KETONE METABOLISM

Ketogenesis, Ketosis

Under conditions of abundant glucose (and sufficient insulin sensitivity) the brain is primarily converting glucose to pyruvate that is then shuttled into the mitochondria and converted into acetyl CoA. Acetyl CoA (which is also a direct byproduct of fatty acid breakdown) is then combined with oxaloacetate and so begins the tricarboxylic acid cycle, which generates all the reducing agents to feed the electron transport chain and generate massive amounts of ATP.

In the absence of acetyl CoA, to spare muscle fat and proteins, our liver can produce ketone bodies that are produced when fatty acids are broken down in excess. The two main ketone bodies are acetoacetate and β-hydroxybutyrate, the latter being produced from the former through the reversible enzymatic action of hydroxybutyrate dehydrogenase (BDH). Acetone, the third one, cannot be converted back to acetyl-CoA, so it is excreted in the urine and exhaled, contributing to the characteristic “fruity” odor of the breath of patients in ketotic states.

ketone-off

Production of these compounds is called “ketogenesis”, a process that is necessary in small amounts as source of fuel for brain, heart and muscle. They become the major energy source (about 75%) for brain during starvation. When excess ketone bodies accumulate, this abnormal (but not necessarily harmful) state is called ketosis. When even larger amounts of ketone bodies accumulate such that the body’s pH is lowered to dangerously acidic levels, this state is called ketoacidosis.