Ketone Bodies 

Ketone bodies are water-soluble molecules generated in the liver as a result of fatty acid metabolism. They provide an alternative energy source for various tissues, particularly when carbohydrate intake is low, during extended fasting, or amid intense physical activity.

1.0Ketone Bodies Definition

• Acetoacetate, β- hydroxybutyrate and acetone are collectively called ketone bodies. The liver hepatocyte is the major site of their synthesis. 
• All normal individuals partition a portion of acetyl CoA towards ketone body formation. 
• They function as water-soluble transportable forms of acetyl units and are relatively less toxic than fatty acids. 
• Acetoacetate and 3-hydroxybutyrate are the preferred normal fuels of respiration as compared to glucose for skeletal and heart muscle and renal cortex. 
• The ratio of 3-hydroxybutyrate / acetoacetate in the blood varies between 1:1 to 10:1 depending on the NADH/ NAD+ ratio in the mitochondria. 

2.0Synthesis of Ketone Bodies

• The synthesis of ketone bodies in the liver mitochondria begins with condensing two molecules of acetyl CoA by thiolase (acetyl CoA acetyltransferase), forming acetoacetyl CoA. 
• The next step is a condensation of acetoacetyl CoA with another molecule of acetyl-CoA by HMG CoA synthase. 
• The condensation product, β-hydroxyβ-methylglutaryl-CoA (HMG-CoA), is then split by HMG-CoA lyase to acetyl CoA and acetoacetate. 
• The lyase is present only in the mitochondria.
• The other two ketone bodies can be synthesized from acetoacetate. 
• It may be reduced by β-hydroxybutyrate dehydrogenase to D- β-hydroxy butyrate. 
• Recall that β-oxidation of fatty acids produces the L-stereoisomer of D-hydroxy acyl CoA. 
• Finally, acetoacetate may be decarboxylated non-enzymatically or by acetoacetate decarboxylase to acetone, an exhaled volatile compound. 
• The liver releases acetoacetate and β-hydroxy butyrate into circulation to be picked up by extrahepatic tissues. 

3.0Utilization of Ketone Bodies

• The extrahepatic tissues convert ketone bodies back to acetyl CoA in the mitochondria.
• An enzyme missing in the liver and present in all tissues holds the key to the utilization of ketone bodies. 
• The enzyme is βketoacyl CoA transferase (or thiophorase) that activates acetoacetate by transferring the CoA group from succinyl CoA. 
• The next step is the thiolytic cleavage by acetoacetyl CoA thiolase. In the case of β-hydroxybutyrate, it is first oxidized to acetoacetate by β-hydroxybutyrate dehydrogenase. 
• The resultant acetyl-CoA units can now enter the TCA cycle for complete oxidation. 
• The dehydrogenase and thiolase function in both synthesis and utilization of ketone bodies. 

4.0Ketosis Definition

• Ketogenesis occurs at moderate levels under normal physiological conditions and when carbohydrates are not available in adequate amounts. 
• However, when ketone bodies are synthesized at higher than normal amounts, their levels also increase markedly in blood and urine. 
• These conditions are known as ketonemia and ketonuria, respectively. 
• The ketone bodies are moderately strong acids and are buffered in blood and tissues.
• Their excretion leads to a progressive decrease in buffer cation, which in turn leads to a drop in blood pH. This results in a condition called ketoacidosis. 
• It is commonly observed in prolonged starvation, untreated type I diabetes and even under conditions of high-fat feeding. 
• Ketone bodies such as acetone (familiar as nail polish remover) are organic volatiles that have a characteristic fruity aroma. They are easily detected on the breath of individuals metabolizing them. 
• The triad of ketonemia, ketonuria and acetone odor is collectively termed ketosis.