Keton Bodies: Types, Biosynthesis, Utilization and Disorders
Ketone bodies are water-soluble compounds produced mainly in the liver during
fasting, starvation, prolonged exercise and uncontrolled diabetes mellitus.
They serve as an alternative source of energy when glucose availability is low.
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:
- Acetoacetate
- β-Hydroxybutyrate
- Acetone
However, β-hydroxybutyrate is still classified as a ketone body because it is:
- Produced in the liver along with the other ketone bodies during ketogenesis.
- Interconverted with acetoacetate, which is a true ketone.
- Used by extrahepatic tissues (brain, heart, skeletal muscle, kidney) as an important energy source during fasting, starvation, prolonged exercise, or uncontrolled diabetes.
Biosynthesis of Ketone Bodies (Ketogenesis)
The biosynthesis 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, Carbohydrates or some amino acids, are the precursor for ketone bodies and this process is called Ketogenesis.
Steps of Ketogenesis
Ketogenesis occurs through the following reactions:
- Step 1: Two moles of acetyl CoA condense to form acetoacetyl CoA. This reaction is catalysed by enzyme thiolase.
- Step 2:Acetoacetyl CoA combines with another molecule of acetyl CoA to produce β-hydroxy β-methyl glutaryl CoA (HMG CoA). HMG CoA synthase, catalysing this reaction, regulates the synthesis of ketone bodies.
- Step 3:HMG CoA lyase cleaves HMG CoA to produce acetoacetate and acetyl CoA.
- Step 4:Acetoacetate can undergo spontaneous decarboxylation to form acetone.
- Step 5:Acetoacetate can be reduced by a dehydrogenease to β-hydroxybutyrate.
The rate-limiting enzyme of ketogenesis is HMG-CoA Synthase.
Utilization of Ketone Bodies
Normally, the body uses glucose as its main source of energy. However, during fasting, starvation, prolonged exercise, or uncontrolled diabetes mellitus, glucose becomes less available to the cells. In these situations, the liver starts breaking down fats and produces ketone bodies to provide energy.
Ketone bodies are water-soluble, so that they dissolve easily in blood. Therefore, they can be transported from the liver to different organs without needing any special carrier.
Many organs can use ketone bodies as a source of energy, such as:
Major Organs Using Ketone Bodies
- Skeletal muscles
- Heart
- Kidneys
- Brain (during prolonged starvation)
These organs convert ketone bodies into ATP (energy) inside their mitochondria.
Why are ketone bodies important during starvation?
During starvation, the body's glucose stores become very low.
- First, the body uses stored glucose.
- Then it starts breaking down fats.
- The liver converts fatty acids into ketone bodies.
- These ketone bodies are sent through the blood to different organs to provide energy.
Thus, ketone bodies help the body survive when glucose is not available.
Normally, the brain uses only glucose for energy.
The brain cannot use fatty acids directly and efficiently because fatty acids cannot cross the blood-brain barrier in significant amounts.
However, ketone bodies can cross the blood-brain barrier easily.
During prolonged starvation (after about 2–3 days, and especially after 1–2 weeks), the brain gradually starts using ketone bodies.
At this stage, ketone bodies can supply about 50–70% of the brain's energy, reducing the need to break down body proteins to produce glucose.
Remember
Fatty acids cannot cross the blood-brain barrier efficiently, whereas ketone
bodies can do it easily.
Metabolism (utilization) of ketone bodies to acetyl CoA.
After ketone bodies are produced in the liver, they travel through the blood to other organs such as skeletal muscles, heart, kidneys, and brain (during prolonged starvation). These organs convert ketone bodies into acetyl-CoA, which enters the Krebs (TCA) cycle to produce ATP (energy).
- Step 1: β-Hydroxybutyrate is first converted back into acetoacetate by the enzyme β-hydroxybutyrate dehydrogenase.
- Step 2:Acetoacetate cannot directly produce energy. It must first be converted into acetoacetyl-CoA.
This reaction is carried out by the mitochondrial enzyme Thiophorase (Succinyl-CoA : Acetoacetate CoA Transferase)
- Step 3:The enzyme thiolase splits one molecule of acetoacetyl-CoA into two molecules of acetyl-CoA.
These two acetyl-CoA molecules then enter the Krebs (TCA) cycle and produce ATP (energy).
Why Liver Cannot Use Ketone Bodies?
Although the liver synthesizes ketone bodies, it cannot utilize them because it
lacks the enzyme Thiophorase (Succinyl-CoA:Acetoacetate CoA Transferase).
- Liver → Produces ketone bodies
- Extrahepatic Tissues → Utilizes ketone bodies
Disorders Due to Ketone Bodies
Normally, the liver continuously produces small amounts of ketone bodies, and extrahepatic tissues such as muscles, heart, kidneys, and brain (during fasting) use them for energy. Therefore, the level of ketone bodies in blood remains very low (about 1 mg/dL), and they are almost absent in urine.
When the liver produces more ketone bodies than the body can use, their level in the blood increases. This condition is called ketonemia. When excess ketone bodies are excreted in urine, it is called ketonuria. The combined condition of ketonemia and ketonuria is known as ketosis.
A common sign of ketosis is the fruity smell of acetone in the breath.
- Ketonemia: Increased ketone bodies in blood.
- Ketonuria: Ketone bodies in urine.
- Ketosis: Presence of both ketonemia and ketonuria.
Causes of Ketosis
- Prolonged starvation
- Uncontrolled diabetes mellitus
Clinical Sign:
Patients with ketosis often have a characteristic fruity odour of acetone in
their breath.
Key Points
- Ketone bodies are synthesized in the liver.
- They are water-soluble.
- Major precursor is acetyl-CoA.
- Brain uses ketone bodies during prolonged starvation.
- Liver cannot utilize ketone bodies because thiophorase is absent.
- Excess production results in ketosis.
