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LIPID METABOLISM.

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Presentation on theme: "LIPID METABOLISM."— Presentation transcript:

1 LIPID METABOLISM

2 Metabolism (Catabolism and Anabolism), Regulation and
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 -Eicosanoids

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

4 R – COOH carboxylic acid O R – C - acyl = FA -
GLYCEROL MG DG TG R – COOH carboxylic acid CHOLESTEROL – FA = CH. ESTER O R – C - acyl = FA - FA FA FA FA FA P P-X P-X PA PL LYSO-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 duodenum small intestine
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 DIGESTION AND ABSORPTION OF LIPIDS
pan.lipase apoprotein MG MG LCTG FA FA TG 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

8 CHYLOMICRON

9 steatorrhea Possible causes of 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

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

11 ; 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 lingual lipase

12 FATTY ACIDS :     1. CHAIN : RCOOH
short chain (SC) medium chain (MC) long chain (LC) very long chain (VLC) (<4) (6 – 12) ( ) (>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, : 3▲9,12, : 4▲5,8,11,14

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

14 FATTY ACID ACTIVATION AND TRANSPORT
Activation: cytosol O RCOOH + CoA + ATP RCSCoA + 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

15 mito-memb. cytosol matrix outer inner
ACTIVATION TRANSLOCATION 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

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

17 BETA – OXIDATION (not found in nerve and red cells)
(-) 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 - DHase 2 FADH2 R – CH2 – CH = CH – CO ~S CoA ▲2- TRANS - ENOYL CoA H2O 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

18

19

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

21 B12 DEF : PROPIONIC ; Mt – MALONIC ACID
FATE OF PROPIONYL CoA : COOH CO2 ATP ADP , Pi CH2 CH3 HC CH3 C ~ S CoA C ~ S CoA CARBOXYLASE O O ( B7 ) ( BIOTIN ) PROPIONYL CoA D – Mt – MALONYL 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 )

22 Acyl CoA dehydrogenase 1. short-chain acyl CoA dehydrogenase
- oxidised 4 and 6 carbon 2. medium-chain acyl CoA dehydrogenase - oxidised carbon 3. long-chain acyl CoA dehydrogenase - oxidised 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

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

24 UNSAT. double bond at an odd-numbered carbon
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 Ac. CoA 12 3 O ISOMERASE ▲3 - CIS - O 12 S CoA 6Ac. CoA 2 ▲2 - TRANS -

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

26 POLYUNSAT. Acyl CoA DH

27 cis

28 -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

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

30 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

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

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

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

34  - 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 H2O (dioxygenase) , 4H-biopterin COOH -OH – FA dehydrogenase H2 OH COOH Lyase + oxidation O OH + CO2 Pristanic acid Isobutyryl CoA 3 Acetyl CoA 3 Propionyl CoA O

35 + O2 CO2

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

37 2. ORGAN general general, brain L , others
FA OXIDATION :    - 1. SITE mito microsome 2. ORGAN general general, brain L , others 3. P’ way major minor 4. FA even , odd Br , OH - MC , LC sat , unsat 5. ENZYME multi oxygenase ( hydroxylase ) 6. PRODUCTS : Ac. CoA FA ( - 1C )  - Propionyl CoA + CO2 DI - COOH 7. NEXT O : TCA   - ^ ( KREBS )

38 summary LIPOLYSIS

39 -mitochondrial matrix -significant amount of HMG-CoA synthase*
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 *

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

41 KETOGENESIS AND KETOLYSIS

42

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

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

45 liver, lactating mammary gland, adipose tissue
FA SYNTHESIS : cytosol , ACP palmitic acid Note: ACP = acyl carrier protein liver, lactating mammary gland, adipose tissue Acetyl CoA malonyl CoA NADPH2 Palmitic Acid (C16) CoA NADP CO H2O

46 A. Production of cytosolic acetyl CoA
fat

47 B. Carboxylation of acetyl CoA to form malonyl CoA

48

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

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

51

52 D. Fatty acid synthesis Palmitoyl thioesterase (TE) Liberation of palmitate product

53

54 TE TE

55 FATTY ACID SYNTHESIS synthase transacetylase transferase

56 FATTY ACID SYNTHESIS TE

57 2. MICROSOME : SAT. , UNSAT. FA ; Mal. CoA
FA ELONGATION : 1. MITO : SAT. FA ; Ac. CoA 2. MICROSOME : SAT. , UNSAT. FA ; Mal. CoA PEROXISOME : VERY LONG CHAIN FA : Ac. CoA Peroxisome are required for normal brain development and function and formation of myelin, the whitest substance that coats the nerve fiber and are also required for normal eye, liver, kidney and bone functions. Defects called Zellweger syndrome. R CH2 COSCoA NADPH ACETYL CoA ( MITO ) elongase R (CH2)3 COSCoA NADP CoA

58 β-trans-Enoyl-CoA reductase

59 FA. DESATURATION : SAT. FA UNSAT. FA
desaturase FA. DESATURATION : SAT. FA UNSAT. FA - MICROSOME ; ER of liver , adipose tissue - MONOXYGENASE SYSTEM : NADPH2 , O2 CH3 – (CH2)7 – CH2 – CH2 – (CH2)7 –COOH NADPH2 , O2 desaturase CH3 – (CH2)7 – CH = CH – (CH2)7 –COOH NADP+ + 2H2O

60 DESATURATION OF FATTY ACID
non-heme iron

61 FATTY ACID SYNTHESIS IN PLANT AND ANIMAL
essential fatty acid deficiency - dermatitis - poor wound healing (in mammals) EPA and DHA support neural and visual development Eicosanoids synthesis (ω6-series)

62 FISH OIL - Linolenic, C 18:3 6, 9, 12 C 18:4 6, 9, 12, 15 -2H
Linoleic, C 18: ,  - Linolenic, C 18: , 12, 15 (C 18:2n-6) (C 18:3n-3) -2H 6 - desaturase - Linolenic, C 18: , 9, C 18: , 9, 12, 15 (C 18:3n-6) (C 18:4n-3) C2 elongase Dinorno - y - linolenic, C 20: , 11, C 20: , 11, 14, 17 (C 20:3n-6) (C 20:4n-3) -2H 5 - desaturase Arachidonic, C 20: , 8, 11, 14 Eicosapentaenoic, C 20: , 8, 11, 14, 17 (C 20:4n-6) (C 20:5n-3) C2 EPA elongase C 22: , 10, 13, C 22: , 10, 13, 16, 19 (C 22:4n-6) (C 22:5n-3) -2H 4 -desaturase FISH OIL C 22: , 7 10, 13, C 22: , 7, 10, 13, 16, 19 (C 22:5n-6) (C 22:6n-3) Docosahexaenoic DHA

63 Fish oil benefit (ω3-series)
- supports brain and retina development - slow or prevent progression of osteoarthritis by inhibition : proteoglycan (aggrecan) degrading enzyme (aggrecanase) : expression of inflammation- inducible cytokines - IL-1α - TNF-α - cyclooxygenase-2 (COX-2) not COX-1

64 Function of COX - constitutive COX-1 : cytoprotective stomach
: renal function : platelet homeostasis : vascular tone of endothelium - inducible COX-2 : เกี่ยวข้องกับการอักเสบ ทำให้ปวด บวม ร้อน Note: COX เป็นเอนไซม์ที่เปลี่ยน arachidonic acid ให้เป็น PGs ชนิดต่างๆ มีตัวยับยั้งคือ aspirin and NSAIDs

65 SUMMARY OF FA SYNTHESIS + ELONGATION
(Ac.CoA) C C2 - C (MALONYL CoA) ATP + CO2 1 2NADPH2 2NADPH2 CO2 C2 - C2 3 CO2 2 C2 - C C2 2CO2 C2+2C3 CH3- CH2 - CH2 - CH2 - CH2 COOH C6 : 0 C6 : CH3 CH2 - CH = CH - CH2 COOH + C2 C8 : CH3 CH2 - CH = CH - CH2 CH CH2 COOH DESATURATION : -H2 , NADPH2 , O2 STEARIC ; CH3 : -(CH2)7 - CH2 - CH2 - (CH2) 7 COOH (C18 : 0) OLEIC ; CH3 : -(CH2)7 - CH = CH - (CH2)7 COOH (C18 : 1 9) PLANT -2H ANIMAL, คน 9 LINOLEIC (ω-6) C18 : , C18: , 9 (ω-9) (ω-3) H C18 : , 6, 9 LINOLENIC C18 : , 12, 15

66 Triacylglycerol (fat) synthesis
Glycerol phosphate production Liver and adipose tissue synthesized from dihydroxyacetone phosphate (DHAP) by glycerol phosphate dehydrogenase 2. Liver synthesized from glycerol by glycerol kinase

67 SYNTHESIS OF GLYCEROL 3 - PO4
INSULIN LIVER AND ADIPOCYTE LIVER ONLY

68 3. Conversion of free fatty acid to its activated form
- Attached to CoA by fatty acyl CoA synthetase before participating in TG synthesis

69

70 4. Fate of TG - TG is stored in adipose tissue and serves as depot fat - TG in liver is exported through apo B-100 in the form of lipoprotein particles called VLDL and secreted into the blood to the peripheral tissue

71 VLDL C Apo C-II Apo C-III
Tg, triglyceride; CE, cholesterol ester; FC, free cholesterol; Pl, phospholipid

72 adipocyte (visceral fat) adipocytokines (adipokines)
- plasminogen activator inhibitor-1 (PAI-1) tumor necrosis factor-α (TNF- α) : induce inflammation : thrombosis and insulin resistance adiponectin : insulin-sensitizing, anti-atherogenic effect interleukin-6 (IL-6) monocyte chemotactic protein-1(MCP-1) : inflammation : กระตุ้น NADPH oxidase reactive oxygen species (ROS) T2DM, CAD, liver cancer

73 Obesity Elevated levels of fatty acids
increase oxidative stress via NADPH oxidase activation - decrease antioxidant enzymes In addition, T2DM are accompanied with obesity thus the elevated levels of fatty acids will increase oxidative stress via NADPH oxidase activation leading to antioxidant enzymes reduction such as SOD (superoxide dismutase), catalase and GSH-PX (Glutathione peroxide)

74 NEFA (nonesterified fatty acid or free fatty acid) ยับยั้ง glycolysis ในกล้ามเนื้อ และกระตุ้น gluconeogenesis ที่ตับ ทำให้เกิด hyperglycemia Insulin resistance T2DM

75 Fatty liver ก. steatosis โดยเฉพาะในตับ ทำให้เกิด insulin resistance ยังไม่มีอาการของตับ risk factors 1. DM 2. protein mulnutrition 3. hypertension 4. obesity 5. anoxia 6. alcohol 7. cell toxin

76 ข. non-alcoholic steatohepatitis (NASH)
Alcohol and FA synthesis Ethanol + NAD+ Acetaldehyde + NADH Acetyl CoA+ NADH Alcohol DH Aldehyde DH, NAD+ ข. non-alcoholic steatohepatitis (NASH) มีอาการตับอักเสบเรื้อรังเกิดจาก TNF-α ที่ไม่ได้เกิดจากเชื้อ hepatitis B, C, alcohol หรือรับประทานยา

77

78 Treatment - reduce weight by diet control - follow healthy diet
- increase physical activity - avoid alcohol - avoid unnecessary medications - metformin and orlistat may be used - take antioxidants

79 Cholesterol synthesis
cholesterol is the least soluble membrane lipid only important membrane steroid in animals most of it are in the form of “free” (unesterified) cholesterol in cellular membrane - brain contains large amounts of cholesterol - brain is considered as unhealthy kind of food - also used for synthesized steroid hormones and bile salts

80 Steroid hormones Progestins (Progesterone) Glucocorticoids (Cortisol)
Mineralocorticoids ( Aldosterone) Androgens (Testosterone) Estrogens (Estradiol)

81 CHOLESTEROL SYNTHESIS
occur in liver and intestine cytosol, ER

82 CHOLESTEROL SYNTHESIS
* Regulation of cholesterol synthesis - HMG CoA reductase is allosteric enzyme - feedback-inhibited by free cholesterol - insulin stimulates HMG CoA reductase

83

84 liver intestine

85 HMG CoA REDUCTASE INHIBITORS

86 Plant sterols inhibit cholesterol absorption
found in cereals and vegetables (most), fruit (less)

87 EXOGENOUS DIET CHOLESTEROL
ENDOGENOUS SYNTHESIS PERIPHERAL LIVER C TISSUE INTESTINE EXOGENOUS DIET CHOLESTEROL SAT. FA ไขมันสัตว์ กะทิ สมอง ไข่แดง ตับ เนย หอยนางรม LDL-RECEPTOR RESIN HMG CoA REDUCTASE INHIBITORS CHOLESTEROL CATABOLISM EXCRETION HORMONES: STEROID SEX CELL MEMB. BILE ACIDS COPROSTEROL FECES CHOLESTEROL METABOLISM

88 CBH MET. IN LIVER

89 LIPID MET. IN LIVER

90 DIABETES MELLITUS 1.IDDM: INSULIN DEPENDENT
2.NIDDM: INSULIN INDEPENDENT

91

92

93

94

95 LIPID METABOLISM IN DIABETES MELLITUS
CHOLESTEROL KETOLYSIS ( Is dependent,indirect )


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