KETONE BODY
METABOLISM
Dr.Siddiqui Abdulmoeed
Associate Professor of Biochemistry
College of Medicine
Al-jouf University
OBJECTIVES
• Define ketone bodies. List the functions of
ketone bodies
• Describe the synthesis of ketone bodies
(Ketogenesis)
• Describe the catabolism of ketone bodies
(ketogenolysis)
• Define Ketoacidosis, list its main metabolic
causes & explain its mechanism of occurrence.
Define ketone bodies.
KETONE BODIES [KBs] are water
soluble organic compounds
generated in human body under
certain metabolic conditions. The
compounds acetone, acetoacetate
and β–hydroxy butyrate are known as
ketone bodies.
Importance and functions
• Ketone bodies being water soluble are
easily transported from liver to various
tissues.
• The two ketone bodies acetoacetate and
β–hydroxy butyrate serve as important
sources of energy for peripheral tissues
like skeletal muscle, cardiac muscle, renal
cortex etc.
Importance ad functions-contd
• The production and utilization of KBs becomes
more significant when glucose is in short supply
to tissues as observed in starvation and diabetes
mellitus
• During prolonged starvation KBs are the major
source of fuel for brain and other parts of Central
Nervous System.
• RBCs lack mitochondria, hence cannot utilize
KBs.
Synthesis of Ketone bodies- ketogenesis
• Site of Ketogenesis:
•
It occurs in liver and the enzymes
responsible for it are located in
mitochondrial matrix
• Steps
•
•
•
•
•
Formation of Acetoacetyl CoA.
Enzyme involved is β-Thiolase.
Formation of HMG-CoA. Enzyme
involved is HMG Co A Synthase
which also regulates KB synthesis.
Breakdown of HMG-CoA to
acetoacetate and acetyl CoA by
HMG-CoA lyase.
spontaneous breakdown of
Acetoacetate to Acetone.
Formation of β-hydroxy butyrate by
enzyme β–hydroxy butyrate
dehydrogenase
Catabolism of ketone bodies (ketolysis)
• During prolonged starvation KBs are the
major source of fuel for brain and other
parts of Central Nervous System.
• This an adaptation to survive during periods
of food deprivation.
Liver lacks Thiophorase enzyme hence
cannot utilize KBs
• .
Ketone Bodies As Energy Sources
In liver
-Hydroxybutyrate
Acetoacetate
Acetoacetate is major energy
source in cardiac muscle and
renal cortex; also in brain in
starvation and diabetes
Succinyl CoA
Thiophores
Not found in liver
Thiolase
2 Acetyl CoA
Acetoacetyl CoA
Succinate
Combines with
oxaloacetate
TCA Cycle
8
Ketoacidosis
• In normal humans there is a constant
production of ketone bodies by liver and their
utilization by extra hepatic tissues.
• The blood level of KBs is about 1 mg/dl in a
normal human adult. Their excretion in urine is
very low and undetectable by routine tests.
• When the rate of synthesis of ketone bodies
exceeds the rate of utilization , their level
increases in blood. This is known as ketonemia.
• Ketonemia is produced due to increased
production rather than decreased utilization.
• In ketinemia , the excretion of KBs increases in
urine, this is known as ketonuria.
• The overall picture of ketnemia and ketonuraia is
called as Ketosis.
• Both acetoacetate and β–hydroxy butyrate are
strong acids. They dissociate in blood and
release H+ ions, which lowers the pH. This
decrease in blood pH as a result of severe
ketosis is called as Ketoacidosis.
Metabolic causes of Ketoacidosis
• Starvation:
– In starvation the fatty acids [and amino acids]
are used for energy needs of the body after
the glucose reserves are finished.
– This results in overproduction of Acetyl CoA
which is not fully handled by TCA cycle .
– TCA cycle is impaired due to deficiency of
oxaloacetate which is diverted to
gluconeogenesis.
– The final result is overproduction of KBs from
acetyl CoA.
• Diabetes Mellitus
– Uncontrolled DM is associated with
impaired carbohydrate metabolism and
increased lipolysis, both of which lead to
accumulation of Acetyl CoA and its
ultimate conversion to KBs.
– In severe Diabetes the KB levels in
blood may reach as high as 100 mg /dl
and urinary excretion may be as high
as 500 mg/day.
– In diabetes loss of glucose and water in
urine leads to decrease in blood volume
and further complicate the condition.
– Diabetic Ketoacidosis is dangerous and
may result in coma and death if
untreated.
– Ketosis due to starvation is usually not
accompanied by Ketoacidosis
Thanks &
Best
Wishes