LIPID METABOLISM

1
LIPID METABOLISM

• BY
• Dr OJ Tsotetsi

2
Lipid Metabolism
3
Lipid Metabolism
4
Where when are fatty acids synthesized?

• Synthesis of Fatty Acids (FA) occurs primarily in
  the liver and lactating mammary gland, less so in
  adipose tissue
• FA are synthesized from acetyl CoA derived from
  excess protein and carbohydrate
• FA synthesis uses ATP and NADPH as energy sources

5
FA synthesis requireslots of acetyl CoA

• Transfer of acetyl CoA from mitochondria to
  cytosol involves the citrate shuttle
• Occurs when citrate concentration in mitochondria
  is high due to inhibition of isocitrate
  dehydrogenase by high levels of ATP. (Note
  High ATP levels are also required for FA
  synthesis.)

6
First step in FA synthesis is synthesis of
malonyl CoA

• Energy to form C-C bonds is supplied indirectly
  by synthesizing malonyl CoA from acetyl CoA using
  ATP and CO2
• The reaction is catalyzed by Acetyl CoA
  carboxylase

7
FA synthesis

• After 7 cycles, palmitoyl-S-ACP is produced and
  palmitate is released by palmitoyl thioesterase
• Overall reaction is

8 acetyl CoA 14 NADPH 14H 7ATP
palmitate 8CoA 14 NADP 7ADP 7 Pi 7H2O
8
FA synthesis

• Further elongation and desaturation of palmitate
  and dietary FAs (if required) occurs in
  mitochondria and ER by diverse enzymes

9
FA synthesis

• Sources of NADPH for FA synthesis are the hexose
  monophosphate pathway and the malic enzyme
  reaction that converts malate to pyruvate NADPH
  in the cytosol

10
Fatty Acid Oxidation
11
Beta-oxidation of fatty acids

• ß-oxidation of FA produces acetyl CoA and NADH
  and FADH2, which are sources of energy (ATP)
• First, FA are converted to acyl CoA in the
  cytoplasm

12

• Where does beta-oxidation of fatty acids take
  place?

13
Carnitine shuttle

• For transport into mitochondria, CoA is replaced
  with carnitine by acylcarnitine transferase I
• Inside mitochondria a corresponding enzyme (II)
  forms acyl CoA
• Malonyl CoA inhibits acylcarnitine transferase I
• So, when FA synthesis is active, FA are not
  transported into mitochondria
• Defects in FA transport (including carnitine
  deficiency) are known

14
Reactions of beta-oxidation

• The cycle of reactions is repeated until the
  fatty acid is converted to acetyl CoA

15
Beta Oxidation
16
Energy yield from beta-oxidationof fatty acids

• For palmitate (160) the overall reaction is
• Palmitate 8CoA 7NAD 7FAD 7H2O
• 8 Acetyl CoA 7NADH 7FADH2 7 H
• Energy yield as ATP for palmitate
• 7 FADH2 1.5 x 7 10.5 ATP
• 7 NADH 2.5 x 7 17.5 ATP
• 8 Acetyl CoA 10 x 8 80 ATP
• Total 108 ATP
• But, two high energy bonds used in acyl CoA
  formation, so overall yield is 106 ATP. Why do
  we subtract two ATPs?

17
Energy yield from beta-oxidationof fatty acids

• Energy yield as ATP for palmitic acid
• 7 FADH2 1.5 x 7 10.5 ATP
• 7 NADH 2.5 x 7 17.5 ATP
• 8 Acetyl CoA 10 x 8 80 ATP
• Total 108 ATP
• Two high energy bonds used in acyl CoA formation,
  so overall yield is 106 ATP

18
Beta-oxidation of unsaturated fatty acids

• Unsaturated FA yield a bit less energy than
  saturated FA because they are already partially
  oxidized
• Less FADH2 is produced

19
Why do the Lippincott and Garrett Grisham texts
give different ATP yields for complete oxidation
of palmitate?

• Beta oxidation occurs in mitochondria, so NADH
  and FADH2 can be used directly in electron
  transport, and acetyl CoA can also be used
  directly for production of energy via TCA cycle.
• Theoretical yield of ATP from NADH or FADH2
• 2 ATP per FADH2
• 3 ATP per NADH
• Energy yield as ATP for palmitic acid
• 7 FADH2 2 x 7 14 ATP
• 7 NADH 3 x 7 21 ATP
• 8 Acetyl CoA 12 x 8 96 ATP
• Total 131 ATP
• Two high energy bonds used in fatty acyl CoA
  (palmitoyl CoA) formation, so overall yield is
  129 ATP (according to the Lippincott book)

20
Actual yield of ATP from NADH or FADH2 is thought
to be lower than the theoretical yield because

• Membranes leak some H without forming ATP
• Some of the proton gradient drives other
  mitochondrial processes
• So, actual yield is thought to be closer to
• 1.5 ATP per FADH2
• 2.5 ATP per NADH
• Actual energy yield as ATP for palmitic acid is
  therefore
• 7 FADH2 1.5 x 7 10.5 ATP
• 7 NADH 2.5 x 7 17.5 ATP
• 8 Acetyl CoA 10 x 8 80 ATP
• Total 108 ATP
• Minus the two high energy bonds used in fatty
  acyl CoA formation
• 106 ATP

21
Beta-oxidation of odd-chain fatty acids

• Odd-chain FA degradation yields acetyl CoAs and
  one propionyl CoA
• Propionyl CoA is metabolized by carboxylation to
  methylmalonyl CoA (carboxylase is a biotin
  enzyme)
• Methyl carbon is moved within the molecule by
  methylmalonyl CoA mutase (one of only two Vitamin
  B12 cofactor enzymes) to form succinyl CoA

22
Are fatty acids glucogenic?

• Fatty acids are not glucogenic in animals
• Why cant we make glucose from fatty acids?
• Why are the statements above only 99 true?

23
Ketone bodies

• Excess acetyl CoA (from FA or carbohydrate
  degradation) is converted in liver to ketone
  bodies acetoacetate, acetone, and
  ß-hydroxybutyrate
• Ketone bodies are soluble in blood and can be
  taken up and used by various tissues (muscle,
  heart, renal cortex) to regenerate acetyl CoA for
  energy production via the TCA cycle
• Even brain can use ketone bodies as their
  concentrations in blood rise enough

24
Regulation of Beta Oxidation

• Largely by concentration of free fatty acids
  available
• Malonyl CoAinhibits carnitine transferase which
  will inhibit entry of acyl CoA into mitochondria

25
Ketone bodies

• Acetoacetyl CoA is formed by incomplete FA
  degradation or by condensation of two acetyl CoAs
  by thiolase
• Acetoacetyl CoA condenses with a third acetyl CoA
  to form hydroxymethylglutaryl CoA (HMG-CoA)
• HMG-CoA is cleaved to produce acetoacetate
  acetyl CoA
• Reduction of acetoacetate to ß-hydroxybutyrate,
  or spontaneous decarboxylation to acetone,
  produces the other two ketone bodies

26
KETONE BODIES

• Are an easy way of transporting the energy stored
  in fat from the liver to other tissues because
  they are soluble in the blood.

27

• In tissues that use ketone bodies, acetoacetate
  is condensed with CoA by transfer from succinyl
  CoA
• acetoacetyl CoA can then be converted to two
  acetyl CoAs

28
Ketone bodies

• Excessive ketone bodies can be produced in
  diabetes mellitus or starvation (a lot of acetyl
  CoA in liver)
• When rate of production exceeds utilization,
  ketonemia, ketonuria, and acidemia can result

29
acknowledgement
https//www-s.med.uiuc.edu/m1/biochemistry
Medical biobhemistry