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Acetoacetate, D(-3) -hydroxybutyrate (Beta hydroxy butyrate), and acetone are often referred to as ketone bodies (figure-1).

 Ketone bodies

Figure-1- Acetoacetate is the primary ketone body , the other ketone bodies are derived from it.

The term “ketones” is a misnomer because 3-hydroxybutyrate is not a ketone and there are ketones in blood that are not ketone bodies, eg, pyruvate, fructose.


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.

Steps of synthesis– Acetoacetate (First ketone body) is formed from Acetyl CoA in three steps (Figure-2 ).

1) Two molecules of acetyl CoA condense to form acetoacetyl CoA .This reaction, which is catalyzed by thiolase, is the reverse of the thiolysis step in the oxidation of fatty acids.

2) Acetoacetyl CoA then reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA .The reaction is catalyzed by HMG co A synthase .This enzyme is exclusively present in liver mitochondria. There are two isoforms of this enzyme-cytosolic and mitochondrial. The mitochondrial enzyme is needed for ketogenesis while the cytosolic form is associated with cholesterol biosynthesis.

3) 3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate in the presence of HMG Co A  lyase (Figure-2)

The carbon atoms split off in the acetyl-CoA molecule are derived from the original acetoacetyl-CoA molecule. Both enzymes must be present in mitochondria for ketogenesis to take place. This occurs solely in liver and rumen epithelium.

The other two ketone bodies-Acetone and D(-)- 3-Hydroxybutyrate are formed from Acetoacetate, the primary ketone body.

4) Acetone is formed by decarboxylation in the presence of decarboxylase enzyme and, because it is a beta-keto acid, acetoacetate also undergoes a slow, spontaneous decarboxylation to acetone (figure-2). The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate in the blood.  “Acetone-breath” has been used as  a  crude  method  of  diagnosing  individuals  with  untreated Type  I  diabetes mellitus.

 5) D(-)-3-Hydroxybutyrate is formed by the reduction of acetoacetate in the mitochondrial matrix by D(-)3-hydroxybutyrate dehydrogenase (figure-2).

  • D(-)-3-Hydroxybutyrate is quantitatively the predominant ketone body present in the blood and urine in ketosis.
  • The β-hydroxybutyrate dehydrogenase reaction has two functions: 1) it stores energy equivalent to an NADH in the ketone body  for  export  to the tissues, and  2)  it  produces  a  more  stable molecule. Acetoacetate and β-hydroxybutyrate, in particular, also serve as major substrates for the biosynthesis of neonatal cerebral lipids.
  • The ratio of β hydroxybutyrate to acetoacetate depends on the NADH/NAD+ ratio inside mitochondria , if NADH concentration is high, the liver releases a higher proportion of β-hydroxybutyrate.

In vivo, the liver appears to be the only organ in nonruminants to add significant quantities of ketone bodies to the blood. Extrahepatic tissues utilize them as respiratory substrates .The net flow of ketone bodies from the liver to the extrahepatic tissues results from active hepatic synthesis coupled with very low utilization.The reverse situation occurs in extra hepatic tissues.

While an active enzymatic mechanism produces acetoacetate from acetoacetyl-CoA in the liver, acetoacetate once formed cannot be reactivated directly except in the cytosol, where it is used in a much less active pathway as a precursor in cholesterol synthesis. This accounts for the net production of ketone bodies by the liver.

 Steps of ketogenesis

Figure-2- Steps of ketogenesis

Biological Significance

Ketone bodies serve as a fuel for extra hepatic tissues

The  brain  is  an  important organ. It  is  metabolically  active  and  metabolically privileged. The brain generally uses 60-70% of total body glucose requirements, and always  requires  some  glucose  for  normal  functioning. Under  most  conditions, glucose is essentially the sole energy source of the brain. The brain cannot use fatty acids, which  cannot  cross  the  blood-brain  barrier.  Because  animals  cannot synthesize significant amounts of glucose from fatty acids, as glucose availability decreases, the brain is forced to use either amino acids or ketone bodies for fuel.

Individuals eating diets extremely high in fat and low in carbohydrates, or starving, or  suffering  from  a severe  lack  of  insulin  (Type I  diabetes  mellitus) therefore increase the synthesis and utilization of ketone bodies

During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-Co A are generated.These exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies.The synthesis of the ketone bodies (ketogenesis) occurs in the liver mitochondria allowing this process to be intimately coupled to rate of hepatic fatty acid oxidation.Conversely, the utilization of the ketones (ketolysis) occurs in the peripheral cells, in the cytosol.

The acetyl CoA formed in fatty acid oxidation enters the citric acid cycle only if fat and carbohydrate degradation are appropriately balanced. The reason is that the 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. Oxaloacetate is normally formed from pyruvate, the product of glycolysis, by pyruvate carboxylase (Figure-3). This is the molecular basis of the adage that fats burn in the flame of carbohydrates.

 Conditions causing ketosis

Figure-3- the pathway of ketogenesis in conditions of non availability of Oxaloacetate

In fasting or diabetes, oxaloacetate is consumed to form glucose by the gluconeogenic pathway (figure-3) and hence is unavailable for condensation with acetyl CoA. Under these conditions, acetyl CoA is diverted to the formation of acetoacetate and β-hydroxybutyrate.

These substances diffuse from the liver mitochondria into the blood and are transported to peripheral tissues. These ketone bodies were initially regarded as degradation products of little physiological value. However, Acetoacetate and β-hydroxybutyrate are normal fuels of respiration and are quantitatively important as sources of energy. Indeed, heart muscle and the renal cortex use acetoacetate in preference to glucose. In contrast, the brain adapts to the utilization of acetoacetate during starvation and diabetes. In prolonged starvation, 75% of the fuel needs of the brain are met by ketone bodies.

To be continued …

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