12. KETOGENESIS AND KETOLYSIS

Introduction to ketogenesis and ketolysis:

Ketone bodies are important alternative energy fuels synthesized in the liver during periods of low carbohydrate availability. They include:

  • Acetoacetic acid
  • β-Hydroxybutyric acid
  • Acetone

Among these, acetoacetic acid is the primary ketone body, while β-hydroxybutyric acid and acetone are derived from it. The metabolism of ketone bodies occurs in two main phases:

  1. Ketogenesis – synthesis of ketone bodies (mainly in the liver)
  2. Ketolysis – utilization of ketone bodies (in extrahepatic tissues)

Ketogenesis

Ketogenesis refers to the formation of ketone bodies from acetyl-CoA. This process mainly occurs in the mitochondria of liver cells.

Key Points:

  • When the production of acetyl-CoA from β-oxidation or pyruvate oxidation exceeds the liver’s capacity to utilize it in the TCA cycle, excess acetyl-CoA is diverted to ketone body formation.
  • The liver is the principal site of ketogenesis and acts as the net producer of ketone bodies.

Biological Importance:

  • Ketone bodies provide an efficient way to transport excess fuel (acetyl-CoA) to peripheral tissues for energy production.
  • Even-numbered fatty acids are more ketogenic than odd-numbered ones.
  • Fat is more ketogenic than carbohydrate because it produces more acetyl-CoA upon oxidation.

Reaction Sequence of Ketogenesis

The enzymes responsible for ketone body formation are located in the mitochondria of liver cells. Acetyl-CoA serves as the starting molecule.

  1. Condensation of two acetyl-CoA molecules: Catalyzed by thiolase, forming acetoacetyl-CoA. This is the reversal of the final reaction in β-oxidation.
  2. Formation of HMG-CoA: Acetoacetyl-CoA combines with another acetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), catalyzed by HMG-CoA synthase. This is the major route of ketone body formation.
  3. Cleavage of HMG-CoA: The enzyme HMG-CoA lyase splits HMG-CoA into acetoacetate and acetyl-CoA.
  4. Formation of β-hydroxybutyrate: Acetoacetate is reduced to β-hydroxybutyrate by NADH-dependent dehydrogenase.
  5. Formation of Acetone: Acetoacetate undergoes non-enzymatic decarboxylation to form acetone.

Summary: Acetoacetate, β-hydroxybutyrate, and acetone are the three ketone bodies formed during ketogenesis.

Ketolysis

Ketolysis is the process by which ketone bodies are broken down to release energy. This occurs mainly in extrahepatic tissues such as the heart, kidney cortex, skeletal muscle, and brain (during prolonged fasting).

Key Points:

  • The liver produces ketone bodies but cannot utilize them because it lacks the key enzyme succinyl-CoA: acetoacetate CoA transferase (thiophorase).
  • Peripheral tissues use ketone bodies for ATP production during fasting, starvation, or diabetes.

Reaction Sequence of Acetoacetate Utilization

Acetoacetate is the major ketone body used for energy. It must first be activated before it can enter metabolic pathways.

1. Activation Pathways:

  • Pathway 1: Acetoacetate reacts with ATP, Mg²⁺, and CoA in the presence of acetoacetyl-CoA synthetase to form acetoacetyl-CoA. This reaction releases AMP and PPi.
  • Pathway 2: Acetoacetate accepts CoA from succinyl-CoA via the enzyme succinyl-CoA: acetoacetate CoA transferase (thiophorase), forming acetoacetyl-CoA.

2. Conversion to Acetyl-CoA:

The enzyme thiolase then cleaves acetoacetyl-CoA into two molecules of acetyl-CoA, which enter the TCA cycle for complete oxidation to produce ATP.

Utilization of β-Hydroxybutyrate

β-Hydroxybutyrate can be metabolized in two ways:

  1. Major Route: It is oxidized to acetoacetate by β-hydroxybutyrate dehydrogenase, using NAD⁺ as a hydrogen acceptor. The acetoacetate formed is then used for energy production.
  2. Minor Route: β-Hydroxybutyrate is activated by synthetase to form β-hydroxybutyryl-CoA, which is then converted to acetoacetyl-CoA by dehydrogenase and further to acetyl-CoA by thiolase.

Utilization of Acetone

Acetone is metabolized very slowly and is primarily excreted from the body via urine or expelled as CO₂ through the lungs.

Regulation of Ketogenesis

Ketone body formation is tightly regulated by metabolic conditions and enzyme activities:

  • Mobilization of Fatty Acids: Increased lipolysis in adipose tissue provides more fatty acids for β-oxidation, increasing ketogenesis.
  • Liver Carnitine Acyltransferase-I (CAT-I):
    • During the fed state, malonyl-CoA inhibits CAT-I, reducing fatty acid entry into mitochondria and lowering ketogenesis.
    • During starvation, low malonyl-CoA levels increase CAT-I activity, promoting ketone body formation.
  • ATP Levels: High ATP concentration favors ketone body synthesis, while low ATP levels suppress it.

Medical Importance

  • Normal Blood Ketone Level: Around 1 mg/100 mL.
  • Hyperketonemia: When ketone production exceeds utilization, resulting in elevated blood ketone levels and urinary excretion (ketonuria).
  • Ketosis: Characterized by hyperketonemia and ketonuria, leading to symptoms like headache, nausea, vomiting, and in severe cases, coma. It occurs in:
    • Starvation
    • Uncontrolled diabetes mellitus
    • High-fat diets
    • Prolonged exercise or certain metabolic disorders
  • Ketoacidosis: Excessive ketone body production depletes blood bicarbonate, leading to reduced blood pH (metabolic acidosis). Common in severe diabetes or prolonged fasting.
  • Hypoketonemia: Low ketone body levels occur in disorders like carnitine deficiency or hepatic CAT-I deficiency, where fatty acid transport or oxidation is impaired.

Detailed Notes:

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