Fatty acid oxidation & ketone bodies

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Fatty Acid Oxidation and Ketone Bodies

• M.Prasad Naidu
• MSc Medical Biochemistry,
• Ph.D.Research Scholar

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OXIDATION OF FATTY ACIDS KETOGENESIS

• The initial event in the utilization of fat as an
  energy source is the hydrolysis of
  triacylglycerol by lipases

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• Epinephrine, norepinephrine, glucagon, and
  adrenocorticotropic hormone stimulate the
  adenylate cyclase of adipose cells, and thus
  cause lipolysis.

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Fatty acids are synthesized and degraded by
different mechanisms

• Fatty acids are both oxidized to acetyl-CoA and
  synthesized from acetyl-CoA. Although the
  staring material of one process is identical to
  the product of the other, fatty acid oxidation is
  not the simple reverse of fatty acid
  biosynthesis. It is an entirely different
  process taking place in separate compartment of
  the cell. This allows each process to be
  individually controlled.

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Fatty acids are synthesized and degraded by
different mechanisms Synthesis
Oxidation

• Cytosol
• Intermediates are covalently linked to ACP
• Fatty acid synthase contain multienzyme
  activities
• Utilizes NADP as coenzyme
• Requires both ATP and bicarbonate ion

• Mitochondrial matrix
• Bonded to CoA
• Degradative enzymes are not associated
• Utilizes NAD and FAD as coenzymes
• Generates ATP
• Aerobic process

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Step 1 Activation of fatty acids to acyl-CoA
Acyl-CoA synthetases are found in the endoplasmic
reticulum, peroxisomes, and inside and on the
outer membrane of mitochondria. Several acyl-CoA
synthetases have been described, each for fatty
acids of different chain length.
Acyl CoA AMP 2Pi 2H
R-COO- CoA ATP H20
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Step 2 Long-chain fatty acids penetrate inner
mitochondrial membrane as carnitine derivatives.
Carnitine (ß-hydroxy-g-trimethylammonium
butyrate) is widely distributed and abundant in
muscle. Carnitine palmitoyltransferase-I,
present in the outer mitochondrial membrane,
catalyzes the following reaction
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Step 3 ß-oxidation of fatty acids involves
successive cleavage with release of acetyl-CoA.
Fatty acid oxidase are found in the mitochondrial
matrix or inner membrane adjacent to the
respiratory chain in the inner membrane.
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Oxidation of unsaturated fatty acids occurs by a
modified b-oxidation pathway
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 Oxidation of fatty acids produces a large
quantity of ATP Palmitoyl CoA 7 FAD 7 NAD
7 CoA 7H2O  8 acetyl CoA 7
FADH2 7 NADH 7 H Oxidation of NADH -
3ATP '' FADH2 - 2 ATP
'' Acetyl-CoA - 12 ATP 7 FADH2 yields 147
NADH yields 218 acetyl-CoA yields 96 Total 131
ATP 2 high energy phosphate bonds are consumed
in the activation of palmitate Net yield is 129
ATP or 129 X 51.6 6656 kJ
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TRIACYLGLYCEROLS ARE HIGHLY CONCENTRATED ENERGY
STORES
The initial event in the utilization of fat as an
energy source is the hydrolysis of
triacylglycerol by lipases.
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 -Reduced and anhydrous Complete oxidation of
fatty acids yields 9 kCal/g, where as, proteins
and carbohydrates yield 4 kCal/g. A 70 kg
man 100,000 kCal in triacylglycerols 25,00
0 kCal in proteins (muscles) 600 kCal in
glycogen 400 kCal in glucose -Triacylglycer
ols constitute about 11 kg of his total body
weight. If this amount were stored in glycogen,
his total body weight would be 55 kg greater.-In
mammals, the major site of accummulation of
triacylglycerols is the cytoplasm of adipose
cells (fat cells). Droplets of triacylglycerol
coalesce to form a large globule, which may
occupy most of the cell volume. -Adipose cells
are specialized for the synthesis and storage of
triacylglycerols and for their mobilization into
fuel molecules that are transported to other
tissues by the blood.
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Peroxisomes oxidize very long chain fatty acids

• Very long chain acyl-CoA synthetase facilitates
  the oxidation of very long chain fatty acids
  (e.g., C20, C22). These enzymes are induced by
  high-fat diets and by hypolipidemic drugs such as
  Clofibrate. ß-oxidation takes place and ends at
  octanoyl-CoA. It is subsequently removed from
  the peroxisomes in the form of octanoyl and
  acetylcarnitine, and both are further oxidized in
  mitochondria.

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a- and w-oxidation of fatty acids are specialized
pathways

•  a-oxidation i.e., removal of one carbon at a
  time from the carboxyl end of the molecule has
  been detected in brain tissue. It does not
  generate CoA intermediates and does not generate
  high-energy phosphates.
•  w-oxidation is a minor pathway and is brought
  about by cytochrome P450 in the endoplasmic
  reticulum. CH3 group is converted to a -CH2OH
  group that subsequently is oxidized to -COOH,
  thus forming a dicarboxylic acid. They
  subsequently undergo ß-oxidation and are excreted
  in the urine.

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KETOGENESIS

• It occurs when there is a high rate of fatty acid
  oxidation in the liver
• These three substances are collectively known as
  the ketone bodies (also called acetone bodies or
  acetone). Enzymes responsible for ketone bodies
  formation are associated with mitochondria.

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KETOGENESIS IS REGULATED AT THREE CRUCIAL STEPS

• 1. Adipose tissue Factors regulating
  mobilization of free fatty acids from adipose
  tissue are important in controlling ketogenesis
• 2. Liver After acylation, fatty acids undergo
  ß-oxidation or esterified to triacylglycerol or
  ketone bodies.
• a. CPT-1 regulates entry of long-chain acyl
  groups into mitochondria prior to ß-oxidation.
  Its activity is low in the fed state, and high in
  starvation.

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• Fed state Malonyl-CoA formed in the fed state
  is a potent inhibitor of CPT-1. Under these
  conditions, free fatty acids enter the liver cell
  in low concentrations and are nearly all
  esterified to acylglycerols and transported out
  as VLDL.
• Starvation Free fatty acid concentration
  increases with starvation, acetyl-CoA carboxylase
  is inhibited and malonyl-CoA decreases releasing
  the inhibition of CPT-I and allowing more
  ß-oxidation.
• These events are reinforced in starvation by
  decrease in insulin/glucagon ratio. This causes
  inhibition of acetyl-CoA carboxylase in the liver
  by phosphorylation.

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• In short, ß-oxidation from free fatty acids is
  controlled by the CPT-I gateway into the
  mitochondria, and the balance of free fatty acid
  uptake not oxidized is esterified.
• 3. Acetyl-CoA formed from ß-oxidation of fatty
  acids is either oxidized in TCA cycle or it forms
  ketone bodies.

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CLINICAL ASPECTS

• 1. Carnitine-deficiency can occur in newborn
  or preterm infants owing to inadequate
  biosynthesis or renal leakage. Losses can also
  occur in hemodialysis.
• Symptoms hypoglycemia due to reduced
  gluconeogenesis resulting from impaired fatty
  acid oxidation, resulting in muscle weakness
  (Reye's syndrome).
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• Carnitine is supplemented with diet.
•  
•  

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CLINICAL ASPECTS (cont)

• 2. Deficiency of Carnitine palmitoyltransferase-I
  and -II
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• I Deficiency affects only liver, resulting in
  reduced fatty acid oxidation and ketogenesis with
  hypoglycemia.
• II Deficiency skeletal muscle
• Sulfonylureas (glyburide and tolbutamide) inhibit
  CPT and reduce fatty acid oxidation

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CLINICAL ASPECTS (cont)

• 3. Inherited defects in the ß-oxidation lead to
  nonketotic hypoglycemia, coma, and fatty liver.
  Defects in long-chain 3-hydroxyacyl-CoA
  dehydrogenase, short-chain 3-hydroxyacyl-CoA
  dehydrogenase and 3-ketoacyl-CoA thiolase,
  HMG-CoA lyase are known.
• 4. Jamaican vomiting sickness It is caused by
  eating unripe fruit of the akee tree which
  contains a toxin, hypoglycin, that inactivates
  medium-and short-chain acyl-CoA dehydrogenase,
  inhibiting ß-oxidation resulting in hypoglycemia
  with excretion of medium- and short-chain mono-
  and dicarboxylic acids.

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CLINICAL ASPECTS (cont)

• 5. Dicarboxylic aciduria It is characterized
  by excretion of C6-C10 w-dicarboxylic acids and
  by nonketotic hypoglycemia due to deficiency of
  medium-chain acyl-CoA dehydrogenase. This
  impairs ß-oxidation but increases w-oxidation
  which are then shortened by ß-oxidation to
  medium-chain dicarboxylic acids, which are
  excreted.
• 6. Refsum's disease A rare neurologic disorder
  caused by accumulation of phytanic acid, formed
  from phytol, a constituent of chlorophyll.
  Phytanic acid contains a methyl group on carbon 3
  that blocks ß-oxidation. Normally, an initial
  a-oxidation removes the methyl group, but
  person's with this disease have an inherited
  deficiency in a-oxidation.

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CLINICAL ASPECTS (cont)

• 7. Zellweger's (cerebrohepatorenal) syndrome
  Due to rare inherited absence of peroxisomes in
  all tissues. They accumulate C26-C38 polynoic
  acids in brain tissue owing to inability to
  oxidize long-chain fatty acids in peroxisomes.
• Ketoacidosis results from prolonged ketosis
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• Ketonemia- higher than normal quantities of
  ketone bodies in blood 
• Ketonuria- higher than normal quantities of
  ketone bodies in urine. 
• Ketosis the overall condition is called ketosis.