Ketone Bodies

Ketone Bodies

• In humans and most other mammals, acetyl-CoA formed in the liver during oxidation of fatty acids can either enter the citric acid cycle or undergo conversion to the “ketone bodies”.
• The compounds namely acetone, acetoacetate and β-hydroxybutyrate (or 3-hydroxybutyrate) are known as ketone bodies.
• Only the first two are true ketones while β-hydroxybutyrate does not possess a keto (C=O) group.
• Ketone bodies are water-soluble and energy-yielding.
• Acetone, however, is an exception, since it cannot be metabolized.

Fig: Structures of ketone bodies.

Functions:

• Ketone bodies are formed in the liver and exported to other organs as fuel.
• Acetone, produced in smaller quantities than the other ketone bodies, is exhaled.
• Acetoacetate and D-β-hydroxybutyrate are transported by the blood to tissues other than the liver (extrahepatic tissues).
• Then, they are converted to acetyl-CoA and oxidized in the citric acid cycle, providing much of the energy required by tissues such as skeletal and heart muscle and the renal cortex.
• The brain, which preferentially uses glucose as fuel, can adapt to the use of acetoacetate and D-β-hydroxybutyrate under starvation conditions when glucose is unavailable.
• In this situation, the brain cannot use fatty acids as fuel, because they do not cross the blood-brain barrier.
• The production and export of ketone bodies from the liver to extrahepatic tissues allow continued oxidation of fatty acids in the liver when acetyl-CoA is not being oxidized in the citric acid cycle.

Ketogenesis:

• The synthesis of ketone bodies occurs in the liver.
• The enzymes for ketone body synthesis are located in the mitochondrial matrix.
• Acetyl CoA, formed by oxidation of fatty acids, pyruvate, or some amino acids, is the precursor for ketone bodies.
• Ketogenesis occurs through the following reactions:
  1. The first step in the formation of acetoacetate, which is the enzymatic condensation of two molecules of acetyl-CoA, catalyzed by thiolase; this is simply the reversal of the last step of β oxidation.
  2. Acetoacetyl CoA combines with another molecule of acetyl CoA to produce β-hydroxyβ-methyl glutaryl CoA (HMG CoA). HMG CoA synthase, catalyzing this reaction, regulates the synthesis of ketone bodies. HMG CoA lyase cleaves HMG CoA to produce acetoacetate and acetyl CoA.
  3. The acetoacetate is reversibly reduced by β-hydroxybutyrate dehydrogenase, a mitochondrial enzyme, to β– hydroxybutyrate.
  4. Acetone is formed in very small amounts from acetoacetate, which is easily decarboxylated, either spontaneously or by the action of acetoacetate decarboxylase.
  5. Acetoacetate can be reduced by a dehydrogenase to β-hydroxybutyrate.
• The carbon skeleton of some amino acids (ketogenic) is degraded to acetoacetate or acetyl CoA and, therefore, to ketone bodies, e.g. leucine, lysine, phenylalanine, etc.

Utilization (Metabolism) of ketone bodies:

• The ketone bodies, being water-soluble, are easily transported from the liver to various tissues.
• The two ketone bodies—acetoacetate and β-hydroxybutyrate serve as important sources of energy for the peripheral tissues such as skeletal muscle, cardiac muscle, renal cortex, etc.
• The tissues which lack mitochondria (e.g. erythrocytes) however, cannot utilize ketone bodies.
• Metabolism occurs through the following reactions:
  1. In extrahepatic tissues, D-β-hydroxybutyrate is oxidized to acetoacetate by D-β-hydroxybutyrate dehydrogenase.
  2. The acetoacetate is activated to its coenzyme A ester by transfer of CoA from succinyl-CoA, an intermediate of the citric acid cycle, in a reaction catalyzed by β-ketoacyl-CoA transferase, also called thiophorase.
  3. The acetoacetyl-CoA is then cleaved by thiolase to yield two molecules of acetyl-CoA, which enter the citric acid cycle.
• Thus the ketone bodies are used as fuels in all tissues except the liver, which lacks β-ketoacyl-CoA transferase.
• The liver is, therefore, a producer of ketone bodies for other tissues, but not a consumer.

In Sarvation and diabetes mellitus conditions:

• 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

Starvation:

• During starvation, gluconeogenesis depletes citric acid cycle intermediates, diverting acetyl-CoA to ketone body production
• Ketone bodies are the major fuel source for the brain and other parts of the central nervous system during prolonged starvation.
• It should be noted that the ability of the brain to utilize fatty acids for energy is very limited.
• The ketone bodies can meet 50-70% of the brain’s energy needs.
• This is an adaptation for the survival of the organism during periods of food deprivation.

Diabetes mellitus:

• Diabetes mellitus is associated with insulin deficiency.
• In untreated diabetes, the insulin level is insufficient.
• Extrahepatic tissues cannot take up glucose efficiently from the blood, either for fuel or for conversion to fat.
• This results in impaired carbohydrate metabolism and increased lipolysis, both of them ultimately leading to the accumulation of acetyl CoA and its conversion to ketone bodies.
• In severe diabetes, the ketone body concentration in blood plasma may reach 100 mg/dl and the urinary excretion may be as high as 500 mg/day.

Ketonemia, Ketonuria, and Ketosis:

• When the rate of synthesis of ketone bodies exceeds the rate of utilization, their concentration in blood increases, this is known as ketonemia.
• The term ketonuria represents the excretion of ketone bodies in urine.
• Ketone bodies in the blood and urine of individuals with untreated diabetes can reach extraordinary levels
  • a blood concentration of 90 mg/100 mL (compared with a normal level of <3 mg/100 mL) and urinary excretion of 5,000 mg/24 hr (compared with a normal rate of ≤125 mg/24 hr).
• The overall picture of ketonemia and ketonuria is commonly referred to as ketosis.

Ketoacidosis:

• When ketosis combined with acidosis, is called ketoacidosis.
• Both acetoacetate and β-hydroxybutyrate are strong acids. Increase in their concentration in blood would cause acidosis.
• The carboxyl group has a pKa around 4. Therefore, the ketone bodies in the blood dissociate and release H+ ions which lower the pH.
• If not treated, Diabetic ketoacidosis is dangerous—may result in coma, and even death.
• Ketosis due to starvation is not usually accompanied by ketoacidosis.
  Treatment of ketoacidosis :
• Rapid treatment of diabetic ketoacidosis is required to correct the metabolic abnormalities and the associated water and electrolyte imbalance.
• Administration of insulin is necessary to stimulate uptake of glucose by tissues and inhibition of ketogenesis.

Fig: Summary of ketone body synthesis, utilization and excretion.

Regulation of ketogenesis:

• The ketone body formation (particularly overproduction) occurs primarily due to the nonavailability of carbohydrates to the tissues.
• This is an outcome of excessive utilization of fatty acids to meet the energy requirements of the cells.
• The hormone glucagon stimulates ketogenesis whereas insulin inhibits.
• The increased ratio of glucagon/insulin in diabetes mellitus promotes ketone body formation.
• This is due to disturbances caused by carbohydrate and lipid metabolisms in diabetes.

Ketogenic and antiketogenic substances:

• The ketogenic substances (promote ketogenesis) include fatty acids and certain amino acids (leucine, lysine, tyrosine etc.).
• The antiketogenic substances (inhibit ketogenesis) are glucose, glycerol and glucogenic amino acids (e.g. glycine, alanine, serine, glutamate etc.)