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Metabolism of Lipids Haibin Tian [email protected] Fatty liver Obesity Lipid metabolism disorder Hyperlipoidemia Arteriosclerosis Contents Concept, classification and structure of lipid Metabolism: Decomposition and biosynthesis The factors regulating lipid metabolism Section 1 Introduction of lipid Classfication and structure Distribution and function Digestion and absorption 1. Classfication and structure Lipids are substances that are insoluble in water but soluble in organic solvents. Fat (Triacylglycerol) Glycerophospholipids Phospholipids Lipid Sphingophospholipids Glycolipid lipoid Cholesterol Cholesteryl ester Fat Fat:Triacylglycerols (TAG), esters of fatty acids with glycerol Structure of triacylglycerol Glycerol has three hydroxyl groups and can form esters with three fatty acid. Fatty acids in TG are not always identical O Glycerol FA O FA H3C (CH2)n C FA H2 C O O CH H2 C C (CH2)m CH3 O O C (CH2)k CH3 Fatty acid: Fatty acids are carboxylic acids with hydrocarbon chains and carboxylic group The predominate fatty acid residues in plants and animals are C16 and C18 Common fatty acid Saturated fatty acid Unsaturated fatty acid Unsaturated fatty acid nomenclature △nomenclature, Indicating the number and position of double bonds counting from carboxylic group ω or n nomenclature, Indicating the number and position of double bonds counting from methyl group 15 12 9 △ 20:4 △5C,8C,11C,14C 20:4 ω 6C,9C,12C,15C Essential Fatty Acids(EFA): Some fatty acids that are necessary for human nutrition, but can’t synthesis in the body, must obtain from food . Including: (18:2) (18:3) Lipoid Lipoid includes phospholipids、 glycolipids、 cholesterol and cholesteryl ester Phospholipids: Lipids containing fatty acids and a phosphoric acid residue. Glycolipids: lipids containing carbohydrate Cholesterol: Forming ester by hydroxyl group Phospholipids Glycerophospholipids O O H2C H3C (CH2)n C O O CH H2C C (CH2)m CH3 O O P O X OH X = Choline、Ethanolamine、 serine 、 myoinositol 、 Phosphatidylglycerol Sphingophospholipids Amido bond Creamide X = Choline、Ethanolamine、 Cholesteryl ester Cholesterol FA Cholesterol Classfication and structure Fat (Triacylglycerols) Glycerophospholipids Phospholipids Lipid Sphingophospholipids Glycolipid lipoid Cholesterol Cholesteryl ester 2. Lipid distribution and function Fat:Exists with small oil drips in the cytoplasm of adipocytes in vertebrates Fat is also called as variable fat lipoid: Structure components of biomembranes lipoid is also called as fixed lipid Functions of fat 1) Energy storage 2) Prevent body from heat lose Functions of lipoid Structure components of biomembranes Material for steroid-hormones, bile acid, and Vitamin A、D、E、K 3. Digestion and absorption of Lipids The site of digestion: duodenum, small intestine Condition: 1. bile salts (emulsification) 2. lipolytic enzymes Pancreatic lipase Phospholipase A2 Cholesteryl esterase Process of digestion : bile salts Food lipids particles small pancreatic lipase( colipase, ) triglyceride 2monoacylglycerol + 2FFA phospholipase A2 phospholipid lysophosphatide + FFA Emulsification Bile acts to some extent as a surfactant, helping to emulsify the fats in the food. Bile salt anions have a hydrophilic side and a hydrophobic side, and therefore tend to aggregate around droplets of fat (triglycerides and phospholipids) to form micelles, with the hydrophobic sides towards the fat and hydrophilic towards the outside. Process of digestion : bile salts Food lipids particles small pancreatic lipase( colipase, ) 2-单酰甘油 triglyceride 2monoacylglycerol + 2FFA 溶血磷 phospholipase A2 脂 phospholipid lysophosphatide + FFA Colipase Duodenum pancreatic acini Proenzyme Trypsin Colipase Pentapeptide Binding pancreatic lipase Trigger lipase activity Process of digestion : bile salts Food lipids particles small pancreatic lipase( colipase ) triglyceride 2monoacylglycerol + 2FFA phospholipase A2 phospholipid lysophosphatide + FFA Absorption of lipids: Medium(6-10C) and short chain (2-4C) triglyceride Emulsification by bile salts Intestine mucosal cells Degradated by lipase FFA and glycerol portal vein transport blood circulation epithelial cells (to Long chain fatty acids (1226C)+monoacylglycerol synthesize TG) epithelial cells (to synthesize CE) cholesterol + FFA epithelial cells (to synthesize PL) lysophosphatide + FFA TG、CE、PL blood circulation lymphatic system + Apo(载脂蛋白) (chylomicron, CM,) Contents of lipid metabolism Concept, Classfication and Structure of Lipids Degradation and Biosynthesis of Lipids Factors Regulating Lipid Metabolism Section 2. Fat metabolism 1. Fat mobilization and hydrolysis 2. Fatty acid β-oxidation 3. Ketone body formation 4. Fat synthesis Fatty acid and glycerol synthesis 1. Fat mobilization and hydrolysis Fat mobilization (Lipolysis): The TG stored in the adipocytes are hydrolyzed by hormone-sensitive triacylglycerol lipase (HSL), produce free fatty acids (FFA) and glycerol, which are released into the blood, these process is called as fat mobilization. Process: TG lipase TG DG lipase DG FFA Glycerol FA FA FA MG lipase MG FFA glycerol FFA TG------triacylglycerol DG------diacylglycerol MG-----monoacylglycerol Lipase Hormone-sensitive lipase (HSL) HSL is expressed in all the tissues, but mainly in fat tissue HSL can also act on Cholesteryl ester Pancreatic lipase : Digestive tract Lysosomal lipase : Lysosome Lipoprotein lipase :Blood Hepatic lipase :Liver Regulation of HSL by hormone Lipolytic hormones : stimulate TG hydrolysis Glucagons Adrenocorticotropic hormone (ATCH) Epinephrine Norepinephrine Anti-lipolytic hormones: inhibit TG hydrolysis Insulin Regulation of HSL by hormone Lipolysis is activated when we are in hungry and excited state Section 2. Fat metabolism 1. Fat mobilization and hydrolysis 2. Fatty acid β-oxidation 3. Ketone body formation 4. Fat synthesis Fatty acid and glycerol synthesis 2. Beta-Oxidation of fatty acids Fatty acids show a lower solubility in water and are combined with serum albumin when transferred in plasma Fatty acids are oxidized to acetyl-CoA in all tissues except for brain and erythrocyte Fatty acid oxidation was found to occur in mitochondria FAs are the major energy source of human of the biologically available energy in TGs: ~ 95 % in their 3 long-chain FA ~ 5% in their glycerol Step 1 Fatty acid’s activation On the outer membrane of mitochondria Fatty acids are converted to fatty acyl-CoA (a high energy compound) via a fatty-acyl-adenylate intermediate by the action of fatty acyl-CoA synthetase (also called fatty acid thiokinase). Pyrophosphate is hydrolyzed by inorganic pyrophosphatase Fatty 脂 肪acid 酸 ATP O RCH2CH 2C~SCoA Acyl-CoA 脂 酰~SCoA AMP +PPi = = O RCH2CH2C-OH + CoA-SH Acyl CoA synthetase Step 2 Activated fatty acids are carried into the matrix by Carnitine Mitochondria consists of outer and inner membranes Permeability of outer membrane allows passage of molecules of 5000 Daltons or less, semipermeability of inner membrane allows passage of only small molecules Carnitine -Acylcarnitine 3-hydroxy-4-(trimethylammonio)butyrate Transport of Acyl-CoA into mitochondria : Carnitine acyltransferase I Carnitine acyltransferase II Carnitine/acylcarnitine transporter Carnitine acyltransferase I Transport of Acyl-CoA into mitochondria is the ratelimiting step for oxidation of fatty acids Carnitine acyltransferase I is the rate-limiting enzyme Malonyl-CoA is allosteric inhibitor of carnitine acyltransferase I. Insulin inhibits oxidation of fatty acids by promoting malonyl-CoA synthesis Insulin activate Carboxylase Acetyl-CoA Malonyl-CoA Carnitine acyltransferase I Supplementary Information: Carnitine – losing weight? Diet pills on the market No strong evidence shows carnitine can reduce body weight Reasons Rate-limiting enzyme? Food? Energy demand? Step3. β-oxidation of Acyl CoA Early labeling experiments (1904): fatty acids are degraded by sequential removal of two-carbon units Franz Knoop’s labeling Experiments (1904): fatty acids are degraded by oxidation at the βcarbon, i.e., β-oxidation β-oxidation of Acyl-CoA 1. Dehydrogenation 2. Hydration 3. Dehydrogenation 4. Thiolysis Dehydrogenation Fatty acyl-CoA Enoyl-CoA Hydration enoyl-CoA β -hydroxylacyl-CoA Dehydrogenation b -hydroxylacyl-CoA ketoacyl-CoA Thiolysis ketoacyl-CoA thiolase Fatty acyl-CoA Four steps in one cycle : = O RCH2CH2C~SCoA Dehydrogenation FAD FADH2 acyl CoA dehydrogenase α O = β RCH=CHC~SCoA Hydration H2 O ⊿2-- enoyl-CoA hydratase Dehydrogenation α = O RCHOHCH2C~SCoA β L(+)- β-hydroxyacyl CoA dehydrogenase NAD+ NADH+H+ = β α O RCOCH2C~SCoA Thiolysis β-ketoacyl-CoA CoA-SH = O RC~SCoA + CH3CO~SCoA Energy calculate (ATP amount) 1 C16 1 molecule of palmitoyl-CoA 2 (16C) will pass through the 3 sequence 7 times, eventually be oxidized to produce: 8 Acetyl CoAs 7 NADHs 7 FADH2s 4 5 6 7 Acetyl -CoA 7× FADH2: 7×1.5 7×NADH2: 7×2.5 8×acetyl CoA: 8×10 Activation of FA consuming 2ATP Totally: (7×1.5)+(7×2.5)+(8×10)-2 =106 β-oxidation of the odd-chain fatty acids β-oxidation of the odd-chain fatty acids, which are relatively rare in nature, produce a propionyl CoA in the final round. Propionyl- CoA can be converted to via a carboxylation, an epimerization and an intramolecular group shifting. β-oxidation of unsaturated fatty acids Accessory enzymes are required for dealing with fatty acids having double bonds. Basically the cis double bonds in unsaturated fatty acids have to be converted to trans double bonds to allow beta oxidation to continue. Beta oxidation of unsaturated fatty acids Isomerase (异构酶) and a reductase (还原酶) are needed for oxidizing a unsaturated fatty acid. Significance of β-oxidation : Provide energy: The oxidation of fatty acids yields significantly more energy per carbon atom than does the oxidation of carbohydrates. Provide acetyl CoA ( then into TCA cycle, ketone bodies, cholesterol and FA); Fat metabolism (脂肪代谢) 1. Fat mobilization and hydrolysis 脂肪的动员和水解 2. Fatty acid β-oxidation 脂肪酸β-氧化 3. Ketone body formation 酮体产生 4. Fatty acid synthesis 脂肪酸合成 5. Fat synthesis 脂肪合成 3. Ketone body formation and utilization Concept: The special intermediate products of β-oxidation of fatty acids in liver , including acetoacetate (30%), βhydroxybutyrate (70%) , acetone Place produced : Generated in liver (mitochondria), used by other tissues Precursor: Acetyl-CoA ( from β- oxidation of FA) Ketone body formation Thiolase : Two acetyl-CoA formed in βoxidation condense with one another to form acetoacetyl-CoA by a reversal of the thiolase HMG-CoA synthase Condensation of acetoacetyl-CoA with another molecule of acetylCoA by 3-hydroxy-3methylglutaryl-CoA synthase forms HMG-CoA HMG-CoA lyase : catalyze the formation of acetoacetate β-hydroxybutyrate dehydrogenase (β-羟丁酸脱氢酶): Reduce acetoacetate to form βhydroxybutyrate Acetoacetate can be transformed into acetone Utilization of ketone bodies (heart, kidney, brain, skeletal muscles) OH CH3CHCH2COOH Succinyl CoA D( ) β 羟丁酸 β-hydroxybutyrate transsulfurase NAD+ NADH+H+ CoASH+ATP = = PPi+AMP Succinyl CoA succinate CoASH thiokinase 硫激酶 = = O O CH3CCH2COH 乙酰乙酸 acetoacetate O O CH3CCH2CSCoA (乙酰乙酰 CoACoA ) Acetoacetyl = O 2 CH3CSCoA Acetoacetyl CoA thiolase 硫解酶 Physiological significance of ketogenesis 1) ketone bodies are normal physiological responses to carbohydrate shortages, HMG-CoA synthase only exists in liver, and Succinyl-CoA transsulfurase exists in extrahepatic tissue. 2)Under starveling condition, ketogenesis is increased. This allows the heart ,the brain and skeletal muscles use ketone bodies as energy. 3) The normal concentration of ketone bodies in blood is very low.﹤0.5mmol/L. Under some pathological condition (such as diabetes), the synthesis is faster than utilization, so the concentration of ketone bodies in the blood is high, (up to 20mmol/L) which is called as ketonemia ( 酮 血 症 ), and they may be excreted in the urine, which is called as ketonuria (酮 尿症). 5) Ketone bodies are acidic compounds, the accumulate of them in the blood will cause ketoacidosis (酮症酸 中毒). nausea and vomiting of pregnancy, NVP Summary Ketone bodies:acetoacetate, β-hydroxybutyrate , acetone Formation and Usage:Formation in liver and usage in Liver extrahepatic tissue Extrahepatic Acetyl-CoA Acetoacetate β-hydroxybutyrate Acetone tissue Acetoacetate β-hydroxybutyrate Acetone Acetyl-CoA The oxidation of glycerol Entry of glycerol into the glycolytic Pathway, Gluconeogenesis and TG synthesis pathway Abundant of glycerol kinase in liver, kidney and mucous membrane of small intestine 1. Which two fatty acids are essential fatty acids? A palmitoleic acid; B oleic acid; C linoleic acid; D linolenic acid Which one is anti-lipolytic hormone? A glucagon; B epinephrine; C norepinephrine; D insulin Fat metabolism 1. Fat mobilization and hydrolysis 2. Fatty acid β-oxidation 3. Ketone body formation 4. Fat synthesis Glycerol-phosphate, fatty acid 4. Biosynthesis of triacylglycerols Location: All tissues, fat, intestine and liver are most active tissues. Material: glycerol ( glycerol 3-phosphate) FA (acyl CoA) (1) The formation of glycerol 3-phosphate 1) In intestine, liver and adipose tissues: Glycolysis glucose dehydrogenase glycerol 3dihydroxyacetone phosphate phosphate 2) In liver and intestine: glycerol phosphorylation glycerol 3-phosphate glycerokinase (2) FA Biosynthesis FA synthesis is not the reverse reaction of FA degradation: by different pathways, different enzymes, and in different part of cells. Site: Cytosol of liver, adipose tissue, kidney, brain and breast. Materials Acetyl-CoA provides the first two carbons, which is elongated by sequential addition of two-carbon units donated from malonyl-CoA, NADPH is the reductant. ATP provides energy. Acetyl CoA (Come mostly from glucose) NADPH (Pentose phosphate pathway , or produced by malate enzyme ATP Carbonate (HCO3-) Step1. Transport of the acetyl groups from the mitochondrion into the cytosol The acetyl-CoAs are shuttled into the cytosol in the form of citrate via the citrate transporter of the inner membrane. Citric acid transport pathways Acetyl-CoA is regenerated by the action of ATPdependent citrate lyase in the cytosol. Oxaloacetate is shuttled back into the mitochondria as malate (苹果酸) or pyruvate (丙酮酸) 乙酰CoA Step 2. Malonyl-CoA formation 丙二酰CoA合成 acetyl-CoA carboxylase Acetyl-CoA carboxylase The enzyme has three functional parts: a biotin carrier protein; an ATP-dependent biotin carboxylase; and a transcarboxylase Acetyl-CoA carboxylase catalyzes the two-step carboxylation reaction of acetyl-CoA on two active sites. Regulation on acetyl-CoA carboxylase Acetyl-CoA carboxylase has two forms:inactive dimer (二聚体)and active polymeric (多聚体)form Acetyl-CoA carboxylase is regulated by phoshporylation Glucagon and epinephrine promote phosphorylation and depolymerization of the enzyme (inactive) Insulin induces the synthesis and dephosphorylation of the enzyme (active) Allosteric regulation :citrate promotes polymerization, long chain fatty acid promote depolymerization Step 3. Fatty acid synthesis Fatty acid synthase complex in mammals Multienzyme (多功 能酶)polypeptide complex containing seven enzyme activities 250 kDa dimer ACP:acyl carrier protein, no enzyme activity KS: β-ketoacyl-ACP synthase酮脂酰合酶 MT:malonyl-transacylase 丙二酰基转移酶 KR: β -ketobutyryl-ACP reductase酮脂酰还原酶 DH: β -hydroxybutyryl-ACP dehydratase脱水酶 ER: enoyl-ACP reductase烯脂酰还原酶 AT: acetyl-CoA-ACP transacetylase乙酰基转移酶 TE: acyl-CoA thioesterase 硫脂酶 ACP: acyl carrier protein Hydrosulfuryl group Process of Palmitic Acid synthesis Acetyl-CoA combines with –SH group or KS catalyzed by acetyl β-ketoacyl-ACP synthase transacylase (转酰基酶) Malonyl-CoA combines with the adjacent-SH group of ACP of the other monomer (单体) β-ketoacyl-ACP synthase (KS) β-酮脂酰ACP合成酶 β-ketobutyryl-ACP β-酮丁酰ACP Step 1: condensation (AT,KS,MT,ACP) Step 2: β-ketobutyryl-ACP is reduced to D- β -hydroxybutyryl-ACP, using NADPH and the β -ketoacyl-ACP reductase (KR) Step 3: A water molecule is removed from b-hydroxybutyryl-ACP to produce trans-2-butenoyl-ACP in a reaction catalyzed by b-hydroxyacyl-ACP dehydratase (HD) 脱水酶 Step 4: The carbon-carbon double bond in trans-2-butenoyl-ACP is reduced 丁烯酰 by NAPDH in a reaction catalyzed by enoyl-ACP reductase (ER), producing a saturated acyl on ACP (butyryl-ACP) 丁酰-ACP acyl-CoA thioesterase The overall process of palmitate synthesis Fatty acids are synthesized by a repeating fourstep reaction sequence Condensation、Reduction、Dehydration、Reduction Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H+ →Palmitate + 7 CO2 + 8 CoA + 14 NADP+ + 6 H2O Synthesis of polyunsaturated FA In humans: There are Δ4、Δ5、Δ8、Δ9 desaturase, can produce palmitoleic acid (16:1 Δ9) and oleic acid (18:1 Δ9) from palmitate and stearate But there are no desaturases in human can produce double bonds beyond 10 carbon position. Palmitate is the Precursor for the biosynthesis of other fatty acids 5. Process for synthesis of TG: Monoacylglycerol (MG) pathway (intestine) Diacylglycerol (DG) pathway (liver, adipose) (1) monoacylglycerol pathway (In intestine) ① Acyl CoA synthetase CoA-SH + RCOOH ATP AMP PPi RCOCoA H2O ② = monoacylglycerol CoA = R2COCoA O CH2O-C-R2 Acyl CoA O transferase CHO-C-R1 O R3COCoA CoA CH2O-C-R3 = Acyl CoA transferase = CH2OH = = CH2OH O CHO-C-R1 O CH2O-C-R2 O CHO-C-R1 CH2OH 1,2-diacylglycerol triacylglycerol (2) Diacylglycerol pathway:liver , adipose O CH2O-C-R1 = CH2OH Acyl CoA transferase CHOH CH2O- Pi Glycerol 3 - 磷酸甘油 3-phosphate R1COCoA CHOH CoA CH2O- Pi R2COCoA = Pi O CH2O-C-R3 = Phosphatidate 磷脂酸 磷脂酸 = CH2O- Pi Acyl CoA transferase O CHO-C-R2 = = O CH2O-C-R1 O CHO-C-R2 = = O CH2O-C-R1 phosphatidase CoA 溶血磷脂 Lysophosphatidate 1-酯酰-3 - 磷酸甘油 O CH2O-C-R1 O CHO-C-R2 Acyl CoA transferase CH2OH R3COCoA 1,2-甘油二酯 Diacylglycerol Materials:acyl-CoA and provided by glucose CoA 甘油三酯 Triacylglycerol glycerol 3-phosphate, Regulation of triacylglycerol metabolism Hormone-sensitive triglyceride lipase Carnitine acyltransferase Ⅰ Acetyl CoA carboxylase (ACC) Section 3. Metabolism of Phospholipid Phospholipids (PL) lipoid cholesterol and cholesteryl ester glycolipids Concept of Phospholipid: A group of lipids containing phosphate present in all cells as well as in the plasma. Classification: glycerophospholipid→having glycerol 甘 油 鞘 氨 醇 FA FA Pi X sphingosine glycerol Sphingolipids → having sphingosine FA Pi X 1.The metabolism of glycerophospholipid Structure: O O CH2O-C-R1 R2C-O-CH O CH2O-P-OX Substitute group OH function: The basic structure of biomembrane Major classifications of glycerophospholipid choline Phosphatidylcholine (PC) lecithin Phosphatidylethanolamine (PE) cephaline serine Phosphatidylserine (PS) ethanolamine inositol Phosphatidylinositol (PI) Phosphatidylglycerol (PG) Glycerol Diphosphatidylglycerol (DPG) Cardiolipin 乙脑—磷脂酰乙醇胺 (脑磷脂) 二心—二磷脂酰甘油 (心磷脂) 暖壶的胆—磷脂酰胆碱 (卵磷 2. Metabolism of Phospholipid Synthesis of glycerophospholipids Degradation of glycerophospholipids (1) Synthesis of glycerophospholipids ① synthesis site: Tissue: all tissue of body, most active places are liver, kidney. Cell site: endoplasmic reticulum (ER) ② Precursor and cofactor : glycerol a. FA : From carbohydrate (glucose metabolism) poly unsaturated fatty acid from plant oil b. Glycerol: From TG degraded c. Choline, ethanolamine, Serine, Inositols e. ATP, CTP 甘 油 FA FA Pi X ③ process of synthesis A. Diacylglycerol (DAG ) -pathway for lecithin and Cephalin (卵磷脂与脑磷脂) glucose Glycerol-3-phosphate Phosphotidic acid Diacylglycerol serine CDPethanolamine Phosphatedyl ethanolamine Cephalin CDP-choline Phosphatedyl choline lecithin Acyl-CoA triacylglycerol CO2 Serine HOCH2-CH-COOH NH2 ethanolamine Choline +CH3 HOCH2CH2N+(CH3)3 HOCH2CH2NH2 ATP ATP ADP ADP P OCH2CH2N+(CH3)3 P OCH2CH2NH2 CTP CTP PPi PPi CDP-OCH2CH2NH2 CDP-OCH2CH2N+(CH3)3 DG Cephalin lecithin B. CDP-DAG pathway O O CH2O-C-R1 R2C-O-CH O Glucose Glycerol-3-phosphate 2 acyl-CoA CH2O-P-OX OH OH Phosphotidic acid CTP CDP-diacylglycerol Serine Phosphatedyl serine 磷脂酰丝氨酸 Inositol Phosphatedyl inositol 磷脂酰丝氨酸 Phosphatedyl Acyl-CoA glycerol Diphosphatedyl glycerol Cardiolipin (2). Degradation of glycerophospholipid Enzyme: phospholipase (磷脂酶, PLA) including A1,A2,B1,B2,C,D. 溶血磷脂II Lysophospholipid II O PLA1 CH2OH R2C-O-CH O O CH2O-P-O—X CH2O-C-R1 R2C-O-CH PLD PLB2 OH O PLB1 CH2O-P-O—X PLA2 O OH PLC 溶血磷脂 I O CH2O-C-R1 HO-CH O CH2O-P-O—X Lysophospholipid I Lysophospholipid can cause hemolysis (溶血)。 1. Some snake venom contain phospholipase A1 or A2. Bited by these snakes, may suffer from hemolysis, shock(BP), even renal failure 2. Pancreatitis : Some reasons to activate phospholipaseA2 (existed in most cells) cause Pancreatitis. Dipalmitoyl phosphatidylcholine Lung surfactant , which is synthesized shortly before parturition in full-term infants. Deficiency of lung surfactant in the lungs of many preterm newborns gives rise to respiratory distress syndrome Sphingolipids sphingosine 鞘 氨 醇 X---- Choline Ethanolamine FA Pi X ceramide X = Choline、Ethanolamine、 Multiple sclerosis Multiple sclerosis which is a demyelinating disease, there is loss of both phospholipids (particularly ethanolamine plasmalogen) and of sphingolipids from white matter, Thus, the lipid composition of white matter resembles that of gray matter. Healthy neuron Partly demyelinated Injured neurofilament Section 4. Cholesterol metabolism Cholesterol : A solid compound contains hydroxy group, which is firstly isolated from animal Cholelithiasis. Cholesteryl ester : combined with long-chain fatty acid Plants and fungus do not contain cholesterol, but have sitosterol (谷固醇), ergosterol (麦角固醇) Bacteria do not contain sterol material * Structure of cholesterol: Derivant of cyclo-pentano-phenanthrene ring 环戊烷多氢菲 12 13 11 1 C H H 10 9 2 H B A 3 4 5 6 H 8 7 17 16 D 14 H 15 Cholesterol in animals:(27C) O Cholesteryl ester C R O β-sitosterol (谷固醇) Plant sterol:(29C) β -ergosterol (麦角固醇) Yeast:(28C) * Functions of cholesterol: (1) Essential component of biomembrane (2) Transform into many kinds of physical active materials. Such as, bile acid, VitD3 , steroid hormone. ( progesterone, testosterone and cortisol) (睾丸激素) (3) Component of plasma lipoprotein. * Content and distribution in body. Content: about 140g Distribution: appear in most of tissue. a)about ¼ in brain and nerve tissue. b)Adrenal gland and ovary organ are high c)A little bit high in liver, kidney, intestines, skin, fat tissue. d)Distributing low in muscle. The existed form: Free cholesterol Cholesteryl ester 1. Synthesis of cholesterol Place : All tissue except brain and mature red blood cells. more active in liver ( 80%), intestine, cortex of adrenal, sexual gland. Location: In cytosol and endoplasmic reticulum Materials: 1) 18×acetyl CoA (the only carbon source) from glucose aerobic oxidation 2) 16 ×NADPH(H+) from pentose phosphate pathway (provide H) 3) 36×ATP (provide energy) 甲羟戊酸 mevalonate HMG-CoA HMG-CoA reductase Isopentenyl pyrophosphate 二甲丙烯焦磷酸 焦磷酸法尼酯 squalene cholesterol 27C 羊毛固醇 30C 鲨烯 The process: has four major steps 1). Acetyl-CoAs are converted to 3-hydroxy-3- methylglutaryl-CoA (HMG-CoA) 2). HMG-CoA is converted to mevalonate (甲羟戊酸) 3). Mevalonate is converted to squalene (鲨烯) 4). Squalene is converted to cholesterol. 2. Regulation of cholesterol synthesis key enzyme : HMGCoA reductase 1) Fasting and food full (饥饿和饱食) a. fasting enzyme activity↓ cholesterol↓ as materials is shortage b. food full enzyme activity↑ cholesterol↑ 2) Cholesterol cholesterol↑ enzyme activity↓(feedback ) 3) Hormone 1) Insulin HMG reductase synthesis↑ Cholesterol↑ 2) Glucagons, Adrenal cortical hormone HMG reductase synthesis↓ Cholesterol ↓ HMGCoA reductase 3) Thyroxine HMGCoA reductase ↑ Cholesterol ↑ thyroxine Cholesterol converted to bild acid ↑ Cholesterol ↓↓ 4) Cycle rhythm (周期节律) in midnight Enzyme activity↑↑ synthesis ↑↑ noon as Enzyme activity↓↓ synthesis ↓↓ The de novo synthesis of cholesterol is regulated to complement the dietary uptake X represents unidentified metabolites of cholesterol that stimulate proteolysis of HMG-CoA reductase. HMG-CoA Digestion and absorption of Cholesterol We need about 1g cholesterol every day and most of it is synthesized by our bodies The free cholesterol in food can be absorbed directly, and cholesteryl ester can be digested by cholesteryl esterase and then be absorbed (消化吸收). Most of cholesterol in food can not be absorbed Our bodies seldom absorb plant sterols (植物固醇) and the latter disturb the normal absorption of cholesterol Synthesis of cholesteryl esters In cell: Acyl-CoA cholesterol acyltransferase, ACAT Acyl-CoA + Cholesterol Cholesteryl ester + CoA In plasma: Lecithin cholesterol acyltransferase, LCAT Phosphatidylcholine + Cholesterol Cholesteryl ester + lysophosphatidylcholine Transformation of cholesterol Cholesterol can not be totally metabolized, it transforms into many kinds of physical active materials, such as, bile acid, VitD3, steroid hormone steroid hormones: progesterone, testosterone, cortisol, estradiol, aldosterone Case III Hypercholestrolemia The serum cholesterol is correlated with the incidence of atherosclerosis and coronary heart disease Hereditary factors, dietary and environmental factors influence serum cholesterol concentration Polyunsaturated fatty acids (Fish oil ) reduce serum cholesterol concentration HMG-CoA reductase inhibitor (lovastatin) Sitosterol inhibits cholesterol absorbtion Section 5. the metabolism of plasma lipoprotein 1. Blood lipid Concept: all the lipids contained in plasma, including TAG, phosphalipids, cholesterol and their ester, FA. Lipoprotein: The form of blood lipid exist and transport. protein£¨ apolipoprotein£¬Apo£© TAG Cholesterol and their ester phospholipid Lipoproteins are globular, micelle-like particles consisting of a hydrophobic core of triacylglycerols and cholesterol esters surrounded by an amphipathic coat of protein, phospholipid and cholesterol. 2. Type and component of plasma lipoprotein Classification (1)Electrophoresis : according to the velocity - Lipoprotein pre b-Lipoprotein b-Lipoprotein CM (chylomicron) slow CM b preb ♁ fast (2) Ultra centrifugation:according to the density Low CM (chylomicron ) VLDL (pre-β- lipoprotein) LDL (β- lipoprotein ) HDL (α-lipoprotein) High rotor Lipoproteins observed under electron microscope Characteristics of the four classes of lipoproteins CM density lipid protein content Apoprotei ns 载脂 蛋白 <0.95 TG richest 80~90% VLDL LDL HDL 0.95~1.006 1.006~1.063 1.063~1.210 TG rich Ch and CE PL 50% 40~50% 50~70% Poorest 1% 5~10% 20~25% apoB48、E apoB100、 apoB100 AⅠ、AⅡ CⅠ、CⅡ AⅣ、CⅠ CⅢ、 E CⅡ、CⅢ rich, about 50% apo AⅠ、 AⅡ Apolipoprotein, apo Concept: The protein in the plasma lipoprotein Category(have 5 classes and 18 subunit) apo A: AⅠ、AⅡ、AⅣ apo B: B100、B48 apo C: CⅠ、CⅡ、CⅢ apo D apo E Function: ① Combination and transport of lipids ② Recognizing the lipoprotein receptors AⅠ recognizing HDL receptor B100,E recognizing LDL receptor ③ Regulating key enzymes of lipoprotein metabolism apo A I activate LCAT apo C II activate lipoprotein lipase(LPL) apo A II activate hepatic lipase(HL) apo CⅢ inhibit LPL 3. Metabolism of plasm lipoprotein Enzymes: Lipoprotein lipase (LPL):Synthesized in all tissue and locates at the membrane surface of microvascular endothelium , it can hydrolyze TG in CM and VLDL, ApoC-II can activate this enzyme Hepatic lipase (肝脂肪酶, HL):Synthesized in liver and locates at surface of liver cells, it can digest the TG in remnants of CM and VLDL Lecithin cholesterol acyltransferase (LCAT):Synthesized in liver and secreted into blood, it act on free cholesterol on surface of HDL and drive cholesterol into the core of HDL, ApoA-I is its activator 1). Metabolism of CM 小肠上皮 血管内皮 乳糜微粒残粒 2). Metabolism of VLDL and LDL 3). Metabolism of LDL Liver receptor ① modified LDL ② ① Other tissue LDL receptor scavenger receptor macrophage /endothelial cell 4). Metabolism of HDL LDL受体 scavenger receptor class B type I Site and function of the four classes of lipoproteins sorts CM VLDL LDL HDL Produce site intestine liver cell VLDL transform in blood Liver,intestine function transport exogenous TG and Ch from intestine to liver transport endogenous TG produced in liver and metabolized into LDL transport endogenous ChE produced in liver to other tissues. transport ChE from extrahepatic tissues to liver. 1. Which of the plasma lipoproteins is best described as follows: synthesized in the liver, containing a high concentration of triacylglycerol and mainly cleared from the circulation by adipose tissue and muscle? A. Chylomicrons; B. High-density lipoprotein; C.Intermediate density lipoprotein; D. Low-density lipoprotein; E. Very low-density lipoprotein 2. The subcellular site of the synthesis of cholesterol is: A.The cytosol and the endoplasmic reticulum B.The matrix of the mitochondria C.The mitochondrial intermembrane space D.The Golgi apparatus