Formation of Acetoacetic Acid in the Liver and Its Transport in the Blood
A large share of the initial degradation of fatty acids occurs in the liver, especially when excessive amounts of lipids are being used for energy. However, the liver uses only a small proportion of the fatty acids for its own intrinsic metabolic processes. Instead, when the fatty acid chains have been split into acetyl-CoA, two mole-cules of acetyl-CoA condense to form one molecule of acetoacetic acid, which is then transported in the blood to the other cells throughout the body, where it is used for energy. The chemical processes are the following:
Part of the acetoacetic acid is also converted into β-hydroxybutyric acid, and minute quantities are converted into acetone in accord with the following reactions:
The acetoacetic acid, β-hydroxybutyric acid, and acetone diffuse freely through the liver cell membranes and are transported by the blood to the peripheral tissues. Here they again diffuse into the cells, where reverse reactions occur and acetyl-CoA molecules are formed. These in turn enter the citric acid cycle and are oxidized for energy, as already explained.
Normally, the acetoacetic acid and β-hydroxybutyric acid that enter the blood are transported so rapidly to the tissues that their combined concentration in the plasma seldom rises above 3 mg/dl. Yet despite this small concentration in the blood, large quantitiesare actually transported, as is also true for free fatty acid transport. The rapid transport of both these substances results from their high solubility in the membranes of the target cells, which allows almost instantaneous dif-fusion into the cells.
Ketosis in Starvation, Diabetes, and Other Diseases. The con-centrations of acetoacetic acid, β-hydroxybutyric acid, and acetone occasionally rise to levels many times normal in the blood and interstitial fluids; this condition is called ketosis, because acetoacetic acid is a keto acid. The three compounds are called ketone bodies. Ketosis occurs especially in starvation, in diabetes mellitus, and sometimes even when a person’s diet is composed almost entirely of fat. In all these states, essentially no carbohydrates are metabolized—in starvation and with a high-fat diet because carbohydrates are not available, and in diabetes because insulin is not available to cause glucose transport into the cells.
When carbohydrates are not used for energy, almost all the energy of the body must come from metabolism of fats. We shall see later that the unavail-ability of carbohydrates automatically increases the rate of removal of fatty acids from adipose tissues; in addi-tion, several hormonal factors—such as increased secre-tion of glucocorticoids by the adrenal cortex, increased secretion of glucagon by the pancreas, and decreased secretion of insulin by the pancreas—further enhance the removal of fatty acids from the fat tissues. As a result, tremendous quantities of fatty acids become available (1) to the peripheral tissue cells to be used for energy and (2) to the liver cells, where much of the fatty acids is converted to ketone bodies.
The ketone bodies pour out of the liver to be carried to the cells. For several reasons, the cells are limited in the amount of ketone bodies that can be oxidized; the most important reason is the following: One of the prod-ucts of carbohydrate metabolism is theoxaloacetate that is required to bind with acetyl-CoA before it can be processed in the citric acid cycle. Therefore, deficiency of oxaloacetate derived from carbohydrates limits the entry of acetyl-CoA into the citric acid cycle, and when there is a simultaneous outpouring of large quantities of acetoacetic acid and other ketone bodies from the liver, the blood concentrations of acetoacetic acid and β-hydroxybutyric acid sometimes rise to as high as 20 times normal, thus leading to extreme acidosis.
The acetone that is formed during ketosis is a volatile substance, some of which is blown off in small quanti-ties in the expired air of the lungs. This gives the breath an acetone smell that is frequently used as a diagnostic criterion of ketosis.
Adaptation to a High-Fat Diet. When changing slowly froma carbohydrate diet to an almost completely fat diet, a person’s body adapts to use far more acetoacetic acid than usual, and in this instance, ketosis normally does not occur. For instance, the Inuit (Eskimos), who some-times live almost entirely on a fat diet, do not develop ketosis. Undoubtedly, several factors, none of which is clear, enhance the rate of acetoacetic acid metabolism by the cells. After a few weeks, even the brain cells, which normally derive almost all their energy from glucose, can derive 50 to 75 per cent of their energy from fats.