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Transcript
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Fatty Acid Oxidation and Ketone Bodies
OXIDATION OF FATTY ACIDS: KETOGENESIS
The initial event in the utilization of fat as an energy source is the hydrolysis of
triacylglycerol by lipases
Epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone
stimulate the adenylate cyclase of adipose cells, and thus cause lipolysis.
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
Mitochondrial matrix
Intermediates are covalently •
Bonded to CoA
linked to ACP
Fatty acid synthase contain
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Degradative enzymes are not
multi enzyme activities
associated
Utilizes NADP+ as coenzyme
Requires both ATP and
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Utilizes NAD+ and FAD as
bicarbonate ion
coenzymes
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Generates ATP
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Aerobic process
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.
R-COO- + CoA + ATP + H20-> Acyl CoA + AMP + 2Pi + 2H+
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:
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.
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
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FADH2 - 2 ATP
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Acetyl-CoA - 12 ATP
7 FADH2 yields 14
7 NADH yields 21
8 acetyl-CoA yields 96
Total 131 ATP
2 high energy phosphate bonds are consumed in activation of palmitate
Net yield is 129 ATP or 129 X 51.6 = 6656 kJ
Triacylglycerols are highly concentrated energy stores
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
25,000 kCal in proteins (muscles)
600 kCal in glycogen
400 kCal in glucose
Triacylglycerols 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.
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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.
- and -oxidation of fatty acids are specialized pathways
-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.
-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.
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.
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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.
Fed state
Fed state:
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Malonyl-CoA formed in the fed state is a potent inhibitor of CPT-1.
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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
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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.
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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.
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).
Carnitine is supplemented with diet.
Clinical aspects:
2. Deficiency of Carnitine palmitoyltransferase-I and -II:
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
Clinical aspects:
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.
5.
Clinical aspects:
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.
Clinical aspects:
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:
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.
The end