About 40 per cent of the calories in a typical American diet are derived from fats, which is almost equal to the calories derived from carbohydrates. Therefore, the use of fats by the body for energy is as important as the use of carbohydrates is. In addition, many of the carbohydrates ingested with each meal are converted into triglycerides, then stored, and used later in the form of fatty acids released from the triglycerides for energy.
Hydrolysis of Triglycerides. The first stage in using triglycerides for energy is their hydrolysis into fatty acids and glycerol. Then, both the fatty acids and the glycerol are transported in the blood to the active tissues, where they will be oxidized to give energy. Almost all cells—with some exceptions, such as brain tissue and red blood cells—can use fatty acids for energy.
Glycerol, on entering the active tissue, is immediately changed by intracellular enzymes into glycerol-3-phosphate, which enters the glycolytic pathway for glucose breakdown and is thus used for energy. Before the fatty acids can be used for energy, they must be processed further in the following way.
Entry of Fatty Acids into Mitochondria. Degradation and oxidation of fatty acids occur only in the mitochondria. Therefore, the first step for the use of fatty acids is their transport into the mitochondria. This is a carrier-mediated process that uses carnitine as the carrier substance. Once inside the mitochondria, fatty acids split away from carnitine and are degraded and oxidized.
Degradation of Fatty Acids to Acetyl Coenzyme A by BetaOxidation. The fatty acid molecule is degraded in the
(1) RCH2CH2CH2COOH + CoA + ATP > RCH2CH2CH2COCoA + AMP + Pyrophosphate
(Fatty acid) (Fatty acyl-CoA)
(2) RCH2CH2CH2COCoA + FAD — RCH2CH=CHCOCoA + FADH2
(3) RCH2CH=CHCOCoA + H2O >■ RCH2CHOHCH2COCoA
(4) RCH2CHOHCH2COCoA + NAD+ RCH2COCH2COCoA + NADH + H+
(5) RCH2COCH2COCoA + CoA RCH2COCoA + CH3COCoA
(Fatty acyl-CoA) (Acetyl-CoA)
Beta-oxidation of fatty acids to yield acetyl coenzyme A.
mitochondria by progressive release of two-carbon segments in the form of acetyl coenzyme A (acetyl-CoA). This process, which is shown in Figure 68-1, is called the beta-oxidation process for degradation of fatty acids.
To understand the essential steps in the betaoxidation process, note that in equation 1 the first step is combination of the fatty acid molecule with coenzyme A (CoA) to form fatty acyl-CoA. In equations 2, 3, and 4, the beta carbon (the second carbon from the right) of the fatty acyl-CoA binds with an oxygen molecule—that is, the beta carbon becomes oxidized.
Then, in equation 5, the right-hand two-carbon portion of the molecule is split off to release acetyl-CoA into the cell fluid. At the same time, another CoA molecule binds at the end of the remaining portion of the fatty acid molecule, and this forms a new fatty acyl-CoA molecule; this time, however, the molecule is two carbon atoms shorter because of the loss of the first acetyl-CoA from its terminal end.
Next, this shorter fatty acyl-CoA enters into equation 2 and progresses through equations 3,4, and 5 to release still another acetyl-CoA molecule, thus shortening the original fatty acid molecule by another two carbons. In addition to the released acetyl-CoA molecules, four atoms of hydrogen are released from the fatty acid molecule at the same time, entirely separate from the acetyl-CoA.
Oxidation of Acetyl-CoA. The acetyl-CoA molecules formed by beta-oxidation of fatty acids in the mitochondria enter immediately into the citric acid cycle (see Chapter 67), combining first with oxaloacetic acid to form citric acid, which then is degraded into carbon dioxide and hydrogen atoms. The hydrogen is subsequently oxidized by the chemiosmotic oxidative system of the mitochondria, which was also explained in Chapter 67. The net reaction in the citric acid cycle for each molecule of acetyl-CoA is the following:
CH3COCo-A + Oxaloacetic acid + 3H2O + ADP
Citric acid cycle
Thus, after initial degradation of fatty acids to acetyl-CoA, their final breakdown is precisely the same as that of the acetyl-CoA formed from pyruvic acid during the metabolism of glucose. And the extra hydrogen atoms are also oxidized by the same chemiosmotic oxidative system of the mitochondria that is used in carbohydrate oxidation, liberating large amounts of adenosine triphosphate (ATP).
Tremendous Amounts of ATP Are Formed by Oxidation of Fatty Acids. In Figure 68-1, note that the 4 separate hydrogen atoms released each time a molecule of acetyl-CoA is split from the fatty acid chain are released in the forms FADH2, NADH, and H+. Therefore, for every stearic fatty acid molecule that is split to form 9 acetyl-CoA molecules, 32 extra hydrogen atoms are removed. In addition, for each of the 9 molecules of acetyl-CoA that are subsequently degraded by the citric acid cycle, 8 more hydrogen atoms are removed, making another 72 hydrogens. This makes a total of 104 hydrogen atoms eventually released by the degradation of each stearic acid molecule. Of this group, 34 are removed from the degrading fatty acids by flavoproteins, and 70 are removed by nicotinamide adenine dinucleotide (NAD+) as NADH and H+.
These two groups of hydrogen atoms are oxidized in the mitochondria, as discussed in Chapter 67, but they enter the oxidative system at different points, so that 1 molecule of ATP is synthesized for each of the 34 flavoprotein hydrogens, and 1.5 molecules of ATP are synthesized for each of the 70 NADH and H+ hydrogens. This makes 34 plus 105, or a total of 139 molecules of ATP formed by the oxidation of hydrogen derived from each molecule of stearic acid. Another 9 molecules of ATP are formed in the citric acid cycle itself (separate from the ATP released by the oxidation of hydrogen), one for each of the 9 acetyl-CoA molecules metabolized. Thus, a total of 148 molecules of ATP are formed during the complete oxidation of 1 molecule of stearic acid. However, two high-energy bonds are consumed in the initial combination of CoA with the stearic acid molecule, making a net gain of 146 molecules of ATP.
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 molecules 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:
Acetyl-CoA CH3COCH2COOH + 2HCo-A
Part of the acetoacetic acid is also converted into b-hydroxybutyric acid, and minute quantities are converted into acetone in accord with the following reactions:
The acetoacetic acid, b-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 b-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 quantities are 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 diffusion into the cells.
Ketosis in Starvation, Diabetes, and Other Diseases. The concentrations of acetoacetic acid, b-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 in the chapter that the unavailability of carbohydrates automatically increases the rate of removal of fatty acids from adipose tissues; in addition, several hormonal factors—such as increased secretion 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 products of carbohydrate metabolism is the oxaloacetate 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 b-hydroxybutyric acid sometimes rise to as high as 20 times normal, thus leading to extreme acidosis, as explained in Chapter 30.
The acetone that is formed during ketosis is a volatile substance, some of which is blown off in small quantities 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 from a 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 sometimes 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.
Whenever a greater quantity of carbohydrates enters the body than can be used immediately for energy or can be stored in the form of glycogen, the excess is rapidly converted into triglycerides and stored in this form in the adipose tissue.
In human beings, most triglyceride synthesis occurs in the liver, but minute quantities are also synthesized in the adipose tissue itself. The triglycerides formed in the liver are transported mainly in very low density lipopro-teins to the adipose tissue, where they are stored.
Conversion of Acetyl-CoA into Fatty Acids. The first step in the synthesis of triglycerides is conversion of carbohydrates into acetyl-CoA. As explained in Chapter 67, this occurs during the normal degradation of glucose by the glycolytic system. Because fatty acids are actually large polymers of acetic acid, it is easy to understand how acetyl-CoA can be converted into fatty acids. However, the synthesis of fatty acids from acetyl-CoA is not achieved by simply reversing the oxidative degradation described earlier. Instead, this occurs by the two-step process shown in Figure 68-2, using malonyl-CoA and NADPH as the principal intermediates in the polymerization process.
Combination of Fatty Acids with a-Glycerophosphate to Form
Triglycerides. Once the synthesized fatty acid chains have grown to contain 14 to 18 carbon atoms, they bind with glycerol to form triglycerides. The enzymes that cause this conversion are highly specific for fatty acids with chain lengths of 14 carbon atoms or greater, a factor that controls the physical quality of the triglycerides stored in the body.
As shown in Figure 68-3, the glycerol portion of triglycerides is furnished by a-glycerophosphate, which is another product derived from the glycolytic scheme of glucose degradation. This mechanism is discussed in Chapter 67.
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