Ketone Bodies

Free fatty acids are the precursors of ketone bodies in the liver. 

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.

Ketone bodies include acetoacetic acid and β-hydroxybutyrate, which are formed in the liver, and acetone, which is spontaneously formed from excess acetoacetate in the blood.

Starvation results in glycogen depletion and deficiency of carbohydrates, causing an increased use of lipids as energy sources.

Increased oxidation of fatty acids produces acetyl coenzyme A (CoA) and acetoacetyl CoA, a precursor of ketone bodies.

Although the liver synthesizes ketone bodies from excess acetyl CoA produced by β-oxidation of fatty acids, it cannot use ketone bodies as fuel for energy.

Insulin deficiency in diabetes mellitus, like starvation, depletes carbohydrate energy sources because glucose cannot enter cells.

Increased oxidation of fatty acids again results in increased production of ketone bodies by the liver.

Children with inherited blocks in fatty acid oxidation such as medium-chain CoA dehydrogenase deficiency cannot switch to fatty oxidation when illness or overnight fasting causes carbohydrate depletion.

They often present with nonketotic hypoglycemia.

The unavailability of fatty acid oxidation as an alternative energy source may lead to energy depletion, organ failure, and unexpected “sudden death” in an otherwise healthy child.

Increased fatty acid oxidation is a characteristic of starvation and diabetes mellitus, and leads to ketone body production by the liver (ketosis). 

Under metabolic conditions associated with a high rate of fatty acid oxidation, the liver produces considerable quantities of acetoacetate and beta-hydroxybutyrate.

Acetoacetate continually undergoes spontaneous decarboxylation to yield acetone.

C i.e. HMG-Co-A Synthase

A i.e. Liver

Answer is C (> 180 mg/dL);

`The patient in question is a case of diabetic Ketoacidosis.

Diabetic Ketoacidosis is associated with serum glucose levels between 250-300 mg/dl’

 The production of ketone bodies and their utilization become more significant when glucose is in short supply to the tissues, as observed in starvation, and diabetes mellitus

Ketone bodies

They are water-soluble compounds produced as by-products when fatty acids are broken down for energy in the liver and kidney.

They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting.

The three endogenous ketone bodies are acetone, acetoacetic acid, and beta-hydroxybutyric acid.

Although beta-hydroxybutyric acid is not technically a ketone but a carboxylic acid.

Other ketone bodies such as beta-ketopentanoate and beta-hydroxypentanoate may be created as a result of the metabolism of synthetic triglycerides such as triheptanoin.

Ketone bodies can be used for energy. Ketone bodies are transported from the liver to other tissues, where acetoacetate and beta-hydroxybutyrate can be reconverted to acetyl-CoA to produce energy, via the citric acid cycle.

The heart gets little energy from ketone bodies except under special circumstances; it uses mainly fatty acids. The brain gets a portion of its energy from ketone bodies when glucose is less available (e.g., during fasting, strenuous exercise, low carbohydrate, ketogenic diet and in neonates).

After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of its energy from ketone bodies.

After about 4 days, this goes up to 70% (during the initial stages the brain does not burn ketones since they are an important substrate for lipid synthesis in the brain).

Ketone bodies are produced from acetyl-CoA mainly in the mitochondrial matrix of hepatocytes when carbohydrates are so scarce that energy must be obtained from breaking down fatty acids.

Ketone bodies

• In the liver, Acetyl CoA is used to form the ketone bodies.
• Two of the three are used as a source of energy in the heart and brain while the third (acetone) is a waste product excreted from the body.
• In the brain, they are a vital source of energy during fasting. The brain can metabolize ketone bodies to meet about 20% of its energy requirements; the remainder must be supplied by glucose.

The three endogenous ketone bodies are:

– Acetone,

-Acetoacetic acid

-Beta-hydroxybutyric acid

Ans. is ‘d’ i.e., HMG CoA reductase is the rate-limiting enzyme 

Ans. is ‘d’ i.e., Hepatocytes

• Ketone bodies are synthesized by liver and are utilized by extrahepatic tissues like heart, muscles, renal cortex and brain (in starvation).
• Liver cannot utilize ketone bodies because it lacks enzyme succinyl-CoA-acetoacetate CoA transferase, which is required for the activation of ketone bodies.
• The first reaction in use of ketone bodies is activation of acetoacetate.

                                              CoA-transferase

Succinyl CoA + acetoacetate ___________________  Acetoacetyl CoA + succinate

Ans. is ‘c’ i.e., RBC 

• Only glucose is the sole fuel for RBCs.
• As RBCs have no mitochondria, they oxidize glucose anaerobically to lactate.
• Liver also cannot use ketone bodies because of lack of succinyl-CoA-acetoacetate-CoA transferase, which is required for activation of ketone bodies.