There are three important ketone bodies - aceto-acetate, acetone, and β-hydroxybutyrate. Ketone body synthesis occurs in the liver from acetyl-CoA but their utilization occurs in other tissues like cardiac muscle and brain. Ketone bodies are produced during periods of fasting or starvation and act as an alternative fuel source. Increased ketone body production can lead to metabolic acidosis if the buffering system is overwhelmed by too many hydrogen ions being released.

1. By
Dr. Inayat ur Rahman Abbasi
MBBS, M.Phil Biochemistry
Associate Professor of Biochemistry
Azad Jammu & Kashmir Medical
College Muzaffarabad

2.  There are three important compounds in the body
which are collectively called ketone bodies or
acetone bodies or incorrectly ketones,
 Because all ketones are not KB and all KB are not
chemically ketones.
Dr. Inayat u Rahman Abbasi 2

3.  These are Aceto-acetate (primary KB), Acetone &
β-Hydroxy Butyrate (secondary KB).
 Ketogenesis starts from mitochondrial Acetyl CoA
in Liver, synthesis is mainly hepatic in nature but
liver due to absence of enzyme thiophrase or
Aceto-acety CoA transferase is unable to utilized
KB as source of energy.
 So KB’s synthesis is hepatic but their utilization is
extra-hepatic in nature.
Dr. Inayat u Rahman Abbasi 3

4.  These are the source of energy (when needed)
especially for cardiac, skeletal muscles, brain
and adrenal cortex.
 These are soluble in aquous solution, so in
plasma these are transported as such and do not
required any lipoproteins.
Dr. Inayat u Rahman Abbasi 4

5.  Ketogenesis and their utilization is
taking place even in normal
conditions but both process occur at
slow level in such a way that their
normal level remains <1.0 mg/dl.
Dr. Inayat u Rahman Abbasi 5

6.  KB concentration when increased in body
indicates:
 Excessive production acetyl CoA (increased
Lipolysis) or
 Depressed utilization of acetyl CoA by TCA-Cycle.
 Main causes are uncontrolled Diabetes,
starvation, prolonged fasting, excessive diarrhea/
vomiting.
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7.  Ketone bodies (being an acid) when increased in
plasma, liberate H+ ions, which are buffered by
HCO3-/H2CO3 buffere system. But if their
production is high, buffer will fail leading to high
concentration of H+ ion or decrease pH of plasma
causing metabolic Acidosis.
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8.  Aceto-acetate is first to form called Primary KB
while other KB are formed from it & are called
Secondary KB.
 Acetone is the only volatile KB that can be expired
through lungs, giving typical smell in breath;
especially seen in uncontrolled Diabetes or DKA.
While β-OH-butyrate is the KB that is found in
highest conc. in blood. Ketosis is the combination
of ketonaemia & ketonuria
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9.  Two molecules of Acetyl CoA are condensed to
form Aceto-acetyl CoA by Aceto-acetyl CoA
synthase enzyme, to that one more molecule of
Acetyl CoA is added to form HMG-CoA by HMG-
CoA synthase enzyme.
 This is a rate limiting step of ketogenesis,
Dr. Inayat u Rahman Abbasi 9

10.  upto HMG-CoA production keto-
genesis and cholesterol synthesis
both share the same steps,
 after that two cycles have difference,
 cytocolic HMG-CoA reduced to form
cholesterol
 while mitochondrial HMG-CoA is
lysed to form ketone bodies.
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11.  Finally HMG-CoA (a 6-carbon compound) is lysed
to form first primary KB called Aceto-acetate,
 this KB is not only form from Acetyl-CoA but can
also be form from degredation of carbon skeleton
of some ketogenic amino acids like Isoleu, leu,
Phe, Lys, Tyr etc.
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12.  Once aceto-acetate is formed it can give rise to
two other KB called secondary KB.
 Aceto-acetate can be spontenously
decarboxylated (without any enzyme) to form
Acetone
 or it can be dehydrogenated by NADH-dependant
dehydrogenase to form β-OH-butyrate.
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13.  2 x Acetyl CoA (2C)
 ↓ Synthase
 Aceto-acetyl CoA (4C) + Acetyl CoA
(2C)
 ↓ Synthase
 HMG- CoA (6C)
 ↓ Lyase
 Aceto-Acetate + Acetyl CoA
 Decarboxylase↓Dehydrogenase
 Acetone (3C) OR β-OH-butyrate (4C)
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14.  Ketosis when present shows excessive lipolysis in
the body or excessive burn of body fats to provide
energy in body.
 Signs & symptoms are increase urination,
vomiting, dehydration and coma.
 While laboratory findings are increased KB in
blood, increased H+ or ↓pH of blood, increased
urinary KB and Na+ excretion.
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