More Fun With Fat: Ketone Formation

Stored fat is the major source of energy during both short term and long term fasting. During fasting, the level of glucose in the blood drops, which causes the level of insulin to drop. This stimulates the release of fatty acids into the blood, as triglycerides are broken down. The fatty acids, bound to albumin, travel mainly to the liver which converts them in one of several ways: Beta-oxidation (energy producing), ketone formation (alternate route of energy production), or to VLDL. The pathway taken will depend on conditions and the body’s needs at the moment.
Ketones are produced as an alternate source of energy, especially for the muscles and the brain, when glucose levels in the cells are extremely low, i.e. during starvation. Ketone formation goes up as the level of fatty acids in the blood increases, or starvation continues. Once starvation has continued for 2-3 days, ketones can enter the brain to be used as its energy source (the brain’s preferred source, as with other cells, is glucose).
People with diabetes (especially type 1) are prone to ketone formation, since they don’t produce insulin. If someone with type 1 diabetes does not take their insulin, glucose cannot get into their cells to be used for energy. Therefore, their body adapts by using fat as an energy source, and goes toward ketone formation if the conditions continue. It can be very dangerous if ketone levels get too high, because ketones are acids. A very acidic blood pH can result in the body’s enzymes not functioning, and this condition is known as ketoacidosis.
Ketones are produced in the liver from the CoA that is made through Beta-oxidation. The ketones formed are acetoacetate and beta-hydroxybutyrate. Two acetyl CoA’s are needed to begin the process, which are the same two from the final cycle of beta-oxidation. Normally, these two would just go on to the TCA cycle to make energy, but when acetyl CoA is very high, due to such a large amount of fatty acid stores being used for energy, ketone formation will occur.
1.The first reaction is catalyzed by the enzyme thiolase, and causes the two molecules of acetyl CoA to join into one molecule of acetoacetyl CoA.
2.The second reaction uses the enzyme HMG CoA synthase and acetyl CoA to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
3.Next, HMG-CoA is cleaved by HMG-CoA lyase to form acetyl CoA and acetoacetate, while losing a hydrogen.

The acetoacetate may enter the blood directly, or form the other major ketone, Beta-hydroxybutyrate, with the enzyme Beta-hydroxybutyrate dehydrogenase which adds a hydrogen at the second carbonyl carbon. Or, as an alternate, acetoacetate may become acetone, which mainly gets expired by the lungs.
The ketones can go on to make energy in muscle and skeletal tissue. Nearly all cell and tissue types, aside from the liver and red blood cells, can use ketones. In the mitochondrial matrix, the beta-hydroxybutyrate is oxidized back to acetoacetate, with the help of the enzyme beta-hydroxybutyrate dehydrogenase, which produces NADH. Acetoacetate then accepts a CoA group from succinyl in a transferase reaction. This results in the formation of acetoacetyl CoA, which can then be broken into 2 acetyl CoA’s with a thiolase enzyme reaction. These acetyl CoA’s then enter the TCA cycle to make energy.
Even during prolonged fasting (30-40 days) levels of glucose and free fatty acids remain constant. A person can actually live this long without food by using their fat stores, and eventually their muscle protein stores. The use of ketones for energy is an adaptive measure taken by the body to spare muscle protein for as long as possible. The level of glucose can stay constant because, although it tries to keep it minimal, the body can make glucose from the amino acids being released from the muscle.