Ketone bodies and their biological significance- lecture 1

Ketone bodies

Ketone bodies can be regarded as a water-soluble, transportable form of acetyl units. Fatty acids are released by adipose tissue and converted into acetyl units by the liver, which then exports them as ketone bodies.

Acetoacetate, D(-3) -hydroxybutyrate (Beta-hydroxybutyrate), and acetone are often referred to as ketone bodies (figure-1).

Figure-1- showing the structure of ketone bodies.

The term “ketones”  is a misnomer because 3-hydroxybutyrate is not a ketone, and there are ketones in the blood that are not ketone bodies, e.g., pyruvate, fructose.

Biological Significance

Ketone bodies serve as a fuel for extrahepatic tissues

The brain is an important organ.  It is metabolically active and metabolically privileged. The brain generally uses 60-70% of total body glucose requirements, and always requires some glucose for normal functioning.  Under most conditions, glucose is essentially the sole energy source of the brain. The brain cannot use fatty acids, which cannot cross the blood-brain barrier.  Because animals cannot synthesize significant amounts of glucose from fatty acids, as glucose availability decreases, the brain is forced to use either amino acids or ketone bodies for fuel.

Individuals eating diets extremely high in fat and low in carbohydrates or starving, or  suffering  from  a severe  lack  of  insulin  (Type  I  diabetes  mellitus)  therefore increase the synthesis and utilization of ketone bodies

During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-Co A are generated. These exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies. The synthesis of the ketone bodies (ketogenesis) occurs in the liver mitochondria allowing this process to be intimately coupled to the rate of hepatic fatty acid oxidation. Conversely, the utilization of the ketones (ketolysis) occurs in the peripheral cells in the cytosol.

The acetyl CoA formed in fatty acid oxidation enters the citric acid cycle only if fat and carbohydrate degradation are appropriately balanced. The reason is that the entry of acetyl CoA into the citric acid cycle depends on the availability of oxaloacetate for the formation of citrate. Still, the concentration of Oxaloacetate is lowered if carbohydrate is unavailable or improperly utilized. Oxaloacetate is normally formed from pyruvate, the product of glycolysis, by pyruvate carboxylase (figure-2). This is the molecular basis of the adage that fats burn in the flame of carbohydrates.

Figure-2-showing the pathway of ketogenesis in conditions of non-availability of Oxaloacetate

In fasting or diabetes, oxaloacetate is consumed to form glucose by the gluconeogenic pathway (figure-2) and hence is unavailable for condensation with acetyl CoA. Under these conditions, acetyl CoA is diverted to the formation of acetoacetate and β-hydroxybutyrate.

These substances diffuse from the liver mitochondria into the blood and are transported to peripheral tissues. These ketone bodies were initially regarded as degradation products of little physiological value. However, the results of studies revealed that these derivatives of acetyl CoA are important molecules in energy metabolism. Acetoacetate and β-hydroxybutyrate are normal fuels of respiration and are quantitatively important as sources of energy. Indeed, heart muscle and the renal cortex use acetoacetate in preference to glucose. In contrast, the brain adapts to the utilization of acetoacetate during starvation and diabetes. In prolonged starvation, 75% of the fuel needs of the brain are met by ketone bodies.