NADP+ CH3 HOOCCH2C CH2CH2OH OH 甲羟戊酸 (MVA,C6 ) Cholesterol Synthesis -2 OH OH MVA P H OCH2CH2CCH2COOH P OCH2CH2CCH2COOH CH3 CH3 P P OCH2CH2C CH2 异戊烯焦磷酸 (IPP,C5) CH3 P 胆固醇(C2 7) ? HO P OCH2CH (3×) P P 头 羊毛固醇 头 ( C3 0) 头 头 鲨烯(C3 0) C CH3 二甲丙烯焦磷酸 (DPP,C5) CH3 焦磷酸法尼酯 (FPP,C15) O O P P O P P Cholesterol Synthesis Summary HMG CoA reductase Phosphorylation HMG CoA reductase – OH (active) HMG CoA reductase – P (inactive) AMP-Activated Protein Kinase (high activity) (+) phosphatase AMP (+) (+) Insulin kinase AMP-Activated Protein Kinase (low activity) increase cAMP Glucagon/epi Conversion of Cholesterol • Bile acid: liver (2/5) • Steroids: adrenal cortex, testicle,ovary • Vitamin D: skin(7-dehydrocholeterol and Vitamin D3) 本小节要求 • 掌握胆固醇结构特点、合成原料、限速酶; 了解其合成过程;熟悉胆固醇的转化产物。 • 熟悉各种血脂的分类、组成特点;掌握其 功能;了解载脂蛋白的功能; Section IV Metabolism of Plasma Lipoproteins •Plasma lipids •Plasma lipoproteins •Apolipoproteins • Metabolism of Plasma Lipoproteins • Medical implications Plasma Lipids ----Lipids in plasma – TG:100mg/dl – PL: 200mg /dl lecithins 70% nerve sphingomyelin 20% cephalin 10% – Ch and CE:200mg /dl Ch:55mg /dl; CE:145mg /dl – FFA:15mg /dl Origin of plasma lipids: Exogenous: dietary lipids Endogenous: synthetized by liver, adipose tissue and other tissues Plasma Lipoproteins Classes: – electrophoresis:CM (Chylomicron) 、β、 pro-β、α – ultracentrifugation: CM、VLDL(very low density lipoprotein)、LDL、HDL Compositions of plasma lipoproteins CM VLDL 0.950 LDL 1.006 1.019 1.063 IDL CM VLDL d=80-500nm Pr=0.5-2% TG=80-95% PL=5-7% C=1-4% apoA apoB48 apoC HDL 1.125 HDL2 LDL 1.210 HDL3 HDL d=25-80 d=20-25 d=7.5-10 Pr=5-10% Pr=20-25% TG=10% PL=20% C=45-50% apoB100 apoE Pr=50% TG=5% PL=25% C=20% TG=50-70% PL=15% C=15% apoB100 apoC apoE apoAⅠ apoAⅡ apoC apoE apoD Apolipoproteins (apo) -1 Type Association Function B48 Chylomicron Carry cholesterol esters Lacks LDL recpt binding domain B100 VLDL,IDL,LDL Binds LDL recpt. C-II Chyl. VLDL, IDL, HDL Activates LPL C-III Chyl. VLDL, IDL, HDL Inhibits LPL E Chyl. Remnant, VLDL, IDL HDL Binds LDL recpt A-1 HDL/Chylomicron AⅡ AⅣ HDL HDL,CM LCAT activator (lecithin:cholesterol acyltransferase) HL(+);稳定HDL LPL(+) Apolipoprotein (apo) -2 Type Association Function D HDL transports CE J HDL binds and transports lipids CETP HDL transports CE,TG PTP HDL transports PL Major Enzymes for Lipoprotein Metabolism • lipoprotein lipase,LPL • hepatic lipase,HL • lecithin: cholesterol acyltransferase, LCAT • acyl-CoA: cholesterol acyltransferase, ACAT • lipoprotein lipase,LPL O R2 C O O CH2 O C R1 C H O CH2 O C R3 TG DG FFA • hepatic lipase,HP glycerol MG FFA FFA lecithin: cholesterol acyltransferase, LCAT O R2 C O O CH2 O C R1 C H O CH3 CH2 O P O CH2 CH2 N+ CH3 CH3 OH O HO OH LCAT R2COO HO CH2 O C R1 C H O CH2 O P O CH2 CH2 CH3 N+ CH3 CH3 acyl-CoA: cholesterol acyltransferase,ACAT RCOSCoA CoA ACAT HO RC O O CM Metabolism 食物 TG 新生CM apoCⅡ激活LPL B48 TG C,PL A 成熟CM 小肠 apoC,E A TG C,PL C E C A PL C E HDL Ch 肝 FFA B48 脂蛋白脂肪酶 apoA,C B48 apoE 受体 FFA TG C,PL E CM残粒 肝外组织 甘油 VLDL Metabolism 新生 VLDL apoCⅡ激活LPL B100 TG C,PL 成熟 VLDL apoC,E C A PL C E FFA Ch 肝 C HDL apoE 受体 B100 TG C,PL 肝外组织 E 脂蛋白脂肪酶 apoC apoE FFA B100 B100 LDL受体 LPL C LDL LDL受体 溶酶体 HL TG C,PL E IDL (VLDL 残粒) 肝外组织 甘油 CE LDL Metabolism 核 LDL HMGC oA 还原酶 LDL受体 溶酶体 ACAT Ch CE 氨基酸 LDL 结合 内吞 溶酶体 水解 游离 胆固醇 细胞膜 (- ) HMGCoA还原酶 (- ) 胆固醇合成 (+) ACAT (Ch CE) (- ) LDL 受体 (- ) LDL摄取 HDL Metabolism 合成胆汁酸 或从胆汁排出? 肝 小肠 Ch pL 新生HDL LDL 受体 HDL 受体 CE LDL LCA T LCA T CET P CE HDL2 CM 残粒 IDL CE PL apo AⅠ apo AⅡ LPL 肝外组织 HDL3 apo C apo E CM VLDL Ch 组织 Ch Function of plasma lipoproteins • CM:Transport dietary from intestine to liver (exogenous) • VLDL: Transport lipids from liver to peripheral tissues (endogenous • LDL:endogenous Cholesterol transport • HDL:reverse Cholesterol transport Clinical importance for disease Hypertriglyceridemia and CHD Risk: Associated Abnormalities Accumulation of chylomicron remnants Accumulation of VLDL remnants Generation of small, dense LDL Association with low HDL Increased coagulability - plasminogen activator inhibitor (PAI-1) - factor VIIc - Activation of prothrombin to thrombin Genetic Disease •LPL Deficiency •LDL receptor Deficiency 复习题 • 一、名词解释 1、血脂;2、血浆脂蛋白;3、载脂蛋白 • 二、问答 1、简述胆固醇的转化产物。 2、试述血浆脂蛋白的分类(电泳法、超 速离心法)、合成部位及功能。