Ketone body metabolism

Definitions & Key takeaways

Ketone bodies like beta-hydroxybutyrate and acetoacetate are an alternative source of energy in states of prolonged starvation. Ketone body synthesis occurs in the liver in physiologic states like prolonged fasting or exercise, as well as in pathological states like type 1 diabetes mellitus or alcoholism. Once synthesized, ketone bodies can leave the liver, and enter into peripheral cells such as the brain, skeletal muscle and kidney to serve as energy sources.

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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 the a free CoA molecule.
This step with HMG-CoA synthase is the rate-limiting step of ketone synthesis. In other words, the rate of this reaction determines the overall rate of ketone synthesis - it’s like the slowest step in the assembly line for a factory.
Next, the enzyme HMG-CoA lyase removes acetyl-CoA from HMG-CoA, leaving behind an acetoacetate molecule - so two acetyls and no CoA molecules.
Acetoacetate is our first ketone body. Acetoacetate can also be converted into another ketone body.
This happens when the enzyme beta-hydroxybutyrate dehydrogenase takes hydrogens from a nicotinamide adenine dinucleotide, or NADH molecule and gives them to acetoacetate, forming beta-hydroxybutyrate, our second ketone body.
However, acetoacetate can also enter the bloodstream. At this point some acetoacetate molecules remain in that form, and some acetoacetate molecules spontaneously lose a carbon - no enzymes required - to create acetone, our 3rd ketone body.
But this acetone is metabolically useless to cells, so it’s simply exhaled from the lungs. That’s why in pathological states like diabetic ketoacidosis, the breath smells a bit like fruit - that’s the smell of acetone.
Now, these ketone bodies are acidic molecules that like to donate their protons, so they can lower the blood pH, causing a metabolic acidosis.
Once beta-hydroxybutyrate and acetoacetate are in the bloodstream, they can diffuse into the mitochondria of peripheral tissues, like the brain, skeletal muscle and kidneys.
One cell that can’t use ketone bodies is the red blood cell, because it doesn’t have mitochondria. Initially, beta-hydroxybutyrate is converted back to acetoacetate by the same enzyme, beta-hydroxybutyrate dehydrogenase.
However this time, the enzyme takes hydrogen from beta-hydroxybutyrate and gives it to NAD+, making NADH. Next, acetoacetate needs a CoA molecule to be converted to acetoacetyl-CoA.
But unfortunately, peripheral tissues don’t have a lot of acetyl-CoA, so the enzyme thiophorase grabs it from succinyl-CoA, resulting in acetoacetyl-CoA and succinate.
Ironically, liver cells don’t have this thiophorase enzyme, so they can’t use ketone bodies for energy, they can only make them for other cells.
A great example, of how the liver is the humble servant of the body. Finally, an enzyme called beta-ketothiolase cleaves acetoacetyl-CoA, and then adds an extra CoA, making 2 acetyl-CoA molecules, which can then enter the citric acid cycle to make ATP.
Alright, a quick recap. Ketone bodies like beta-hydroxybutyrate and acetoacetate are an alternative source of energy in states of prolonged starvation.
Ketone body synthesis occurs in the liver, where excess acetyl-CoA from fatty acid breakdown is used as a substrate. Once synthesized, ketone bodies can leave the liver, and enter into peripheral cells such as the brain, skeletal muscle and kidney, where they can be reconverted back into 2 acetyl-CoA molecules that can be used to make ATP.