Lipid metabolism

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Lipid metabolism
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Digestion of dietary lipids

• There are 2 important secretions that are
  essential for digestion of triglycerides
• 1) Bile salts
• Act as emulsifier
• 2) Pancreatic lipase
• Removes 2 fatty acids from triglycerides

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Action of pancreatic lipase
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Triacylglycerol degradation
O

CH2 - O - C - (CH2)n - CH3
O

CH - O - C - (CH2)n - CH3
O

CH2 - O - C - (CH2)n - CH3
Glycerol Fatty acid
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Why Fatty Acids are used for storage of energy?

• Two reasons
• The carbon in fatty acids (mostly CH2) is almost
  completely reduced (so its oxidation yields the
  most energy possible).
• Fatty acids are not hydrated (as mono- and
  polysaccharides are), so they can pack more
  closely in storage tissues
• Result fatty acids have 6 more energy of the
  corresponding amount of proteins or glycogen

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Hormones signal the release of fatty acids from
adipose tissue
Adrenaline
Insulin

cAMP
ATP
AMP
Inactive PK
Active PK
Inactive HSL
Active HSL
FFA glycerol
TG
HSL hormone sensitive lipase
PK protein kinase
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Fate of Glycerol

• From action of lipoprotein lipase and
  hormone-sensitive lipase
• Glycerol is converted to the Glycolysis/
  gluconeogenesis intermediate-- dihydroxyacetone
  phosphate

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• Glycerol is converted to dihydroxyacetone
  phosphate, by reactions catalyzed by
• 1 Glycerol Kinase
• 2 Glycerol Phosphate Dehydrogenase.

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b-Oxidation of fatty acids

• Martius Knoop (1902) fed dogs even- and
  odd-carbon fatty acids labelled with a benzene
  ring in place of the terminal methyl group.

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• Fatty acid oxidation occurs by removal of 2-C
  units at a time with oxidation at the b-carbon of
  the fatty acid

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Fatty Acid ?-Oxidation

• All cells except for RBCs and brain can use fatty
  acids for energy.
• ?-Oxidation occurs in Mitochondria
• Three Steps
• A.activation
• B.transport into mitochondria
• C.oxidation

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A. Fatty acid activation

• Acyl-CoA Synthetase of ER outer mitochondrial
  membranes, catalyzes fatty acid activation.

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Fatty Acid Activation

• fatty acid ATP ? acyladenylate PPi
• PPi ? 2 Pi
• acyladenylate HS-CoA ? acyl-CoA AMP
• Overall
• fatty acid ATP HS-CoA
• ? acyl-CoA AMP 2 Pi
• Exergonic hydrolysis of PPi (PP), catalyzed by
  Pyrophosphatase, makes the coupled reaction
  spontaneous.

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• Fatty acids are linked to CoA in the cytosol.
  Enzymes of the b-Oxidation Pathway are in the
  mitochondrial matrix.
• Transfer of the fatty acid across the inner
  membrane involves carnitine (??).

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B. Carnitine carries fatty acyl groups across the
inner mitochondrial membrane

• The carnitine shuttle system transfers long-chain
  fatty acyl CoA from the cytosol into the
  mitochondria

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Carnitine shuttle system
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C. The Reactions of b-oxidation

• The b oxidation pathway is cyclic.
• One round of b oxidation 4 enzyme steps produce
  acetyl CoA from fatty acyl CoA
• Strategy create a carbonyl group on the ?-C
• First 3 reactions do that fourth cleaves the
  "?-keto ester"
• Products an acetyl-CoA and a fatty acid two
  carbons shorter, FADH2, NADH

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• 1.Acyl-CoA Dehydrogenase catalyzes oxidation of
  the fatty acyl-CoA, to form a C2 to C3 double
  bond.

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• FAD is the e- acceptor for Acyl-CoA
  Dehydrogenase.
• FADH2 is reoxidized by transfer of 2 e- to an
  electron transfer flavoprotein (ETF), which
  passes 2 e- to coenzyme Q of the respiratory
  chain.

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• 2.Enoyl-CoA Hydratase catalyzes hydration of the
  trans double bond, yielding L-hydroxyacyl-Coenzyme
  A.

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• 3.Hydroxyacyl-CoA Dehydrogenase catalyzes
  oxidation of the hydroxyl in the b position (C3)
  to a ketone.
• NAD is the electron acceptor.

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• Process similar to succinate oxidation in the
  Citric Acid Cycle (dehydrogenation, hydration,
  dehydrogenation)

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• 4. b-Ketothiolase catalyzes thiolytic cleavage
  yielding fatty acyl-CoA (2 C shorter) and
  releasing Acetyl-CoA.

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H out
oxidation
1
1.5
(dehydrogenase)
hydration
2
H2O in
(hydratase)
b
H out
oxidation
3
2.5
(dehydrogenase)
b
Split
thiolysis
4
(thiolase)
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b- Oxidation Pathway

• The b oxidation pathway is cyclic. The product,
  2 C shorter, is the input to another round of the
  pathway.
• Products an acetyl-CoA and a fatty acid two
  carbons shorter, FADH2, NADH
• If the fatty acid contains an even number of C
  atoms, Final cleavage product is acetyl CoA.
• If the number is odd,final cleavage product is
  propionyl CoA .

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• one round of the b-oxidation pathway
• fatty acyl-CoA FAD NAD HS-CoA ?
• fatty acyl-CoA (2 C less) FADH2 NADH
  H acetyl-CoA
• Acetyl-CoA can enter Krebs cycle, yielding
  additional NADH, FADH2, and GTP

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Energetics of ?-Oxidation
Occurs only once
1.5
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14
14
10
2.5
Last 2 carbons dont undergo b oxidation
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14
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Complete ?- oxidation of 1 mol palmitic acid
yields 106 mol ATP

• How many cycles occurred in the oxidation of
  palmitic acid? (C/2) 1 (16/2) 1 7
• 14 ATP per cycle 7 14
  98
• the last 2 carbons
  10
• Subtract 2 for the initial activation 2
• Net ATP formed 106

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• Fatty acid oxidation is a major source of cell
  ATP
• It also produces large amounts of metabolic
  water( 130 H2O per palmitoyl-CoA).
• The ship of the desert sails on its own
  metabolic water.

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?-Oxidation of Unsaturated and Odd Chain Fatty
Acids

• Variations on ?-Oxidation - extra enzymes
  required
• Unsaturated FA (C181, C182, C183 and others)
• require two extra enzymes to get double bonds in
  the right place for enzymes of ?-oxidation to
  work(cis-trans isomerase, reductase)
• skip one or more oxidation steps -Slightly less
  Energy derived as these molecules are slightly
  more oxidized to begin with

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b- Oxidation of Odd-Chain Fatty Acids

• Odd-chain fatty acids occur in plants and
  microorganisms
• Final cleavage product is propionyl CoA rather
  than acetyl CoA
• Three enzymes convert propionyl CoA to succinyl
  CoA (citric acid cycle intermediate)

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Conversion of propionyl CoA to succinyl CoA

• Succinyl CoA --gt oxalacetate--gt glucose
  (gluconeogenesis)

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• During CHO starvation, oxaloacetate in liver is
  depleted due to gluconeogenesis. This impedes
  acetyl-CoA entry to Krebs cycle. Acetyl-CoA in
  liver mitochondria is converted then to ketone
  bodies.

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Metabolism of ketone bodies

• Acetone, Acetoacetate, ß- hydroxybutyrate are
  called ketone bodies.
• Produced in liver,Diffuse out of the liver into
  the blood .Acetone is exhaled by the lungs,
  Acetoacetate and beta hydroxybutyrate are taken
  up by extrahepatic tissues and catabolized for
  energy.

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Ketone bodies

• Fuel molecules
• derived from excess acetyl CoA
• Water soluble
• readily and quickly transported to other tissues
  for energy
• Major source of energy for brain in starvation
  (skeletal muscle and kidney, also)

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Ketone Bodies Oxidized in Mitochondria of
Extrahepatic Tissues