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Chapter 5 lipids metabolism

Chapter 5 lipids metabolism. 生化教研室：牛永东. Outline. 1. Classification of Lipids /FA and Nomenclature 2. Digestion of T ri g lyceride 3. Metabolism of TG 4. Metabolism of phospholipids 5. Metabolism of cholesterol 6. Lipoprotein s metabolism. LIPIDS.

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Chapter 5 lipids metabolism

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  1. Chapter5 lipids metabolism 生化教研室：牛永东

  2. Outline 1. Classification of Lipids /FA and Nomenclature 2. Digestion of Triglyceride 3. Metabolism of TG 4. Metabolism of phospholipids 5. Metabolism of cholesterol 6. Lipoproteins metabolism

  3. LIPIDS • Water-insoluble substances that can be extracted from cells by nonpolar organic solvents

  4. Section 1 ClassificationandFunctions of Lipids 1. Triglyceride, TG（Variable lipids）: - As storage and transport form of metabolic fuel • 9 kcal/gram due to energy rich fatty acid chain - 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

  5. Glycerol + 3 FFA TG + 3 H2O Triglyceride Triglycerides（triacylglycerols）,called “Neutral Fats” - made of 3 free fatty acids and 1 glycerol - FA 4-22 Carbons long (mostly 16-20) - 95% of dietary lipids (fats & oils)

  6. Classification of FAand Nomenclature（命名） • FA：acids obtained by the hydrolysis of fats and oils • According to the number of carbon atom • short chain(2~4C), medium chain (6~10C) and long chain(12~26C) fatty acid • According to whether it contains double bond or not • (saturate & unsaturate fatty acid) • Systemic nomination • ( catalogue,  or n catalogue)

  7. Unsaturated FA andEssential FA • Saturated (have only single bonds) • Unsaturated (have doublebonds) • Essential FA - the body cannot synthesize - must originate from dietary sources - polyunsaturated fatty acids linoleic:(18:2,9,12) 亚油酸 linoleinic:(18:3, 9,12,15) 亚麻酸 arachidonic acid :(20:4, 5,8,11,14) 花生四烯酸

  8. Sources of omega-3 fatty acid: soybean, salmon…… Eicosapentaenoic acid( 20:5 ω-3,廿碳五烯酸 EPA): found in oils of shell fish, cold-water tuna, sardines, and sea mammals Docosapentaenoicacid 廿二碳五烯酸 DPA （22:5 ω-3） Docosahexaenoic acid 廿二碳六烯酸 DHA（22:6 ω-3） Sources of omega-6 fatty acids Vegetable oils Nuts and seeds Omega-3 / Omega-6 Fatty Acids

  9. Section 2 Digestionand absorption of Triacylglycerols

  10. 6 Steps ofDigestion and Absorption of lipids 1. Minor digestion of triacylglycerols in mouth and stomach by lingual lipase and gastric lipase 2. Major digestion of all lipids in the lumen of the duodenum(十二指肠) and jejunum （空肠）by Pancreatic lipases 3. 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

  11. 4. Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell glycerol and FA <12 carbons in length pass thru the cell into the blood without modification. 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 5. Re-esterificationof 2-monoacylglycerol, lysolecithin（溶血卵磷脂）, and cholesterol with free fatty acids inside the intestinal enterocyte 6. Assembly and exportfrom intestinal cells to the lymphatics of chylomicrons coated with Apo B48 and containing triacylglycerols, cholesterol esters and phospholipids Absorption of lipids

  12. Section 3 Metabolism of TG • Synthesis of TG • Catabolism of TG • Lipogenesis: Fatty Acid Synthesis • Some poly-unsaturated FA ramification

  13. 1. The synthesis of TG 1). Mono-acylglycerol pathway (MAG pathway) 2). Diacylglycerol pathway (DAG pathway)

  14. acyl CoA synthase CoA + RCOOH RCOCoA ATP AMP PPi acyl CoA transferase acyl CoA transferase R2COCoA CoA R3COCoA CoA 1).MAG pathway (dietary fat digestion and absorption in intestinal mucosal cell )

  15. acyl CoA transferase acyl CoA transferase acyl CoA transferase phosphatase CoA CoA CoA R1COCoA R2COCoA R3COCoA Pi 2). DAG pathway (for TG synthesis of in adipose tissue, liver and kidney) ADP ATP

  16. 2. Catabolism of TG TG Catabolism of TG involves two separate pathways： 1). Glycerol pathway 2). Fatty acids pathway

  17. 1). Glycerol pathway • The glycerol is absorbed by the liver and converted to glycolyticintermediates

  18. 2). Fatty acids pathway--- catabolism of FA • Mobilization of triacylglycerols • Fatty acid bata oxidation • Ketosis

  19. Mobilization of triacylglycerols in the adipose tissue, breaksdowntriacylglycerols tofree fatty acids and glycerol (fatty acids arehydrolyzed initially from C1or C3 ofthe fat)

  20. Limiting enzyme – triglyceride lipase • hormone sensitive lipase （HSL） Hormone-sensitive lipase is the key enzyme responsible for the mobilization of free acids from adipose tissue, It is the rate limiting enzyme in the degradation of triacylglycerol to diacylglycerol and free fatty acids. It’s hydrolyzing activity is under tight hormonal control • lipolytic hormone • antilipolytic hormone (insulin)

  21. ** Fatty acid bata oxidation 1. Evidence 2. Steps in Beta Oxidation : - activation - transport - reaction process

  22. 1. evidence Franz Knoop 1904 Even carbon atoms β α C6H5-CH2-CH2-CH2-CH2-CH2-CH2-CH2-COOH C6H5-CH2-COOH (PhenylaceticAcid,苯乙酸) + Gly phenylacetylglycine(苯乙尿酸)

  23. Franz Knoop 1904 Odd carbon atoms β α C6H5-CH2-CH2-CH2-CH2-CH2-CH2-COOH C6H5-COOH (Benzoic Acid,苯甲酸) + Gly Hippuric acid(马尿酸)

  24. 2. Steps in Beta Oxidation 1). Fatty Acid Activation by esterification with CoASH （活化） 2). Membrane Transport of Fatty Acyl CoA Esters （转运） 3).Carbon Backbone Reaction Sequence （氧化） - Dehydrogenation (FAD) - Hydration - Dehydrogenation (NAD+) - Thiolase Reaction (Carbon-Carbon Cleavage)

  25. 1). Activation of Fatty Acids • Acyl CoA synthetase reaction occurs on the mitochondrial membrane

  26. 2). Transport into Mitochondrial Matrix • Carnitine carries long-chain activated fatty acids into the mitochondrial matrix

  27. Carnitine carries long-chain activated fatty acids into the mitochondrial matrix

  28. 3). Fatty acid Beta oxidation  • Each round in fatty acid degradation involves four reactions (1) oxidation to （脱氢） trans-∆2-Enoly-CoA Removes H atoms from the  and  carbons -Forms a trans C=C bond -Reduces FAD to FADH2 反⊿2-烯酰CoA

  29. (2) Hydration to L–β–hydroxylacyl CoA（加水） • Adds water across the trans C=C bond • Forms a hydroxyl group (-OH) on the  carbon ⊿2--烯脂酰CoA 水化酶 L(+)-β羟脂酰CoA

  30. (3) Oxidation to （再脱氢） • β–Ketoacyl CoA • Oxidizes the hydroxyl group • Forms a keto group on the  carbon L(+)-β羟脂酰 CoA脱氢酶 β酮脂酰CoA

  31. (4) Thiolysis to produce Acetyl–CoA （硫解） • acetyl CoAis cleaved:By splitting the bond between the  and  carbons. • To form a shortened fatty acyl CoA that repeats steps 1 - 4 of -oxidation β酮脂酰CoA 硫解酶 脂酰（-2C）CoA + 乙酰CoA

  32. -Oxidation of Myristic(14C) Acid

  33. -Oxidation of Myristic (14C) Acid 7 Acetyl CoA 6 cycles

  34. Why call it bata oxidation？

  35. 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

  36. -Oxidation and ATP Activation of a fatty acid requires: 2 ATP One cycle of oxidation of a fatty acid produces: 1 NADH 3/2.5 ATP 1 FADH2 2/1.5 ATP Acetyl CoA entering the citric acid cycle produces: 1 Acetyl CoA 12/10 ATP

  37. ATP for Myristic Acid（14 C） ATP production for Myristic(14 carbons): Activation of lauric acid -2 ATP 7 Acetyl CoA 7 acetyl CoA × 12/10 ATP/acetyl CoA 84/70 ATP 6 Oxidation cycles 6 NADH × 3/2.5ATP/NADH 18/15 ATP 6 FADH2× 2/1.5ATP/FADH2 12/9ATP Total 112/92 ATP

  38. Oxidation of Special Cases (monounsaturated fatty acids)

  39. Odd Carbon Fatty Acids 5 Cycles 5 CH3COSCoA + CH3CH2COSCoA Propionyl CoA Carboxylase ATP/CO2 Propionyl CoA TCA Cycle Epimerase Mutase Vit. B12 Succinyl CoA L-Methylmalonyl CoA D-Methylmalonyl CoA

  40. lipoproteins FABP FA LPL 2 TCA acetyl-CoA 7 cycle A 3 4 C -oxidation FA FA 6 S FA FA albumin acyl-CoA acyl-CoA FABP FA FABP 5 carnitine transporter 1 From fat cell MITOCHONDRION CAPILLARY CYTOPLASM FA = fatty acid LPL = lipoprotein lipase cell membrane FABP = fatty acid binding protein ACS= acyl CoA synthetase Overview of fatty acid degradation

  41. 3. Ketogenesis (Ketosis):formation of Ketone Bodies***** Thiolase CH3COSCoA 2 CH3COSCoA CH3COCH2COSCoA Acetoacetyl CoA HMG CoA Synthase Several steps Cholesterol (in cytosol) OH HO2C-CH2-C-CH2COSCoA CH3 (in liver: mitochon- drial matrix) Hydroxy methylglutaryl CoA (HMG CoA) Ketogenesis

  42. Ketogenesis: formation of Ketone Bodies OH HMG CoA lyase HO2C-CH2-C-CH2COSCoA CH3COCH2CO2H - CH3COSCoA Acetoacetic Acid CH3 HMG CoA NADH + H+ - CO2 Dehydrogenase NAD+ OH CH3COCH3 CH3CHCH2CO2H Acetone (volatile) Hydroxybutyrate Ketone bodies are important sources of energy, especially in starvation

  43. NAD+ Succinyl CoA synthetase = loss of GTP NADH -Hydroxybutyrate Acetoacetate Succinyl CoA -Hydroxybutyrate dehydrogenase Citric Acid Cycle CoA transferase CoA Succinate 2 Acetyl CoA Acetoacetyl CoA Thiolase Oxidation of ketone bodies in brain, muscle, kidney, and intestine

  44. 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 up take 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

  45. Overview Catabolism of TG TG FA TCA

  46. Lipogenesis:Fatty Acid Synthesis • Fatty acid are synthesized and degraded by different pathways • Is the synthesis of fatty acids from acetyl CoA • Synthesis takes place in the cytosol • Intermediates are attached to the acyl carrier protein (ACP) • The activated donor in the synthesis is malonyl–ACP • Fatty acid reduction uses NADPH + H+ • Elongation stops at C16 (palmitic acid)

  47. 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:

  48. OH H H O O OH HO P P N N O O O SR O P H C CH HO O O 3 3 O O HO N N HO NH 2 N N O R = CCH3; Acetyl coenzyme A Structure of Coenzyme A R = H; Coenzyme A

  49. O O HY •• CH3CSCoA CH3C Y •• Reactivity of Coenzyme A Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles(it is an acetyl transfer agent) Nucleophilic acyl substitution + HSCoA

  50. O OH H2C CSCoA CH3CSCoA O CH2CSCoA E Reactivity of Coenzyme A Acetyl coenzyme A reacts with biological electrophiles at its  carbon atom can react via enol E+

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