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LIPID METABOLISM

LIPID METABOLISM. Outlines & Objectives. Metabolism (Catabolism and Anabolism), Regulation and Importance of fatty acids (FÂ) and lipids and clinical applications FÂ - Saturated FÂ -Unsaturated FÂ - Monounsaturated FÂ -Polyunsaturated FÂ

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LIPID METABOLISM

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  1. LIPID METABOLISM

  2. Outlines & Objectives • Metabolism (Catabolism and • Anabolism), Regulation and • Importance of fatty acids (FÂ) • and lipidsand clinical applications • FÂ -Saturated FÂ • -Unsaturated FÂ • -Monounsaturated FÂ • -Polyunsaturated FÂ • -Eicosanoids

  3. Lipids • Storage lipids ; Fat, oils • Membrane lipids • Phospholipids • Glycolipids • Cholesterol • Precursor & derived lipids • Sterols • Polyprenoid compounds

  4. FA FA FA FA FA FA GLYCEROL MG DG TG CHOLESTEROL – FA = CH. ESTER R – COOH carboxylic acid O R – C - acyl = FA - FA FA FA FA FA P-X P P-X LYSO-PL PA PL PA = phosphatidic acid PL = phospholipid = phosphatidyl - x ( x = choline ; lecithin ) LYSO - PL = lysophosphatidyl - x MG = monoacylglycerol CTP = cytidine triphosphate CDP = cytidine diphosphate

  5. Hormones action gastrin stomach - gastric motility cholecystokinin (in blood) + small intestine gut endocrine cells (enlarged) duodenum dietary lipids and proteins + + bicarbonate secretin (in blood) secretes pancreatic enz. + secretes pancreas bile intestinal motility secretes gall bladder

  6. pan.lipase apoprotein MG MG TG LCTG FA FA G G FCH CH CH CH.E CH.E FA FA LPL LPL PL PL FA FA chylomicron MCTG MCTG Int. lipase FFA G DIGESTION AND ABSORPTION OF LIPIDS + alb lymphatic portal vein TG , CHE , PL , PROT. target tissue

  7. CHYLOMICRON

  8. steatorrhea small intestine liver dietary lipids gall bladder bile pancreas pancreatic juice large intestine bile pigment defective cells Intestinal mucosal cells stercobilin ( สี feces ) Excess lipid in feces (steatorrhea) Ca++ + FA Ca SOAP Possible causes of steatorrhea : Feces : bacteria ¼ - ½ total

  9. Orlistat (xenecal, tetrahydrolipstatin) • - Inhibit gastric and pancreatic lipases • Obesity, non-alcoholic steatohepatitis (NASH) • treatment

  10. ENZYMES DIGEST LIPIDS : LIPASE FA ; FA FA + 2FA + 3FA FA TG MG GLYCEROL 1 2 1 PANCREATIC (CO-LIPASE) : LC-FA 2.1 gastric : SC&LC-FA (30% in adults and 50% in infants) 2 2.2 lipoprotein (extrahepatic tiss.) TG in chylomicron , VLDL activated by heparin , apo –C-II 2.3 hormone sensitive lipase in adipocyte : stim. : Gg , Epi , T4 , etc. inh. : Pgs , Is 2.4 Int. Lipase : MCTG 2.5 lingual lipase

  11. FATTY ACIDS : 1. CHAIN : RCOOH short chain (SC) medium chain (MC) long chain (LC) very long chain (VLC) (<4) (6 – 12) ( 12 - 20 ) (>20) 2. ODD CHAIN : WAX ( C25 – C35 ) , EVEN CHAIN 3. SAT. VS. UNSAT. : SAT. : palmitic acid ( C16 : 0 ) stearic acid ( C18 : 0 )     CH3 CH2 CH2 CH2 CH2 CH2 CH2 COOH UNSAT. : oleic acid ( C18 : 1▲9) palmitoleic acid ( C16 : 1▲9) LINOLEIC LINOLENIC ARACHIDONIC 18 : 2▲9,1218 :3▲9,12,1520 :4▲5,8,11,14

  12. FATTY ACID OXIDATION : supply energy : 40 % normal ; 90 + % - fast 3 ways : - (major) ;  - &  - (minor) STEPS : activation : 2ATP (cyto -) GTP (FAs in mito -, severe starvation) transfer ( cyto mito ) - carnitine - oxidation ( mito ) 1. DHase : FAD+ 2. hydratase : + H2O 3. DHase : NAD+ 4. thiolase : 2C end products : Ac. CoA ; propionyl CoA Krebs succinyl CoA palmitic ac. (C16 ) + 23 O2 16 CO2 + 16 H2O + E C16H32O2

  13. FATTY ACID ACTIVATION AND TRANSPORT Activation: cytosol O RCOOH + CoA + ATPRCSCoA + AMP +PPi Acyl CoA synthetase (thiokinase) Acyl CoA ligase Translocation: matrix translocase SC-FA and MCFA can cross the inner membrane of mitochondria without the aid of carnitine or CAT system

  14. TRANSLOCATION ACTIVATION mito-memb. cytosol matrix outer inner O GDP + Pi carnitine PPi RCSCoA RCSCoA + AMP I II GTP ATP CoASH CoASH RCOOH RCO-C RCOOH Acyl CoA-synthetase or thiokinase CAT I : carnitine acyl transferase I is inhibited by malonyl CoA and is stimulated by long chain fatty acyl CoA CAT II : carnitine acyl transferase II

  15. Synthesized from lysine and methionine in liver and kidneybut not in skeletal and heart muscles (MCFAs are plentiful in human milk) Deficiency cause cardiomyopathy and muscle weakness - liver disease - strictly vegetarian diets

  16. BETA – OXIDATION (not found in nerve and red cells) O (-) FA R – CH2 – CH2 – CH2 – C - OH CoA , ATP GTP , CoA 1 THIOKINASE AMP , PPi GDP , Pi R – CH2 – CH2 – CH2 – CO ~S CoA Acyl CoA FAD 2 - DHase FADH2 R – CH2 – CH = CH– CO ~S CoA ▲2- TRANS - H2O ENOYL CoA 3 -hydratase R – CH2 – CH - CH– CO ~S CoA L – 3 – OH – acyl CoA -DHase OH H 4 NADH + H+ R – CH2 – C - CH2 – CO ~S CoA 3 – KETO – acyl CoA O CoA SH THIOLASE 5 R – CH2CO ~S CoA + CH3 CO ~S CoA 2

  17. END PRODUCTS OF β - OXIDATION OF FA EVEN – CARBON FA : O  1 3 2 CH3 – CH2 – CH2 – CH2 – CH2 -CH2 – CH2 –C ~S CoA n ครั้ง ; CH3 CO.SCoA = n + 1 ODD – CARBON FA : O 1 2 CH3 – CH2 – CH2 – CH2 – CH2 -CH2–C ~S CoA 1. PROPIONYL CoA + n ACETYL CoA GLUC. “TCA” OAA SUCCINYL CoA CO2 + H2O + E “KREBS”

  18. FATE OF PROPIONYL CoA : COOH CO2 ATP ADP , Pi CH2 CH3 HC CH3 C ~ S CoA C ~ S CoA CARBOXYLASE O O ( B7 ) ( BIOTIN) D – Mt – MALONYL CoA PROPIONYL CoA RACEMASE COOH COOH MUTASE CH2 H3C CH CH2 ( B12 ) C ~ S CoA CO ~ S CoA O SUCCINYL CoA L – Mt – MALONYL CoA B12 DEF : PROPIONIC ; Mt – MALONIC ACID ACIDEMIA & ACIDURIA ( PERNICIOUS ANEMIA )

  19. Acyl CoA dehydrogenase 1. short-chain acyl CoA dehydrogenase - oxidised 4 and 6 carbon 2. medium-chain acyl CoA dehydrogenase - oxidised 4- 14 carbon 3. long-chain acyl CoA dehydrogenase - oxidised 12-18 carbon Medium-chain acyl CoA dehydrogenase deficiency - deficiency of ketone bodies but high in dicarboxylic acid (use ω-oxidation instead) - fasting hypoglycemia sudden infant death syndrome - avoid excessive fasting

  20. hyhoglycin from unripened akee fruit inhibits acyl CoA DH hypoglycemia Vomiting, convulsion, coma, death (Jamaican vomiting sickness)

  21. BETA - OXIDATION SAT. S CoA C16 7 6 5 4 3 2  1 O PALMITIC ACID Ac. CoA ( n+1 ); n = BETA - OXIDATION UNSAT. double bond at an odd-numbered carbon OLEIC ACID : C18 : 1▲9 CIS- S CoA CIS 18 9 3 2 1 O S CoA + 3 Ac. CoA 12 3 O ISOMERASE ▲3 - CIS - O S CoA 6Ac. CoA 12 2 ▲2 - TRANS -

  22. UNSAT. double bond at an even-numbered carbon CoA 5

  23. POLYUNSAT. Acyl CoA DH

  24. cis

  25. -oxidation of very long chain fatty acid • Peroxisome • Membrane transport is unknown • Peroxisomal oxidation differs from β-oxidation in • the initial dehydrogenase reaction • FADH2 of acyl dehydrogenase in peroxisome • transfers electron to O2 to yield H2O2 • - Catalase is needed to convert H2O2 into H2O and O2 • - Subsequent steps are identical with β-oxidation

  26. catalase H2O + 1/2O2 Acyl-CoA DH hydratase DH β-ketothiolase

  27. Zellweger syndrome (cerebrohepatorenal syndrome) • in the family of leukodystrophies • result from the defect in the import of enzymes into • peroxisome and cause defects in peroxisomal • β-oxidation leading to accumulation of very long chain • fatty acid in plasma and tissue body • characterized by liver, kidney, brain and muscle • abnormalities • - Death by age six to twelve

  28. Symptoms • Enlarged liver • Lack of muscle tone, an inability to move, suck • and/or swallow • Glaucoma (ต้อหิน) • Mental retardation, seizure • albuminuria

  29. พลังงานจากการสลายกรดไขมัน พลังงานจากการสลายกรดไขมัน กรดไขมันแต่ละชนิด ให้พลังงานไม่เท่ากัน ขึ้นอยู่กับจำนวนคาร์บอน และ unsaturation ตัวอย่าง 1. การสลายกรด palmitic ; (กรดไขมันอิ่มตัวมีคาร์บอน 16 ตัว ) ได้ 106 ATP C 16 : 0 Activation - 2 ATP AMP palmitoyl CoA CH3 – CH2 – CH2 – CH2 – CH2 -CH2 – CH2 –C ~S CoA  - oxidation x 7 28 ATP (FADH2 + NADH) x 7 = 4 ATP x 7 8 acetyl CoA TCA cycle x 8 (3NADH+ FADH2 + GTP) x 8 = 10 ATP x 8 80 ATP 16 CO2 Net = 106 ATP

  30. 2. การสลายกรด stearic ; (กรดไขมันอิ่มตัวมีคาร์บอน 18 ตัว ) ได้ 120 ATP C 18 : 0 Activation - 2 ATP AMP  - oxidation x 8 32 ATP 4 ATP x 8 TCA cycle x 9 90 ATP 10 ATP x 9 Net = 120 ATP 18 CO2 3. กรดไขมันไม่อิ่มตัว จะเป็นไปตามปกติจนกว่าจะถึงพันธะคู่ ของกรดไขมัน ซึ่งเป็นแบบ cis จะต้องมีเอนไซม์อื่นช่วยเปลี่ยนให้เป็นแบบ trans เพื่อให้เอนไซม์ตัวที่ 2 ของ  - oxidation ทำงานได้ เนื่องจากมีพันธะคู่แล้ว จึงไม่ได้ FADH2 (1.5 ATP) ทำให้ได้พลังงานน้อยลง 1.5ATP ต่อ 1 พันธะคู่

  31.  - OXIDATION OF FATTY ACIDS : - MICROSOME, PEROXISOME, MITO. (HEART , LIVER , OTHERS) - BRANCHED CHAIN FA , -OH – FA ( CEREBROSIDE in brain) CH3 CH2 CH2 COOH CH3 CH2 COOH + CO2 PHYTOL ( CHLOROPHYLL IN GREEN VEGETABLE ) ^ O COOH ( PHYTANIC ACID )  REFSUM’S DISEASE (phytanic acid storage disease) -hydroxylase deficiency -slowly progressive peripheral neuropathy with weakness and muscle wasting, combined with blindness -avoid green vegetables O2 Hydroxylase , Vc (dioxygenase) , 4H-biopterin H2O COOH -OH – FA dehydrogenase H2 OH COOH Lyase + oxidation O OH + CO2 Pristanic acid 3 Acetyl CoA 3 Propionyl CoA Isobutyryl CoA O

  32. + O2 CO2

  33.  - OXIDATION OF FATTY ACID : - LIVER MICROSOME - MEDIUM , LONG CHAIN FA. - OXYGENASE SYSTEM : ANIMAL : CYT. P 450, NADPH2 BACT : RUBRIDOXIN : HC , DETERGENT   O2 H3C COOH H2C COOH OH HC COOH O  - HOC COOH O

  34. FAOXIDATION :  - - - 1. SITE mitomicrosome 2. ORGAN generalgeneral, brain L , others 3. P’ way majorminor 4. FA even , oddBr , OH -MC , LC sat , unsat 5. ENZYME multioxygenase ( hydroxylase ) 6. PRODUCTS : Ac. CoAFA ( - 1C ) - Propionyl CoA+ CO2DI - COOH ^ 7. NEXT O : TCA  -  - ( KREBS )

  35. summary LIPOLYSIS

  36. KETOGENESIS -liver -mitochondrial matrix -significant amount of HMG-CoA synthase* -HMG CoA synthase is a rate-limiting enzyme -stimulated by fasting, dietary fat, insulin deficiency *

  37. KETOLYSIS • EXTRAHEPATIC TISSUES • brain, heart, kidney, skeletal tissue • mitochondrial matrix • -significant amount of -ketoacyl-CoAtransferase • (thiophorase)* • - stimulated by fasting, dietary • fat, insulin deficiency *

  38. KETOGENESIS AND KETOLYSIS

  39. Myocardial ischaemia reduced O2 -oxidation anaerobic glycolysis lactate increase acetyl CoA increase ketone bodies increase cell acidosis cell acidosis

  40. trimetazidine inhibits -ketothiolase in -oxidation inhibits fatty acid oxidation increases carbohydrate oxidation reduces lactate production higher cell pH reduces angina pectoris (chest pain)

  41. FA SYNTHESIS : cytosol , ACP palmitic acid Note: ACP = acyl carrier protein • liver, lactating mammary gland, adipose tissue Acetyl CoA + 7 malonyl CoA + 14 NADPH2 Palmitic Acid (C16) + 8 CoA + 14 NADP+ + 7 CO2 + 6 H2O

  42. A. Production of cytosolic acetyl CoA fat

  43. B. Carboxylation of acetyl CoA to form malonyl CoA

  44. CONTROL OF FATTY ACID SYNTHESIS NADH, Citrate activates acetyl CoA carboxylase Long chain fatty acyl CoA inhibits acetyl CoA carboxylase

  45. C. Major sources of NADPH required for fatty acid synthesis • Pentose phosphate pathway (major) • NAD(P)+ - dependent malate dehydrogenase • (malic enzyme) (minor)

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