Ketone body metabolism

In life, it’s helpful to have a plan B in case plan A doesn’t work out.

In terms of energy, the body’s plan A is to generate energy from carbohydrates, fats, and proteins - basically in that order.

But if these main fuels aren’t readily available, then plan B is to use an alternative fuel source - ketone bodies.

Ketone bodies are a group of carbon-containing molecules produced by liver mitochondria using a 2-carbon molecule called acetyl-CoA.

The liver makes ketone bodies in physiologic states like prolonged fasting or exercise, as well as in pathological states like type 1 diabetes mellitus or alcoholism.

Ketone bodies can be released into the circulation and get picked up by the majority of cells.

Inside the cells, they’re reconverted back into acetyl-CoA, at which point they can then enter the mitochondria and produce ATP.

The 3 primary ketone bodies are acetoacetate, beta-hydroxybutyrate, and acetone.

Alright, so let’s say you decide to go on a 5-day fast.

About 12 hours into your fast, your blood glucose levels start to dip.

In response, glucagon is secreted from the pancreas and stimulates hepatic glycogenolysis - meaning that the liver begins to break down glycogen into glucose and release that glucose into the blood.

About 24 hours into your fast, your liver begins running out of glycogen, so it starts the process of gluconeogenesis which is where it makes new glucose molecules from substrates like amino acids.

Then, around 1 to 3 days into your fast, your body begins to run out of the necessary substrates to make new glucose.

So, it switches to breaking down fatty acids for energy.

Fatty acids are mobilized from fat stores and are broken down to acetyl CoA through beta oxidation in the mitochondria of most cells - except for brain cells.

See, thing is, fatty acids can’t cross the blood-brain barrier, so brain cells can only use glucose for energy - or, when there’s no glucose they use ketone bodies.

This makes sense from the liver’s standpoint as well because normally, acetyl-CoA combines with oxaloacetate in the citric acid cycle to make citrate.

But since oxaloacetate is also a substrate for gluconeogenesis, so it’s levels are pretty depleted at this point in starvation.

So oxaloacetate basically leaves all that acetyl-CoA hanging out by itself. Not cool oxaloacetate, not cool.

This means that the liver is practically overflowing with acetyl-CoA, and the liver converts it into ketone bodies, that various cells in our body, including the brain cells, can use.

Ketone body synthesis begins with 2 acetyl-CoA molecules getting joined together by the enzyme acetyl-CoA acyl-transferase.

The result is a 4-carbon molecule called acetoacetyl-CoA and then a free CoA molecule.

Next, the enzyme HMG-CoA synthase combines acetoacetyl-CoA and acetyl-CoA to form a 6-carbon molecule called 3-hydroxy-3-methylglutaryl CoA, or HMG-CoA - so 3 acetyls and then a free CoA molecule.