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Chapter 5 lipids metabolism LIPIDS • Water-insoluble substances that can be extracted from cells by nonpolar organic solvents • Characteristics of fat • Hydrophobic because of nonpolar FA chain • Lipids store large amounts of energy • 9 kcal/gram due to energy rich fatty acid chain Outline • • • • • • Classification of FA and Nomenclature Digestion of Triacylglycerols Metabolism of TAG Metabolism of phospholipids Metabolism of cholesterol Lipoproteins metabolism Section 1 Classification of FA and Nomenclature(命名) • According to the number of carbon atom: short chain(2~4C), medium chain (6~10C) & long chain(12~26C) fatty acid • According to whether it contains double bond or not (saturate & unsaturate fatty acid) • According to the number of carbon atom, the source & property. such as: Butyric acid, Arachidonic acid • systemic nomination ( catalogue, or n catalogue) Classification and Functions of Lipids 1. Triglyceride, TG(Variable lipids): - As storage and transport form of metabolic fuel - To keep the body temperature - Fats are solids; oils are liquids - To protect the visceras 2. Lipoid(Basic lipids):Cholesterols, Phospholipids, Glycolipids et al - As structural components of biological membranes. - Cholesterol serves the precursor of bile salt and steroid hormones 3. Lipid ramification: to involve the different functions Fatty Acids Acids obtained by the hydrolysis of fats and oils • Saturated (have only single bonds) • Unsaturated (have double bonds) • Essential -must originate from dietary sources -the body cannot synthesize -Polyunsaturated fatty acids linoleic :(18:2,9,12) linoleinic:(18:3, 9,12,15) arachidonic acid :(20:4, 5,8,11,14) Omega-3 / Omega-6 Fatty Acids – Sources of omega-3 fatty • Sources of omega-6 acid: soybean, fatty acids salmon…… – Vegetable oils – Eicosapentaenoic – Nuts and seeds acid(EPA,fish oil): found in oils of shell fish, coldwater tuna, sardines, and sea mammals Triglyceride Triglycerides(triacylglycerols),Called “Neutral Fats” - made of 3 free fatty acids and 1 glycerol - FFA 4-22 Carbons long (mostly 16-20) - 95% of dietary lipids (fats & oils) Glycerol + 3 FFA TG + H2O Section 2 Digestion of Triacylglycerols 6 Steps of Digestion and absorption of lipids Minor digestion of triacylglycerols in mouth and stomach by lingual lipase Major digestion of all lipids in the lumen of the duodenum(十二指肠) / jejunum (空肠)by Pancreatic lipases Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepatic(肠肝)bile acid recycling Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell,Glycerol & FAs < 12 carbons in length pass thru the cell into the blood without modification. 2-monacylglycerols and FAs > 12 carbons in length are re-synthesized into TGs in the endoplasmic reticulum TGs then form large lipid globules in the ER called nascent chylomicrons (乳糜微粒)”.Several apolipoproteins are required Re-esterification of 2-monoacylglycerol, lysolecithin(溶血卵磷脂), and cholesterol with free fatty acids inside the intestinal enterocyte Assembly and export from intestinal cells to the lymphatics of chylomicrons coated with Apo B48 and containing triacylglycerols, cholesterol esters and phospholipids Section 3 Metabolism of TAG 1. Synthesis of TAG 2. Catabolism of TAG - Fatty acid bata oxidation -Ketogenesis and Ketone Bodies 3. Lipogenesis: Fatty Acid Synthesis 4. Some poly-unsaturated FA ramification The synthesis of TAG 1. Mono-acylglycerol pathway (MAG pathway) (for dietary fat digestion and absorption) CH 2OCOR CHOCOR CH 2OCOR TAG pancreatic lipase FA CH 2OCOR CHOCOR pancreatic lipase CH 2OH DAG FA CH 2OH CHOCOR CH 2OH MAG intestinal lumen FA FA ATP,CoA acyl CoA acyl CoA CH 2OH CHOCOR CH 2OCOR CHOCOR CH 2OH MAG intestinal epithelium CH 2OCOR TAG lymphatic vessels Chylomicrons adipose tissue 2. Diacylglycerol pathway (DAG pathway) (for TAG synthesis of in adipose tissue, liver and kidney) glucose CH 2OH liver adipose tissue CO NADH+H + liver kidney NAD+ CH2OH ADP ATP CH 2OH CHOH CHOH phosphoglycerol glycerol kinase dehydrogenase CH 2O-PO 3H2 CH 2OH CH 2O-PO 3H2 dihydroxyacetone phosphate glycerol 3-phosphoglycerol RCO¡« SCoA acyl CoA transferase HSCoA CH2OCOR HSCoA RCO¡« SCoACH2OCOR CHOCOR CH2OCOR triacylglycerol CHOCOR Pi H2O CH 2OCOR HSCoA RCO¡« SCoA CHOH CHOCOR CH 2OH phosphatase CH2O-PO 3H2 acyl CoA transferase diacylglycerol phosphatidate CH 2OCOR acyl CoA transferase CH 2O-PO 3H2 lysophosphatidate Catabolism of TAG Mobilization of triacylglycerols Mobilization of triacylglycerols: in the adipose tissue, breaks down triacylglycerols to free fatty acids and glycerol (fatty acids are hydrolyzed initially from C1or C3 of the fat) hormone sensitive lipase cleave a fatty acid from a triglyceride, then other lipase complete the process of lipolysis, and fatty acid are released into the blood by serum albumin • The glycerol is absorbed by the liver and converted to glycolytic intermediates Fatty acid bata oxidation CAPILLARY lipoproteins MITOCHONDRION FABP FA LPL FA FA albumin FA 1 3 FA TCA cycle 7 -oxidation 6 acyl-CoA acetyl-CoA 2 FA FABP 4 acyl-CoA FABP CYTOPLASM A C S 5 carnitine transporter From fat cell cell membrane FA = fatty acid LPL = lipoprotein lipase FABP = fatty acid binding protein ACS = acyl CoA synthetase Overview of fatty acid degradation Steps in Beta Oxidation • Fatty Acid Activation by esterification with CoASH • Membrane Transport of Fatty Acyl CoA Esters • ***Carbon Backbone Reaction Sequence • • • • Dehydrogenation Hydration Dehydrogenation Thiolase Reaction (Carbon-Carbon Cleavage) 1. Activation of Fatty Acids • Acyl CoA synthetase reaction occurs on the mitochondrial membrane 2.Transport into Mitochondrial Matrix • Carnitine carries long-chain activated fatty acids into the mitochondrial matrix • Carnitine carries long-chain activated fatty acids into the mitochondrial matrix 3. Fatty acid Beta oxidation • Each round in fatty acid degradation involves four reactions – 1. oxidation to trans-∆2-Enoly-CoA Removes H atoms from the and carbons -Forms a trans C=C bond -Reduces FAD to FADH2 2. Hydration to L–3– Hydroxylacyl CoA – Adds water across the trans C=C bond – Forms a hydroxyl group (—OH) on the carbon 3. Oxidation to – 3–Ketoacyl CoA – Oxidizes the hydroxyl group – Forms a keto group on the carbon 4. Thiolysis to produce Acetyl–CoA – acetyl CoA is cleaved:By splitting the bond between the and carbons. – To form a shortened fatty acyl CoA that repeats steps 1 - 4 of -oxidation -Oxidation of Myristic(C14) Acid -Oxidation of Myristic (C14) Acid 6 cycles 7 Acetyl CoA Cycles of -Oxidation The length of a fatty acid • Determines the number of oxidations and the total number of acetyl CoA groups Carbons in Acetyl CoA -Oxidation Cycles Fatty Acid (C/2) (C/2 –1) 12 6 5 14 7 6 16 8 7 18 9 8 -Oxidation and ATP Activation of a fatty acid requires: 2 ATP One cycle of oxidation of a fatty acid produces: 1 NADH 3 ATP 1 FADH2 2 ATP Acetyl CoA entering the citric acid cycle produces: 1 Acetyl CoA 12 ATP ATP for Myristic Acid C14 ATP production for Myristic(14 carbons): Activation of myristic acid 7 Acetyl CoA 7 acetyl CoA x 12 ATP/acetyl CoA 6 Oxidation cycles 6 NADH x 3ATP/NADH 6 FADH2 x 2ATP/FADH2 Total -2 ATP 84 ATP 18 ATP 12 ATP 102 ATP Oxidation of Special Cases (monounsaturated fatty acids) Odd Carbon Fatty Acids CH3CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2CH2--CH2COSCoA 5 Cycles 5 CH3COSCoA + CH3CH2COSCoA Propionyl CoA TCA Cycle CO2 H Mutase CH3 -C-H HO 2CCH2CH2COSCoA Succinyl CoA Epimerase Vit. B12 COSCoA L-Methylmalonyl CoA Propionyl CoA Carboxylase ATP/CO2 CO2H H-C-CH3 COSCoA D-Methylmalonyl CoA Ketogenesis (Ketosis): formation of Ketone Bodies ***** Thiolase 2 CH3COSCoA CH3COSCoA CH3COCH2COSCoA Acetoacetyl CoA HMG CoA Synthase Cholesterol (in cytosol) Several steps OH HO2C-CH2-C-CH2COSCoA (in liver: mitochondrial matrix) CH3 Ketogenesis -Hydroxy- -methylglutaryl CoA (HMG CoA) Ketogenesis: formation of Ketone Bodies OH HO2C-CH2-C-CH2COSCoA CH3 HMG CoA HMG CoA lyase CH3COCH2CO2H Acetoacetic Acid - CH3COSCoA + NADH + H Dehydrogenase + NAD OH CH3CHCH2CO2H -Hydroxybutyrate - CO2 CH3COCH3 Acetone (volatile) Ketone bodies are important sources of energy, especially in starvation Oxidation of ketone bodies in brain, muscle, kidney, and intestine NAD+ NADH -Hydroxybutyrate Succinyl CoA synthetase = loss of GTP Acetoacetate Succinyl CoA -Hydroxybutyrate dehydrogenase CoA transferase CoA Succinate 2 Acetyl CoA Acetoacetyl CoA Thiolase Citric Acid Cycle The significance of ketogenesis and ketogenolysis • Ketone bodies are water soluble, they are convenient to transport in blood, and readily taken up by non-hepatic tissues In the early stages of fasting, the use of ketone bodies by heart, skeletal muscle conserves glucose for support of central nervous system. With more prolonged starvation, brain can take up more ketone bodies to spare glucose consumption • High concentration of ketone bodies can induce ketonemia and ketonuria, and even ketosis and acidosis When carbohydrate catabolism is blocked by a disease of diabetes mellitus or defect of sugar source, the blood concentration of ketone bodies may increase,the patient may suffer from ketosis and acidosis Overview Catabolism of TAG glycerol TAG ¢Ù FFAs not in adipose tissue and muscle ¢Ý ¢Ú ¦Â-oxidation glycolysis acetyl CoA in liver TCA ¢Û Ketone bodies ¢Ü extrahepatic tissues CO2 + H2O + energy Lipogenesis: Fatty Acid Synthesis • Fatty acid are synthesized and degraded by different pathways – from acetyl CoA – in the cytosol – intermediates are attached to the acyl carrier protein (ACP) – the activated donor is malonyl–ACP – reduction uses NADPH + H+ – stops at C16 (palmitic acid 软脂酸) Reactivity of Coenzyme A Nucleophilic acyl substitution O CH3CSCoA HY •• O CH3C Y •• + HSCoA Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles(it is an acetyl transfer agent) Reactivity of Coenzyme A can react via enol(烯醇) O OH H2C CH3CSCoA CSCoA E+ Acetyl coenzyme A reacts with biological electrophiles at its carbon atom E O CH2CSCoA Formation of Malonyl Coenzyme A Formation of malonyl–CoA is the committed step in fatty acid synthesis O || CH3—C—S—CoA + HCO3- + ATP Acetyl CoA O O || || -O—C—CH2—C—S—ACP + ADP + Pi Malonyl (丙二酰) CoA Formation of Acetyl and Malonyl ACP • The intermediates(acetyl-ACP and malonyl-ACP) in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP) In bacteria the enzymes that are involved in elongation are separate proteins In higher organisms the activities all reside on the same polypeptide – To start an elongation cycle, Acetyl–CoA and Malonyl–CoA are each transferred to an acyl carrier protein O || CH3—C—S—ACP ( Acetyl-ACP) O O || || -O—C—CH2—C—S—ACP (Malonyl-ACP) Condensation and Reduction In reactions 1 and 2 of fatty acid synthesis: • Condensation by a synthase combines acetyl-ACP with malonyl-ACP to form acetoacetyl-ACP (4C) and CO2 (reaction 1) • Reduction converts a ketone to an alcohol using NADPH (reaction 2) Dehydration and Reduction In reactions 3 and 4 of fatty acid synthesis: • Dehydration forms a trans double bond (reaction 3) • Reduction converts the double bond to a single bond using NADPH (Reaction 4) Lipogenesis Cycle Repeats Fatty acid synthesis continues: • Malonyl-ACP combines with the four-carbon butyryl-ACP to form a six-carbon-ACP. • The carbon chain lengthens by two carbons each cycle Lipogenesis Cycle Completed • Fatty acid synthesis is completed when palmitoyl ACP reacts with water to give palmitate (C16) and free ACP. Summary of Lipogenesis Elongation and Unsaturation • Endoplasmic reticulum(内质网) systems introduce double bonds into long chain acyl–CoA's – Reaction combines both NADH and the acyl– CoA's to reduce O2 to H2O • convert palmitoyl–CoA to other fatty acids – Reactions occur on the cytosolic face of the endoplasmic reticulum. – Malonyl–CoA is the donor in elongation reactions Oxidation and Fatty Acid Synthesis Fatty Acid Formation • Shorter fatty acids undergo fewer cycles • Longer fatty acids are produced from palmitate using special enzymes • Unsaturated cis bonds are incorporated into a 10carbon fatty acid that is elongated further • When blood glucose is high, insulin stimulates glycolysis and pyruvate oxidation to obtain acetyl CoA to form fatty acids Stoichiometry of FA synthesis • The stoichiometry of palmitate synthesis: – Synythesis of palmitate from Malonyl–CoA – Synthesis of Malonyl–CoA from Acetyl–CoA – Overall synthesis Sources of NADPH • The malate dehydrogenase and NADP+–linked malate enzyme reactions of the citrate shuttle exchange NADH for NADPH Citrate Shuttle • Acetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol – Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate: Regulation of Fatty Acid Synthesis • Regulation of Acetyl carboxylase(乙酰羧化酶) – Global (+) insulin (-) glucagon (-) epinephrine – Local (+)Citrate (-) Palmitoyl–CoA (-) AMP Eicosanoid Hormones(花生四烯酸类激素) • Eicosanoid horomones are synthesized from arachadonic acid (20:4,二十碳-四烯酸) – Prostaglandins(前列腺素) • 20-carbon fatty acid containing 5-carbon ring • Prostacyclins • Thromboxanes(血栓噁烷) – Leukotrienes(白三烯) • contain three conjugated double bonds Eicosanoid Hormones Eicosanoid Hormones Section 4 Metabolism of phospholipids(磷脂) Phospholipids • Structure – Glycerol + 2 fatty acids + phosphate group • Functions – Component of cell membranes – Lipid transport as part of lipoproteins • Food sources – Egg yolks, liver, soybeans, peanuts Phospholipids • Phospholipids are intermediates in the biosynthesis of triacylglycerols • The starting materials are glycerol 3phosphate and the appropriate acyl coenzyme A molecules Biosynthesis of glycerophospholipids HO-CH2-CH-COOH NH2 serine CO2 HO-CH2-CH2-NH2 ethanolamine ATP kinase ADP 1. DAG shunt is the major pathway for biosynthesis of phosphatidyl choline (lecithin) and phosphatidyl ethanolamine (cephalin) 3(S-adenosylmethionine) + HO-CH2-CH2-N(CH3)3 ATP choline kinase ADP P -O-CH2-CH2-NH2 phosphoethanolamine CTP cytidyl transferase PPi CDP-O-CH2-CH2-NH2 CDP-ethanolamine R2 + -O-CH -CH P 2 2-N(CH3)3 phosphocholine CTP DAG O cytidyl transferase H 2C O C R 1 PPi O C O C H CDP -O-CH2-CH2-N(CH3)3 CDP-choline H C OH 2 diacylglycerol transferase CMP CMP phosphatidyl ethanolamine (PE) phosphatidyl choline (PC) glucose CDP-DAG shunt glycerol 3-phosphate 2 acyl CoA 2. CDP-DAG shunt is the major pathway for the synthesis of phosphatidyl serine, phosphatidyl inositol and cardiolipin - in this pathway, DAG is activated as the form of CDP-DAG 2 CoA Phosphatidic acid CTP PPi CDP-diacylglycerol serine phosphatidyl glycerol inositol CMP CMP CMP diphosphatidyl glycerol (cardiolipin) phosphatidyl inositol phosphatidyl serine O CH 2 O O R2 C O CH CH 2 O O C R1 H2C O P O- O HO C O H P O O CH 2 O - CH O C R3 O CH 2 CH 2 O Cardiolipin (diphosphatidylglycerol) C R4 Degradation of glycerophospholipids O H 2C O C R2 O H2C O C R1 O C O C H R2 O O P _ H2C OH O _ diglyceride O C O C H O P H2C O X _ XOH O OH O phosphatidic acid H2O phospholipase C O H2C O C R2 R1 O C O C H O H2C O P _ H2O phospholipase D R1 glycerophospholipid O X O phospholipase A1 H2C OH R2 O C O C H O H2C O P _ lysophospholipid 2 R1 O O phospholipase B2 phospholipase A2 H2O H2O O C OH O C OH R2 O H 2C O C HO C H X H2O H2O R2 O O C OH R1 C OH O H 2C O P _ R1 lysophospholipid 1 O O phospholipase B1 H2C OH HO C H O H2C O P _ O O X (glycerophophocholine) X Metabolism of sphingolipids O ( CH2)1 2 C H CH CH CH OH NH sphingosine 鞘氨醇 C H2 O P O C H2 CH 2 + N H3 C ( CH3)3 O C phosphate O choline R fatty acid The structure of phosphosphingolipids H3C (CH 2)1 2 C H sphingosine CH CH CH OH NH C C H2 O Sphingolipids are a class of lipids containing sphingosine instead of glycerol include: glycosphingolipids phosphosphingolipids x = monosaccharide cerebroside X sugar O x = sulfated galactose ( = cerebroside sulfate) sulfatide 脑苷脂 硫酸脑苷脂 globoside 红细胞糖苷脂 x = oligosaccharide + sialic acid ganglioside x = oligosaccharide R fatty acid The structure of glycosphosphingolipids 神经节苷脂 note: sialic acid = N-acetylneuraminic acid 唾液酸 N-乙酰神经氨酸 Section 5 Metabolism of cholesterol Structure of Cholesterol 12 11 19 C 13 1 2 A 3 4 10 5 18 14 9 B8 17 16 Fundamental framework of steroids D 15 CH3 CH3 7 CH3 6 CH3 H HO CH3 H H Structure of Cholesterol Cholesterol Biosynthesis 1. Formation of Mevalonate Liver is primary site of cholesterol biosynthesis Thiolase 2 CH3COSCoA CH3COCH2COSCoA CH3COSCoA Acetoacetyl CoA HMG CoA Synthase OH HMGCoA reductase HO2C-CH2-C-CH2CH2OH CH3 3R-Mevalonic acid 甲羟戊酸 CoASH OH HO2C-CH2-C-CH2COSCoA NADP + NADPH +H + Key control step CH3 -Hydroxy-bata-methylglutaryl CoA (HMG CoA) Cholesterol Biosynthesis 2. processing of Squalene OH -O C-CH -C-CH CH OH 2 2 2 2 CH3 Mevalonate OH 2 Steps -O C-CH -C-CH CH OPOP 2 2 2 2 ATP CH3 5-Pyrophospho(焦磷酸)mevalonate - CO2 - H2 O CH3 Isomerase CH3-C=CH2CH2OPOP Dimethylallyl pyrophosphate CH2=C-CH2CH2OPOP Isopentenyl(异戊烯) CH3 pyrophosphate Isoprenoid(异戊二烯)Condensation Dimethylallyl pyrophosphate Tail Head to tail Condensation OPOP Head Tail OPOP Head H Head OPOP Tail Geranyl (牛龙牛儿基) Pyrophosphate (GPP) Isopentenyl Pyrophosphate (IPP) Isoprenes异戊二烯 Tail to tail condensation of 2 FPPs Head to tail condensation of IPP and GPP OPOP Squalene鲨烯 Head Farnesyl(法尼基) Pyrophosphate (FPP) Tail 3. Conversion of Squalene to Cholesterol Squalene2,3-epoxide Squalene monooxygenase O2 Squalene鲨烯 O H 2,3-Oxidosqualene: lanosterol cyclase + CH3 CH3 CH3 CH3 20 Steps CH3 HO H3C HO Cholesterol CH3 Lanosterol羊毛固醇 Transformations of Cholesterol Cholesterol is the biosynthetic precursor to a large number of important steroids: Bile acids Vitamin D3 Corticosteroids Sex hormones Section 6 Lipoproteins metabolism General Features of Lipoproteins Apolipoproteins: specific lipid-binding proteins that attach to the surface intracellular recognition for exocytosis of the nascent particle after synthesis activation of lipid-processing enzymes in the bloodstream, binding to cell surface receptors for endocytosis and clearance Main lipid components: triacylglycerols, cholesterol esters, phospholipids. Major lipoproteins: chylomicrons very low density lipoproteins (VLDL) low density lipoproteins (LDL) high density lipoproteins (HDL) _ _ origin ¦Ã ¦Â ¦Á 2 ¦Á 1 A Subfraction: intermediate density lipoproteins (IDL) Electrophoretic mobility (charge): Plasma lipoproteins HDLs = lipoproteins LDLs = - lipoproteins VLDLs = pre- lipoproteins (intermediate between and mobility) CM ¦Â pre ¦Â ¦Á Model of low density lipoprotein. Other lipoproteins have a similar structure differing in the core content of lipid and the type of apoproteins on the surface of the molecule Functions of apolipoproteins Protein (Enzyme) Site of Action Activator Function LPL (Enzyme) capillary walls apo CII excises FFA from TAGs in chylomicrons and VLDLs for adipose and muscle CERP plasma membrane apo A1 (choles. Induced) flips cholesterol (and lecithin) to outer layer of lipid bilayer for LCAT action in blood Apo A1 blood, plasma membrane none activates LCAT and CERP; binds to apo A1 receptors on cells requiring cholesterol extraction Apo B48 Gut none export of chylomicrons from intestinal cells Apo B100 Various cells none ligand for LDL receptor; export of liver VLDL Apo CII capillary walls none activates lipoprotein lipase Apo E liver none receptor ligand - clears remnants, IDL, and HDL composition of lipoproteins Lipoprotein Total protein Total lipids (%) classes (%) CM VLDL 1.5-2.5 97-99 Percent composition of lipid fractions PL ChE Ch TAG 7-9 3-5 1-3 84-98 (B,C-III,II,I) 5-10 90-95 15-20 10-15 5-10 50-65 75-80 15-20 35-40 7-10 7-10 4 5 (B,C-III,II,I) LDL 20-25 (B) HDL 40-45 (A-I) 55 35 12 intestine Lymph system: Chylomicrons to capillaries via lymph chylomicron interacts with lipoprotein lipase removing FFA Nascent chylomicrons acquire apo CII (C) and E (E) from HDL non-hepatic tissues CE CE CECE CE CECE CE CE ApoB48 aids with chylomicron assembly Chylomicrons carry dietary fatty acids to tissues liver Triacylglycerol in core Chylomicron (or VLDL) To Liver Apo CII Lipoprotein lipase Glycerol Free fatty acids Polysaccharide Chain Capillary Endothelial Surface of cell In cellulo (muscle & adipose) Free fatty acids Lipoprotein lipase action on chylomicron triacylglycerol (an identical reaction occurs with VLDL) Lymph system: chylomicron interacts with lipoprotein lipase removing FFA chylomicron acquires apo CII (C) and E (E) from HDL non-hepatic tissues CE CE CECE CE CECE CE CE C E ApoB48 chylomicron remnants lose CII to HDL E C E E C EE E Liver: apo E receptor takes up remnants to deliver cholesterol LIVER Exogenous pathway of lipid transport Chylomicrons carry dietary fatty acids to tissues and the remnants take cholesterol to the liver B100 (B) helps assemble and export nascent VLDL nascent VLDL acquires apo CII (C) and apo E (E) from HDL LPL hydrolyze TAGs; FFA uptake; LDL circulate to tissues non-hepatic tissues LIVER CE bile acids Cholesterol uptake; excreted as bile acids Apo E binds liver receptor CE CE CE CE CE CE CECE B B CE CE B CII and E release to HDL apo B100 on LDL bind to receptor B B B BB B BB LDL taken into the cell to deliver cholesterol HDL scavenge cholesterol The liver-directed endogenous pathway of lipoprotein metabolism Chylomicrons: Exogenous Pathway Chylomicron Processing and Interface with HDL HDL: Both Pathways B48 E Nascent Chylomicron Assembly in Gut Mediated by B48 E E E B48 apo E & CII CII from HDL Mature Chylomicron Apo E and CII added from HDL E CII activates LPL A1 CII E CII B48 CII Nascent HDL Assembled in liver Loans apo E/ apo CII to nascent chylomicrons Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle CII CII Chylomicron Remnant from mature chylomicron apo CII returned to HDL adipose & muscle FFA apo CII A1 CII E B48 CII CII Triacylglycerol Mature HDL CE from peripheral cells activated by apo A1 Apo CII returned by chylomicrons Cholesterol ester Phospholipid VLDL/LDL Processing and Interface with HDL VLDL/LDL: Endogenous Pathway HDL: Both Pathways E B100 Nascent VLDL Assembly in Liver Mediated by B100 E A1 CII apo CII & E from HDL Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle B100 E B100 CII Mature VLDL Apo E and CII added from HDL CII activates LPL CII adipose & muscle Mature HDL Apo CII/E returned by VLDL A1 E CII FFA apo CII + E CII E E E CII LDL from mature VLDL B100 Clearance of Cholesterol by Liver from Chylomicron Remnants, HDL and LDL Chylomicron Remnant Mature HDL LDL B100 B100 B100 E Receptor E Receptor CE Metabolism B100 receptor Bile acids Consequence of Oxidized LDL Formation LDL Oxidation of LDL Oxidized LDL 1. Uptake by "scavenger receptors" on macrophages that invade artery walls; become foam cells 2. Elicits CE deposition in artery walls Atherosclerosis 动脉粥样硬化 LDL receptor sorting endosome: ligand/receptor dissociation lysosome Golgi late endosome free pool of cholesterol ACEH CE cholesterol ACAT (stimulated by cholesterol) endocytosis Cholesterol release for transport to liver LDL CE CERP Membrane Cholesterol Cholesterol metabolism to bile acids or steroids Apo A1 receptor L C A T CE in nascent HDL CE stored in Cholesterol droplets CE CE Esterase A1 Reverse CholesterolTransport A1 E CII E CII Apo A1 binds to receptor, activates CERP to pump out cholesterol, and LCAT to esterify cholesterol Mature HDL: Cleared by liver Lipoprotein classes Lipoprotein Chylomicrons VLDL LDL HDL Source gut liver Apo Proteins B48, CII*, E* B100, CII*, E* blood B100 liver A1, CII, E("ACE") Protein:Lipid/ Major (minor) Lipid Transported Function 1:49triacylglycerol (CE) Dietary: FFA Adipose/muscle CE Liver via remnants 1:9 triacylglycerol (CE) Synthesized: FFA adipose/muscle CE LDL 1:3 cholesterol ester 1:1 cholesterol ester CE to liver (70%) and peripheral cells (30%) supplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport hypercholesterolemia 家族性高胆固醇血症表现 Guidelines for Appropriate Intake of Fat ☻ reduce fat in diet to <30% ☻ avoid saturated fat (animal fat) ☻ avoid margarine(奶油), baked goods, fried food ☻ mono/polyunsaturated cooking oils are best (olive, corn) ☻ eat foods rich in -3 polyunsaturated fatty acids (e.g, soybean,salmon) 选择题练习 脂代谢 1. 脂肪动员的限速酶是( ) A 激素敏感性脂肪酶(HSL) B 胰脂酶 C 脂蛋白脂肪酶 D 组织脂肪酶 E 辅脂酶 2. 下列不能促进脂肪动员的激素是( A 胰高血糖素 B 肾上腺素 C ACTH D 促甲状腺素 E 胰岛素 ) 3. 下列物质在体内彻底氧化后,每克释放 能量最多的是( ) A 葡萄糖 B 糖原 C 脂肪 D 胆固醇 E 蛋白质 4. 脂肪酸氧化分解的限速酶是( A 脂酰CoA合成酶 B 肉碱脂酰转移酶I C 肉碱脂酰转移酶II D 脂酰CoA脱氢酶 E -羟脱氢酶 ) 5. 脂肪酰进行-氧化的酶促反应顺序为( A 脱氢,脱水,再脱氢,硫解 B 脱氢,加水,再脱氢,硫解 C 脱氢,再脱氢,加水, 硫解 D 硫解,脱氢,加水,再脱氢 E 缩合,还原,脱水,再还原 ) 6. 严重饥饿时,脑组织的能量主要来源于( A 糖的氧化 B 脂肪酸的氧化 C 氨基酸的氧化 D 乳酸氧化 E 酮体氧化 ) 7. 通常生物膜中不存在的脂类是( A 脑磷脂 B 卵磷脂 C 胆固醇 D 甘油三酯 E 糖脂 ) 8. 下列关于HMG-CoA还原酶的叙述哪项事错误的( A 此酶存在于细胞胞液中 B 是胆固醇合成过程中的限速酶 C 胰岛素可以诱导此酶合成 D 经磷酸化后活性可增强 E 胆固醇可反馈抑制其活性 ) 9. 家族性高胆固醇血症纯合子的原发行代谢障碍是( A 缺乏载脂蛋白B B 由VLDL生成LDL增加 C 细胞膜LDL受体功能缺陷 D 肝脏HMG-CoA还原酶活性增加 E 脂酰胆固醇脂酰转移酶(ACAT)活性降低 ) 10. 下列有关脂酸合成的叙述不正确的是( ) A 脂肪酸合成酶系存在于胞液中 B 脂肪酸分子中全部碳原子来源于丙二酰CoA C 生物素是辅助因子 D 消耗ATP E 需要NADPH参与 11. The organ having the strongest ability of fatty acid synthesis is ( ) A fatty tissue B lacteal gland C liver D kidney E brain 12. Which one transports cholesterol from outer to inner of liver? A CM B VLDL C LDL D HDL E IDL 13. Which one is essential fatty acid? A palmitic acid B stearic acid C oleinic acid D octadecadienoic acid E eicosanoic acid 14. The main metabolic outlet of body cholesterol is ( A change into cholesterol ester B change into vitamine D3 C change into bile acid D change into steroid hormone E change into dihydrocholesterol ) 15. 下列物质中与脂肪消化吸收有关的是( A 胰脂酶 B 脂蛋白脂肪酶 C 激素敏感性脂肪酶 D 辅脂酶 E 胆酸 ) 16. 合成甘油磷脂共同需要的原料有( A 甘油 B 脂肪酸 C 胆碱 D 乙醇胺 E 磷酸盐 ) 17. 参与血浆脂蛋白代谢的关键酶( A 激素敏感性脂肪酶(HSL) B 脂蛋白脂肪酶(LPL) C 肝脂肪酶(HL) D 卵磷脂胆固醇酰基转移酶(LCAT) E 脂酰基胆固醇脂酰转移酶(ACAT) ) 18. 脂蛋白的结构是( ) A 脂蛋白呈球状颗粒 B 脂蛋白具有亲水表面和疏水核心 C 载脂蛋白位于表面 D CM VLDL主要以甘油三酯为核心 E LDL HDL主要以胆固醇酯为核心 19. Which can be the source of acetyl CoA? A glucose B fatty acid C ketone body D cholesterol E citric acid 20. The matters which join in synthesis of cholesterol directly are ( ) A acetyl CoA B malonyl CoA C ATP D NADH E NADPH