Download 4. KETONE BODY METABOLISM

Ketogenesis and Ketone Bodies.
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Ketogenesis and Ketone Bodies
In ketogenesis:
 Body fat breaks
down to meet
energy needs.
 Keto
compounds
called ketone
bodies form.
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Ketogenesis
What is it and What For ?
Ketogenesis is the conversion of long chain FA to the
Four- carbon acetoacetate and 3 hydroxy
butyrate (Ketone Bodies).
The primary utility of ketogenesis is to provide a
universally accepted * fuel for energy
production… ( an adaptive response in starvation)
*The Brain oxidizes KB but not Fat.
*Other Tissues oxidize KB and Fat.
Ketone bodies are a major fuel
in some tissues
Ketone bodies diffuse from the liver mitochondria into
the blood and are transported to peripheral tissues.
Heart muscle and the renal cortex use acetoacetate in
preference to glucose in physiological conditions.
The brain adapts to the utilization of acetoacetate
during starvation and diabetes.
Ketogenesis and Ketone Bodies
In ketogenesis:
 Two acetyl CoA molecules combine to form
acetoacetyl CoA.
 Acetoacetyl CoA hydrolyzes to acetoacetate.
 Acetoacetate reduces to -hydroxybutyrate or
loses CO2 to form acetone, both ketone bodies.
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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.
3-Hydroxybutyrate is formed by
the reduction of acetoacetate by
3-hydroxybutyrate
dehydrogenase.
Acetoacetate also undergoes a
slow, spontaneous
decarboxylation to acetone.
The odor of acetone may be
detected in the breath of a person
who has a high level of
acetoacetate in the blood.
Acetoacetate is activated by the
transfer of CoA from succinyl
CoA in a reaction catalyzed by a
specific CoA transferase.
Acetoacetyl CoA is cleaved by
thiolase to yield two molecules
of acetyl CoA (enter the citric
acid cycle).
CoA transferase is present in all
tissues except liver.
Ketone bodies are a watersoluble, transportable
form of acetyl units
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 ßoxidation 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.
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 malonylCoA 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.
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.
The main factors which control Ketogenesis
in the liver
1.
2.
3.
Availability of the substrate (Long Chain Fatty
Acids) : from increased production by lipolysis
with increased delivery of FA to the liver.
The level of Malonyl Co A in the liver, with its
influence to inhibit the Carnitine Palmitoyl
Transferase I (CPT I)
The Glucagon / Insulin Ratio : a high ratio
increases lipolysis and activation of oxidative
ketogenesis , a low ratio counteracts ketogenisis
Ketosis or Keto-Acidosis
A large accumulation of KB is dangerous, because it
leads to profound metabolic acidosis.
The physiologic Ketogenesis of fasting and
the adaptive ketosis in starvation never progress to life
threatening acidosis
Ketosis
Ketosis occurs:
 In diabetes, diets
high in fat, and
starvation.
 As ketone bodies
accumulate.
 When acidic ketone
bodies lowers blood
pH below 7.4
(acidosis).
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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).
 Carnitine is supplemented with diet.
CLINICAL ASPECTS (cont):
 2.
Deficiency of Carnitine palmitoyltransferase-I
and -II:
 I Deficiency– affects only liver, resulting in reduced
fatty
acid
oxidation
hypoglycemia.
and
ketogenesis
with
 II Deficiency– skeletal muscle
 Sulfonylureas (glyburide and tolbutamide) inhibit CPT
and reduce fatty acid oxidation
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 3ketoacyl-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.
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.
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:
 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.
Ketone Bodies and Diabetes
 The blood glucose is elevated
within 30 min following a meal
containing carbohydrates
 The elevated level of glucose
stimulates the secretion of
insulin, which increases the
flow of glucose into muscle
and adipose tissue for
synthesis of glycogen (+
stimulates glycolysis)
 As blood glucose levels drop,
the secretion of glucagon
increases, which stimulates the
breakdown of glycogen in the
liver to yield glucose
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Ketone Bodies and Diabetes
In diabetes:
 Insulin does not function properly.
 Glucose levels in muscle, liver, and
adipose tissue are insufficient for
energy needs.
 As a result, liver cells synthesize
glucose from non-carbohydrate
sources (gluconeogenesis) and fats
are broken down to acetyl CoA.
 The level of acetyl CoA is elevated.
 Excess acetyl CoA undergoes
ketogenesis.
 Ketogenesis produces ketone
bodies.
 Ketone bodies accumulate in the
blood.
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KETOSIS
The absence of insulin in diabetes mellitus
 liver cannot absorb glucose
 inhibition of glycolysis
 activation of gluconeogenesis
 activation of fatty acid
mobilization by adipose tissue
 deficit of oxaloacetate
 large amounts of acetyl CoA which can not be utilized in
Krebs cycle
 large amounts of ketone bodies (moderately strong acids)
 severe acidosis (ketosis)
Impairment of the tissue function, most importantly in the central
nervous system
Clinical correlations
Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB),
the two main ketone bodies of humans, are
important vectors of energy transport from the liver
to extrahepatic tissues, especially during fasting,
when glucose supply is low. Blood total ketone body
(TKB) levels should be evaluated in the context of
clinical history, such as fasting time and ketogenic
stresses. Blood TKB should also be evaluated in
parallel with blood glucose and free fatty acids
(FFA). The FFA/TKB ratio is especially useful for
evaluation of ketone body metabolism.
Insulin suppresses and glucagon and catecholamine
induces the following three steps: 1) free fatty acid
production in adipose tissues, 2) mitochondrial entry
of free fatty acids via malonyl-CoA, 3) ketone body
synthesis at the HMG-CoA syntase. Hence insulindominant conditions such as postprandial state or
hyperinsulinism, ketone production is strongly
suppressed. On the other hand, glucagon and
catecholamine-dominant conditions, such as
fasting, febrile, and/or stress conditions, ketone
production is induced.
Ketosis
Ketosis means a condtion in which blood ketone
level is equal or more than 0.2mM(200μmol/L).
Ketoacidosis is defined as a condition in which
blood ketone level is equal or more than 7 mM.
Blood ketone level decreases to about 0.05~0.1 mM
in postprandial condition, and increases up to 6mM
after 24-hour fast in young children. This means
ketone levels increases 100-fold after fasting.
Clinical symptoms for ketosis and ketoacidosis are
not specific but patients may have acetone
smelling. If ketoacidosis is severe, patients may have
polypnea and various degrees of unconsciousness.
Blood gas data is important to evaluate severity of
ketoacidosis.
Is blood pH less than 7.3? Non-physiological
(pathogenic) ketoacidosis has lower pH because
of insufficient respiratory compensation. For
evaluation of ketone body metabolism, simultaneous
measurement of blood glucose and free fatty acid,
together with blood ketone bodies, is essential.
Clinical judgment is also important to evaluate
ketone body metabolism.
What condition does your patient have ? for example,
two hours after meal, after 15hour-fasting, frequent
vomiting and appetine loss for 10 hours, two days
febrile, etc. Since fasting, febrile, and/or stress induce
ketone body production, the ketone body level in your
child should be evaluated clinically to be
physiological or lower or higher than you expected.
Acetonemic vomiting and ketotic
hypoglycemia are common causes of ketosis and
their symptoms includes vomiting and lethargy.
Hence if patients with such conditions look
serious, especially at the first attack, sufficient
metabolic tests should be done. Onsets of
acetonemic vomiting and ketotic hypoglycemia are
usually after the age of 1 and half years. The onsets
of inborn errors of ketone body utilization are
much earlier than those of acetonemic vomiting
and ketotic hypoglycemia. If you see a 1-year old
patient who is suspected to have severe acetonemic
vomiting or ketotic hypoglycemia, you should
consider underlying metabolic disorders.