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1. KETONE BODIES
METABOLISM
BY
Dr KHALED SALEH ALGARIRI
IMS – MSU
January 2015

2. OBJECTIVES
 What are Ketone Bodies ?
 How they are produced and Utilized ?
 How ketone body metabolism is regulated ?
 When and why excess amount of ketone bodies are produced ?
 What is Ketosis and Ketoacidosis ?
 Biochemical basis for diabetic and starvation ketosis and
ketoacidosis.

3. INTRODUCTION
 When there is a adequate balance between .
Lipid and carbohydrate metabolism, most of the
acetyl CoA produced from the B-oxidation
pathway is further processed through the citric
acid cycle.
 The first step of the citric acid cycle involves the
reaction between oxaloacetate and acetyl
CoA. Sufficient oxaloacetate must be
present for the acetyl CoA to react with.

4.  Certain body conditions upset the lipid-carbohydrate
balance required for acetyl CoA generated by fatty acids to
be processed by the citric acid cycle. These condition
include
 dietary intake high in fat and low in carbohydrates
 Diabetic condition where the body cannot adequately
processed glucose even though it is present
 Prolonged fasting condition, including starvation,
where glycogen supplies are exhausted.
Under these conditions, the problem of adequate oxaloacetate
supplies arises, which is compounded by the body’s using
oxaloacetate that is present to produce glucose through
gluconeogenesis.

5.  Ketone body is one of the three substances
( acetoacetate, B- hydroxybutyrate and
acetone) produced from acetyl CoA when an
excess of acetyl CoA from fatty acid
dergadation accumulates because of
triacylglycerol- carbohydrate metabolic
inbalances. The structural formulas for the
three ketone bodies, two of which are C4
molecules and the other a C3 molecule.

7. Triglyceride
Fatty
Acids
Glycerol
Albumin
adipose
tissue
Fatty
Acids
liver
Fatty Acids
Fatty
Acids
albumin
Acetyl Co A
b-
oxidation
Energy for the Brain and
Extrahepatic tissues
TCA
Cycle
Hormone
Sensitive
Lipase
Glucagon
Epinephrine
Glucocorticoids
+
1
3
2
Fatty
Acids
mitochondria
Ketone
Bodies

8. Ketone bodies
are synthesized
only in liver

9. KETOGENESIS
Ketogenesis takes place in liver using Acetyl co A as a substrate
or a precursor molecule.
Enzymes responsible for ketone body formation are associated
mainly with the mitochondria
• step 1: first condensation:
• Ketogenesis begins as two acetyl CoA molecules combine to
produce acetoacetate CoA, a reversal af the step of the B-
oxidation.
• Step 2: second condensation:
• Acetoacetyl CoA then reacts with a third acetyl CoA and water
to produced 3-hydroxy-3-methlglutary CoA and CoA-SH

10. • Step 3: Chain cleavage.
HMG-CoA is then cleaved to acetyl CoA and
Acetoacetate.
• Step 4: Reduction:
Acetoacetate is reduced to B-hydroxybutyrate. The
reducing agent is NADH.

11. KETOGENESIS

12. The ratio of [3 Hydroxybutyrate] / [Acetoacetate] in
blood varies from 1:1 to 10:1
Acetone is volatile – Expelled out through Lungs
Acetoacetate and 3 Hydroxybutyrate are excreted
through urine
Liver is not able to utilize ketone bodies due to the
absence of the enzyme required to activate acetoacetate
Extrahepatic tissues contain the enzyme required to
activate acetoacetate (They are able to utilize ketone
bodies)
KETOGENESIS

13. β-Hydroxybutyrate
Succinyl CoA
CoA
transferase
CoA-SH
Thiolase
KETOLYSIS
NADHNAD+
The liver has acetoacetate available to
supply to other organs because it
lacks the particular CoA
transferase and that is the reason
that “Ketone bodies are
synthesized in the liver but
utilized in the peripheral tissues”.
β-Hydroxybutyrate
dehydrogenase

16. The liver extracts about 30% of the free
fatty acids passing through it
The factors regulating mobilization of free fatty
acids from adipose tissue are important in
controlling oxidation of fatty acids
Increased Mobilization of fatty acid
Increased Ketogenesis
REGULATION OF KETOGENESIS
Regulated at three crucial steps
1) Lipolysis in Adipose tissue

17. Ketogenesis does not occur unless there is an increase
in the level of circulating free fatty acids that arise
from lipolysis of triacylglycerol in adipose tissue.
 When glucose levels fall, lipolysis induced by
glucagon secretion causes increased hepatic
ketogenesis due to increased substrate (free fatty
acids) delivery from adipose tissue.
 Conversely, insulin, released in the well-fed state,
inhibits ketogenesis via the triggering
dephosphorylation and inactivation of adipose
tissue hormone sensitive lipase (HSL).

18. 2) Fate of fatty acid-free fatty acids are
either oxidized to CO2 or ketone bodies or esterified
to triacylglycerol and phospholipids.
 There is regulation of entry of fatty acids into the
oxidative pathway by carnitine Acyl transferase-
I (CAT-I)
 Malonyl-CoA, the initial intermediate in fatty acid
biosynthesis formed by acetyl-CoA carboxylase in the
fed state, is a potent inhibitor of CAT-I .
 Under these conditions, free fatty acids enter the liver
cell in low concentrations and are nearly all esterified
to acylglycerols and transported out of the liver in very
low density lipoproteins (VLDL).

19. Carnitine Acyl Transferase-I (CAT-I)
[INSULIN] /
[GLUCAGON]
Triglycerol
Fatty Acid
AcetylCoA
Carboxylase
Citrate
Oxaloacetate
Pyruvate
Oxaloacetate
Glucose
Acetyl CoA
Malonyl CoA
Pyruvate
Citrate
CAT - I
_
[INSULIN] /
[GLUCAGON]

20. 3) Fate of Acetyl Co A
 The acetyl-CoA formed in beta-oxidation is oxidized
in the citric acid cycle, or it enters the pathway of
ketogenesis to form ketone bodies.
 As the level of serum free fatty acids is raised,
proportionately more free fatty acids are converted to
ketone bodies and less are oxidized via the citric acid
cycle to CO2.
 Entry of acetyl CoA into the citric acid cycle depends
on the availability of Oxaloacetate for the formation of
citrate, but the concentration of Oxaloacetate is
lowered if carbohydrate is unavailable or improperly
utilized.

21.  Ketosis is a disorder of excessive production of
ketone bodies
 The concentration of total ketone bodies in blood
of well fed mammals does not exceed 0.2mmol/L
 Loss via urine is usually less than 1 mg/24h in
humans
 Blood level of ketone bodies increased –
Ketonemia
 Excretion of ketone bodies in urine increased -
Ketonuria
KETOSIS/ KETONEMIA & KETONURIA

22. CLINICAL SIGNIFICANCE of KETOACIDOSIS
Ketone bodies (acetoacetic acid & 3-OH Butyric acid ) are
acidic in nature
Hydrogen ions are neutralized by bicarbonate (HCO3
-) of the
blood. Bicarbonate (HCO3
-) level of the blood decreases
and results metabolic acidosis.
When ketone bodies are released in large quantities the
normal pH-buffering mechanisms are overloaded ; the
reduced pH, in combination with a number of other
metabolic abnormalities results in KETOACIDOSIS.
In severe ketoacidosis, cells begin to lose ability to use ketone
bodies also.

23. CLINICAL FEATURES OF KETOSIS
 Acidosis
 Smell of acetone in patient's breath.
 Osmotic diuresis induced by ketonuria may lead to
dehydration
 Sodium loss (The ketone bodies are excreted in urine as
their sodium salt)
 Dehydration
 Coma

24. seen when there is excess fatty acid
oxidation by the liver
KETOACIDOSIS
Excess fatty acid oxidation by the liver – when
there is excess mobilization of the fatty acids
from adipose tissue
Excess mobilization of fat from adipose tissue
when (Insulin : Glucagon)
1.Uncontrolled Diabetes Mellitus:
Diabetic ketoacidosis
2. Prolonged Starvation:
Starvation Ketoacidosis

25. STARVATION INDUCED KETOSIS
Prolonged fasting may result
 From an inability to obtain food
 from the desire to lose weight rapidly, or in clinical
situations in which an individual cannot eat because of
trauma, surgery, neoplasms, burns etc.
 In the absence of food the plasma levels of glucose, amino
acids and triacylglycerols fall,
 triggering a decline in insulin secretion and an increase
in glucagon release.

26.  The decreased insulin to glucagon ratio, makes this period of
nutritional deprivation a catabolic state, characterized by
degradation of glycogen, triacylglycerol and protein.
 This sets in to motion an exchange of substrates between liver,
adipose tissue, muscle and brain that is guided by two
priorities-
 (i) the need to maintain glucose level to sustain the energy
metabolism of brain ,red blood cells and other glucose
requiring cells and
 (ii) to supply energy to other tissues by mobilizing fatty
acids from adipose tissues and converting them to ketone
bodies to supply energy to other cells of the body.
STARVATION INDUCED KETOSIS

27.  After about 3 days of starving liver forms lot of ketone
bodies
• Brain fulfils 1/3 of its energy needs from Acetoacetate.
• Heart also uses Ketone bodies
 After several weeks of starvation ketone bodies become
major fuel of brain (brain derives 60-75% of energy from
ketone bodies under conditions of prolonged starvation)
 Now only 40gm glucose / day is needed by brain
compared to 120 gm/day on 1st day of starvation

28. DIABETIC KETOACIDOSIS
 Diabetic Ketoacidosis (DKA) is a state of inadequate insulin
levels resulting in high blood sugar and accumulation of organic
acids and ketones in the blood.
 It happens predominantly in type 1 diabetes mellitus,
 But can also occur in type 2 diabetes mellitus under certain
circumstances.
 This may be due to intercurrent illness (pneumonia,
influenza, gastroenteritis, a urinary tract infection), pregnancy,
inadequate insulin administration (e.g. defective insulin pen
device), myocardial infarction (heart attack), stroke or the use
of cocaine.

29. STARVATION KETOACIDOSIS
Excess mobilization of fatty acids
Hyperglucagonemia alters hepatic metabolism to
favour ketone body formation, through activation of the
enzyme carnitine palmitoyltransferase I(CPT-I).
Excess b-oxidation of fatty acids in the hepatocytes
Excess ketone body formation
[INSULIN] / [GLUCAGON]
Blood glucose level is decreased

30. DIABETIC KETOACIDOSIS
The decreased ratio of insulin to Glucagon promotes
Gluconeogenesis, glycogenolysis, and Ketone body
formation in the liver, as well as increases in substrate delivery
fr from fat and muscle (free fatty acids, amino acids) to the liver
Hyperglucagonemia alters hepatic metabolism to
favor ketone body formation, through activation of the
enzyme carnitine palmitoyltransferase -I.
Excess b-oxidation of fatty acids in the hepatocytes
Excess ketone body formation
DKA results from relative or absolute insulin deficiency combined
with counter regulatory hormone excess( Glucagon, cortisol, and
growth hormone). [Insulin/Glucagon]

31. Diabetic Ketoacidosis may be diagnosed when the combination
of hyperglycemia (high blood sugars), ketones on urinalysis
and acidosis are demonstrated.
DIABETIC KETOACIDOSIS

32. MANAGEMENT OF KETOACIDOSIS
 Treatment is to give insulin and glucose
1- When glucose and insulin are given
intravenously, potassium is trapped within the cells
2-Fatal hypokalemia can occur
3-Clinician should always monitor the electrolytes
 Administration of bicarbonate, and maintenance of
electrolyte and fluid balance