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LIPID METABOLISM.

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

1 LIPID METABOLISM

2 Lipid Digestion, Absorption, and Transport
Triglycerides ~ 90% of dietary lipids Metabolic NRG storage Oxidized to CO2 and H2O

3 oxidation state than glucose metabolism of fats yields ~9 kcal/gram
Triglyerides, cont… oxidation state than glucose metabolism of fats yields ~9 kcal/gram vs ~4 kcal/gm Carbohydrates, proteins

4 Triglyceride Storage, cont…
Stored in anhydrous state Non-polar Provide ~ 6 times energy of hydrated glycogen

5 Triglyceride storage, cont…
Stored in large quantities in cells Non-reactive with other cell components Segregated into lipid droplets Do not affect osmolarity of cytosol

6 To be used as fuel: insoluble in H2O
Triglycerides, cont… To be used as fuel: insoluble in H2O Must emulsify before lipid digestion in intestine Must be “carried” in blood (proteins)

7 Three cellular sources
Triglycerides, cont… Sources of fat Three cellular sources Fat in diet Fat stored in cells Fat synthesized in one organ and transported to another

8 Fats obtained vary by organism Vertebrates
Triglycerides, cont… Fats obtained vary by organism Vertebrates Fat in diet Fat in adipose tissue Convert excess carbohydrate to fat in liver for export

9 Humans Industrialized countries:
Triglycerides, cont… Humans Industrialized countries: ~ 40% of daily calorie consumption is fat Should be < 30%! Atkins kills…

10 Humans, Triglycerides, cont…
Used for > half the energy in: Liver Heart Resting skeletal muscle

11 Humans, Triglycerides, cont…
Hibernating animals and migrating birds sole source of NRG Higher plants: Do not depend on fats for energy Germinating seeds

12 Triglyceride digestion
Lipid digestion, cont… Digestion Triglyceride digestion takes place at lipid-water interfaces Rate is based on surface area at interfaces Peristalsis Emulsification by bile

13 Bile Synthesized from cholesterol, biliverdin By liver
Lipid digestion, cont… Bile Synthesized from cholesterol, biliverdin By liver Stored in gallbladder Released after ingestion of fat

14 Lipid digestion, Bile, cont…
Acts as digestive detergent Converts dietary fats into mixed micelles Micelles contain bile salts and triglycerides

15 Role of lipase Pancreatic lipase:
Lipid digestion, cont… Role of lipase Pancreatic lipase: catalyzes hydrolysis of triglycerides At 1 and 3 positions sequentially Forms 1,2-diglycerol glycerol Soap

16 Role of lipase, Lipid digestion, cont…
Phospholipase A: Pancreatic enzyme Degrades phospholipids Hydrolysis at C(2)

17 Molecules diffuse into cells of intestine Facilitated by bile salts
Absorption of Lipids Absorption Molecules diffuse into cells of intestine Facilitated by bile salts Micelles transport non-polar lipids across aqueous boundary layer

18 Bile salts essential Fatty Acids Fat soluble vitamins A,D,E & K
Absorption, cont… Bile salts essential Fatty Acids Fat soluble vitamins A,D,E & K Biliary disease interferes

19 Lipid Uptake in Vertebrates

20 Reconversion: in mucosa cells Lipid digestive products  triglycerides
Role of Lipase, cont… Reconversion: in mucosa cells Lipid digestive products  triglycerides Packaged into Chylomicrons Lipoprotein aggregates Triglycerides, cholesterol, protein

21 Chylomicron Aggregate of triglycerides, cholesterol, and proteins

22 Reconversion, Role of Lipase, cont…
Released into bloodstream: Via lymphatic system Lacteals Triglycerides synthesized in liver Packaged in VLDL Directly released into blood

23 Form classes based on density
Role of lipase, cont… Transport APOLIPOPROTEINS: lipid-binding blood proteins Transport between organs Form classes based on density

24 Proteins on outside of Chylomicron Are apoproteins
Role of lipase, cont… Proteins on outside of Chylomicron Are apoproteins Act as cell surface receptors for recognition (apo C-II)

25 Lipid Uptake in Vertebrates

26 Transport, Role Chylomicrons, cont…
Chylomicrons and VLDL: Move triglycerides, cholesterol To Skeletal muscle & adipose LIPOPROTEIN LIPASE an extracellular enzyme Activated by apo C II Hydrolyzes triglycerides

27 Chylomicron Carry triglycerides, cholesterol to tissues via lymphatic system (lacteals)

28 Transport, Role of lipase, cont…
Deletes lipoprotein from triglyceride Forms IDL Then LDL LDL: ( mg/dl) removed from plasma at liver, adrenals, adipose HDL: (above 35 mg/dl) moves cholesterol from tissues Sends to liver for excretion in bile salts Ratio LDL:HDL = 2:1

29 Lipid Metabolism, cont…
Uptake by cells FA taken in by: muscle: oxidized for NRG adipose: stored as triglyceride

30 Lipid Uptake in Vertebrates

31 Transport, Role of lipase, cont…
Glycerol Transported to liver or kidney Converted to dihydroxyacetone phosphate And then???

32 Pathway to Glycolosis Conversion of glycerol to dihydroxyacetone phosphate

33 Transport, Role of lipase, cont…
Remnants of Chylomicrons triglycerides; cholesterol and apoproteins (apo E, apo B-48) To liver Uptake by endocytosis Triggered by apolipoproteins

34 Uptake in Liver via Endocytosis

35 Chylomicron Remnants, cont…
Triglycerides Oxidized for energy or Converted to ketone bodies Excess fatty acid Convert to triglycerides Pack into VLDL To adipose for storage

36 Lipid Uptake in Vertebrates

37 Mobilization of Stored Fats
Mobilization of stored triglycerides Triggered by hormones Stimulus is in blood glucose Hormones: Epinephrine Glucagon

38 Mobilization of Stored Fats, Hormone Action, cont…
Activate adenylate cyclase in adipocyte plasma membrane Increases cAMP Activates protein kinase Activates triglycerol lipase Catalyzes hydrolysis of ester bonds in triglycerides

39 Mobilization of Stored Fats
Action of second messenger hormones triggers mobilization of stored triglycerides

40 Free fatty acid released into bloodstream
Role of lipase, cont… Free fatty acid released into bloodstream Binds to serum albumin Carried to tissues Released to diffuse into cells

41 NOTE: Glycerol  glycerol-3-phosphate dihydroxyacetone phosphate 
Role of lipase, cont… NOTE: Glycerol  glycerol-3-phosphate dihydroxyacetone phosphate  glycolysis

42 II. Fatty Acid Oxidation
FA activation: Free FA cannot enter Mitochondria Occurs in cytosol Acyl-CoA synthetases (thiokinases) 3 isozymes mitochondrial membrane

43 FA + CoA + ATP  fatty acyl-CoA + AMP + PPi
FA activation, cont... FA + CoA + ATP  fatty acyl-CoA + AMP + PPi different acyl-CoA’s work on different FA Fatty acyl-CoA: high energy compound

44 Fatty acid oxidation, cont…
Transport across mitochondrial membrane: Formation of fatty acyl-carnitine Carnitine acyl transferase I Outer face of inner membrane Fatty acyl from CoA  carnitine CoA released  cytoplasm

45 Transport across mitochondrial membrane, cont…
Acyl-carnitine/carnitine transporter Carrier Fatty acyl-carnitine  matrix carnitine  to inter-membrane space Facilitated diffusion

46 F.A. Entry into Mitochondria

47 Fatty acid oxidation, cont…
Transfer of acyl from Carnitine to intra-mitochondrial membrane Carnitine acyltransferase II Inner face of inner membrane Regenerates fatty acyl-CoA Frees carnitine  returns to cytosol

48 Carnitine Acyltransferase II, cont…
Two separate pools of CoA (ATP, NAD+) Cytoplasm: makes FA Mitochondria: oxidative degradation Pyruvate FA AA

49 ß-oxidation ß-oxidation: FA dismembered to fatty acyl-CoA
Mitochondrial oxidation of FA Stage One: ß-oxidation Remove 2-C chunks as acetyl-CoA Begins at carboxyl end of fatty acid chain

50 ß-Oxidation Fatty acids are dismembered into Acetyl-CoA subunits
Each acetyl Co-A sends 4 H to NAD, FAD

51 Mitochondrial oxidation, cont…
For example, 16C palmitic acid  acetyl CoA Stage Two: oxidation of acetyl-CoA  CO2 Stage Three: oxidative phosphorylation  ATP (+H2O)

52 ß oxidation, cont… ß oxidation: 4 reactions
Formation of a trans – a, ß double bond Between C-2 (a) and C-3 (ß) Yields: Trans-∆2-enoyl-CoA Acyl-CoA dehydrogenase FAD  2 ATP Similar to succinate dehydration

53 ß-Oxidation First: formation of double bond
Second: hydration of double bond Third: dehydrogenation Fourth: cleavage to Acetyl Co-A

54 Hydration of the double bond
ß-oxidation, cont… Hydration of the double bond By enoyl-CoA hydrase Forms 3-L-hydroxyacyl-CoA Similar to fumarase reaction

55 Dehydrogenation By ß-hydroxyacyl-CoA dehydrogenase To ß-ketoacyl-CoA
ß-oxidation, cont… Dehydrogenation By ß-hydroxyacyl-CoA dehydrogenase To ß-ketoacyl-CoA NAD  3 ATP Similar to malate dehydrogenase reaction

56 Ca -Cß cleavage (thiolysis)
ß-oxidation, cont… Ca -Cß cleavage (thiolysis) Catalyzed by ß-ketoacyl-CoA thiolase (thiolase) Produces: acetyl-CoA fatty acyl-CoA (2 carbons short)

57 ß oxidation: Enzymes in Mitochondrial membranes
3 kinds of acyl-CoA dehydrogenase Specify short, medium, long chain fatty acid Medium-chain acyl-CoA dehydrogenase (MCAD) Deficient in ~10% of SIDS babies More common than PKU

58 Sites of Mitochondrial Enzymes

59 Fatty acid oxidation is highly exergonic Each round of ß-oxidation
ß-oxidation, cont… Fatty acid oxidation is highly exergonic Each round of ß-oxidation 1 NADH 1 FADH2 1 acetyl-CoA

60 ß-oxidation, Energy Payoff
Acetyl-CoA  citric acid cycle Example: PALMITOYL-CoA (16C) 7 rounds of ß -oxidation  7 NADH FADH acetyl CoA So, NADH = 31 x 3 = 93 ATP FADH2 = 15 x 2 = 30 ATP GTP 131 hi-energy molecules for fatty acyl CoA ATP 129 total

61 ß-oxidation, cont… READ IN TEXT: Oxidation of unsaturated fatty acid: additional reactions Oxidation of odd-chain fatty acid: additional reactions

62 III. Ketone Bodies Acetyl-CoA from ß-oxidation
Enters citric acid cycle Converted to KETONE BODIES Water-soluble “equivalent” of FA

63 Ketogenesis Occurs in liver: Primary ketone bodies
Ketone bodies, cont… Ketogenesis Occurs in liver: acetyl CoA  ketone bodies Primary ketone bodies Acetoacetate - out of liver D-ß-hydroxybutyrate - out of liver Acetone - exhaled

64 Ketone Body Formation

65 Function: fuel for peripheral tissues Heart, skeletal muscle Brain
Ketone bodies, cont… Function: fuel for peripheral tissues Heart, skeletal muscle Brain Normal fuel is glucose In starvation: ketone bodies Enzyme production adapts over time >40 days, provide 70% energy

66 Production and transportation
Ketone bodies, cont… Production and transportation Determined by availability of oxaloacetate Combine with acetyl group enter TCA cycle

67 Oxaloacetate pulled from citric acid cycle Used in gluconeogenesis
Ketone bodies, cont… In starvation Oxaloacetate pulled from citric acid cycle Used in gluconeogenesis [oxaloacetate] decreases therefore little  kreb’s cycle Production of ketone bodies is favored

68 Production and transportation, cont…
Overproduction: starvation, diabetes Moved from liver to other tissues Allows fatty acid oxidation in liver In tissues: ketone bodies converted back to acetyl-CoA

69 Production and transportation, cont…
Formation of ketone bodies from acetyl-CoA occurs in the mitochondrial matrix thiolase 2 Acetyl-CoA acetoacetyl-CoA Acetoacetyl-CoA + acetyl-CoA  ß -hydroxy- ß -methylglutaryl-CoA HMG-CoA  free acetoacetate + acetyl-CoA

70 Production and transportation, cont…
Acetoacetate  D- ß -hydroxybutyrate dehydrogenase D-ß-hydroxybutyrate Acetoacetate decarboxylase Acetone High in uncontrolled diabetes

71 Production and transportation, cont…
Ketosis Pathological Acetoacetate produced too fast for elimination Breath smells like acetone Blood pH decreases  acidosis

72 Lipid Biosynthesis “Reverse” of lipid catabolism Know differences
Where in the cell does each occur? What are the e- transport molecules? What are the acyl group carriers? Where does acetyl Co-A “fit into” each set of reactions?

73 Pathway Differences

74 Fatty Acid Biosynthesis
Read in Text For major steps, know Type of reaction Enzyme Product

75 Cholesterol Biosynthesis
Read in Text Know Draw steps Intermediates

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