THE KETONE BODIES: FROM

PROVIDERS OF ENERGY FOR

LIFE TO FATAL KILLERS

By
Prof Morsi Arab
University of Alexandria, Egypt
The Fed State

Storage
Body Energy in {The Fed State}

1. Provision of Energy : by continuous supply from

ingested glucose and fat.

2. Storing of Energy :
In the liver: (Glycogen ) up to 1000 Kcal
In Fat Depots (TG) up to 100000 Kcal

3 Tissue utilization of fuel for Energy:

All Tissues can use glucose or FA .
Except the Brain , only glucose .
In The { Fasting } and { Starvation } States

I. In An Over night Fast

1. Glycogen stores are depleted .(shortage of
glucose)
2. Fat has to be utilized for energy : (TG)

FA + Glycerol
(oxidation for energy) (is used for neoglucogenesis
in the liver )
Acetyl CoA

Ketone Bodies (KB) up to 0.1 - 0.4 mM

II. In Prolonged Fasting ( Starvation ) up to 7-10 mM

Adipose
Blood Liver
Tissue

Insulin

Delivery

FFA

Ketogenesis

KB Glucagon
Insulin
Utilization

Brain
Muscles
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: KB).

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.
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
The Chemical Sequence from FA
to KB (through Acetyl Co A)
2 Acetyl Co A2 Acetoacetyl CoA+CoA
Aceto acetyl Co A +Acetyl Co A
Hydoxymethyl Glutaryl Co A
3. Hyrdoxymethyl Glutaryl Co A
Acetoacetate + Acetyl Co A
4. Acetoacetate + NADH = H2
3-Hydroxy Butyrate
The Mitochondria and the
Carnitine CoA Shuttle

The mitochondria play a major role in

ketogenesis.
Medium chain FA easily enter the
mitochondria , but Long chain FA require
a shuttle to get inside (The Carnitine CoA
Shuttle)
Carnitine Shuttle
The Carnitine CoA Shuttle
Reaction
LCFA (outside MC)----------------- Carnitine
(Carnitine Palmitoyl Transferase I- CPT I)
Carnitine -----------------LCFA (inside MC )
(Carnitine Palmitoyl Transferase II CPT II)
..
Therefore , the CPT I enzyme is a key control
in FA oxidation and in Ketogenesis
Carnitine FA
Co A

CPT1 Malonyl CoA

CPT II

Glucagon

X
KB
Acetyl Co A
The role of Malonyl Co A in Ketogenesis

Malonyl Co A is derived from Acetyl Co A

A high level of Malonyl Co A in the hepatocyte

inhibits the activity of CPT I
and so it damps down ketogenesis.

Insulin increases the production of Malonyl

Co A from Acetyl Co A
 The Role of Insulin in
Ketogenesis
Lack of insulin has been long known to be
related to development of ketosis.

The presence of Insulin blocks Lipolysis, the

source of FFA delivery to the liver, the
substrate needed for ketogenesis.
Insulin increases poduction of Malonyl Co A
(so, inhibits CPT I damps ketogenesis,
inspite of any increased substrate FFA delivery)
 Glucagon and Ketogenesis
Diabetes is not only a disease of Insulin deficiency
but also excess Glucagon.
Glucagon has ketogenic activity . It plays this
role in regulation of ketogenesis independent
from insulin .. ( It activates FA oxidation at the
expense of TG synthesis
The Glucagon / Insulin ratio is more important
than the absolute value of either, in determining
the metabolic events in the hepatocyte
The main factors which control
Ketogenesis in the liver
1. Availability of the substrate (Long Chain Fatty
Acids) : from increased production by lipolysis
with increased delivery of FA to the liver.
2. The level of Malonyl Co A in the liver, with its
influence to inhibit the Carnitine Palmitoyl
Transferase I (CPT I)
3. The Glucagon / Insulin Ratio : a high ratio
increases lipolysis and activation of oxidative
ketogenesis , a low ratio counteracts
ketogenisis

Ketogenesis under
Patho- physiolocal states
 Ketone Bodies in Obesity
1. In obesity, FFA and KB levels are
elevated (independent on normal or
impaired glucose tolerance)
2. KB Clearance is also diminished.
3. But, following an oral glucose load FFA
and KB levels are lowered.
 Ketone Bodies in Type 2
Diabetes
1 FFA and KB are usually elevated
(circulating KB may increase 3 folds in non
obese diabetics even if FFA are normal.)
N.B. Why KB level is increased in type 2
diabetes inspite of increased insulin
(which should counteract ketogenesis ) ?
- because of an also increased Glucagon,
(with finally a lower Insulin / Glucagon
ratio)
 Ketone Bodies in Type 1
Diabetes
1.Insulin is deficient
2. FFA and KB are increased , ketogenesis is
activated to provide energy source substitute.
3. FFA uptake across the splancnic area is
increased . Delivery of FFA substrate to the liver
is not blocked (absence of the blocking effect of
insulin )
3. KB Clearance is diminished.
4. An unrestricted KB accumulation leads to
metabolic acidosis (Diabetic Keto-acidosis )
 Ketone Bodies in
Hyperthyroidism
1. Increased lipolysis ( more FFA) =
augmented substrate delivery
2. Increased lipid oxidation .

All levels of FFA, Glycerol and KB are

elevated .
Alexandrie Palais du Montazah

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