Several chemical compounds in food and in the body are classified as lipids. They include (1) neutral fat, also known as triglycerides; (2) phospholipids; (3) cholesterol; and (4) a few others of less importance. Chemically, the basic lipid moiety of the triglycerides and the phospholipids is fatty acids, which are long-chain hydrocarbon organic acids. A typical fatty acid, palmitic acid, is the following: CH3(CH2)14COOH.
Although cholesterol does not contain fatty acid, its sterol nucleus is synthesized from portions of fatty acid molecules, thus giving it many of the physical and chemical properties of other lipid substances.
The triglycerides are used in the body mainly to provide energy for the different metabolic processes, a function they share almost equally with the carbohydrates. However, some lipids, especially cholesterol, the phospholipids, and small amounts of triglycerides, are used to form the membranes of all cells of the body and to perform other cellular functions.
Basic Chemical Structure of Triglycerides (Neu- tral Fat)
Because most of this chapter deals with the utilization of triglycerides for energy, the following typical structure of the triglyceride molecule should be understood.
Note that three long-chain fatty acid molecules are bound with one molecule of glycerol. The three fatty acids most commonly present in the triglycerides of the human body are (1) stearic acid (shown in the tristearin example), which has an 18-carbon chain and is fully saturated with hydrogen atoms; (2) oleic acid, which also has an 18-carbon chain but has one double bond in the middle of the chain; and (3) palmitic acid, which has 16 carbon atoms and is fully saturated.
Transport of Lipids in the Body Fluids
Transport of Triglycerides and Other Lipids from the Gastrointestinal Tract by Lymph—the Chylomicrons
As explained in Chapter 65, almost all the fats in the diet, with the principal exception of a few short-chain fatty acids, are absorbed from the intestines into the intestinal lymph. During digestion, most triglycerides are split into monoglycerides and fatty acids. Then, while passing through the intestinal epithelial cells, the monoglycerides and fatty acids are resynthesized into new molecules of triglycerides that enter the lymph as minute, dispersed droplets called chylomicrons (Figure 68-1), whose diameters are between 0.08 and 0.6 micron. A small amount of apoprotein B is adsorbed to the outer surfaces of the chylomicrons. This leaves the remainder of the protein molecules projecting into the surrounding water and thereby increases the suspension stability of the chylomicrons in the lymph fluid and prevents their adherence to the lymphatic vessel walls.
Figure 68-1 Summary of major pathways for metabolism of chylomicrons synthesized in the intestine and very low density lipoprotein (VLDL) synthesized in the liver. Apo B, apolipoprotein B; Apo E, apolipoprotein E; FFA, free fatty acids; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase.
Most of the cholesterol and phospholipids absorbed from the gastrointestinal tract enter the chylomicrons. Thus, although the chylomicrons are composed principally of triglycerides, they also contain about 9 percent phospholipids, 3 percent cholesterol, and 1 percent apoprotein B. The chylomicrons are then transported upward through the thoracic duct and emptied into the circulating venous blood at the juncture of the jugular and subclavian veins.
Removal of the Chylomicrons from the Blood
About 1 hour after a meal that contains large quantities of fat, the chylomicron concentration in the plasma may rise to 1 to 2 percent of the total plasma, and because of the large size of the chylomicrons, the plasma appears turbid and sometimes yellow. However, the chylomicrons have a half-life of less than 1 hour, so the plasma becomes clear again within a few hours. The fat of the chylomicrons is removed mainly in the following way.
Chylomicron Triglycerides Are Hydrolyzed by Lipoprotein Lipase, and Fat Is Stored in Adipose Tissue
Most of the chylomicrons are removed from the circulating blood as they pass through the capillaries of various tissues, especially adipose tissue, skeletal muscle, and heart. These tissues synthesize the enzyme lipoprotein lipase, which is transported to the surface of capillary endothelial cells, where it hydrolyzes the triglycerides of chylomicrons as they come in contact with the endothelial wall, thus releasing fatty acids and glycerol (see Figure 68-1).
The fatty acids released from the chylomicrons, being highly miscible with the membranes of the cells, diffuse into the fat cells of the adipose tissue and muscle cells. Once inside these cells, the fatty acids can be used for fuel or again synthesized into triglycerides, with new glycerol being supplied by the metabolic processes of the storage cells, as discussed later in the chapter. The lipase also causes hydrolysis of phospholipids; this, too, releases fatty acids to be stored in the cells in the same way.
After the triglycerides are removed from the chylomicrons, the cholesterol-enriched chylomicron remnants are rapidly cleared from the plasma. The chylomicron remnants bind to receptors on endothelial cells in the liver sinusoids. Apolipoprotein-E on the surface of the chylomicron remnants and secreted by liver cells also plays an important role in initiating clearance of these plasma lipoproteins.
“Free Fatty Acids” Are Transported in the Blood in Combination with Albumin
When fat that has been stored in the adipose tissue is to be used elsewhere in the body to provide energy, it must first be transported from the adipose tissue to the other tissue. It is transported mainly in the form of free fatty acids. This is achieved by hydrolysis of the triglycerides back into fatty acids and glycerol.
At least two classes of stimuli play important roles in promoting this hydrolysis. First, when the amount of glucose available to the fat cell is inadequate, one of the glucose breakdown products, α-glycerophosphate, is also available in insufficient quantities. Because this substance is required to maintain the glycerol portion of triglycerides, the result is hydrolysis of triglycerides. Second, a hormone-sensitive cellular lipase can be activated by several hormones from the endocrine glands, and this also promotes rapid hydrolysis of triglycerides. This is discussed later in the chapter.
On leaving fat cells, fatty acids ionize strongly in the plasma and the ionic portion combines immediately with albumin molecules of the plasma proteins. Fatty acids bound in this manner are called free fatty acids or nonesterified fatty acids, to distinguish them from other fatty acids in the plasma that exist in the form of (1) esters of glycerol, (2) cholesterol, or (3) other substances.
The concentration of free fatty acids in the plasma under resting conditions is about 15 mg/dl, which is a total of only 0.45 gram of fatty acids in the entire circulatory system. Even this small amount accounts for almost all the transport of fatty acids from one part of the body to another for the following reasons:
1. Despite the minute amount of free fatty acid in the blood, its rate of “turnover” is extremely rapid: half the plasma fatty acid is replaced by new fatty acid every 2 to 3 minutes. One can calculate that at this rate, almost all the normal energy requirements of the body can be provided by the oxidation of transported free fatty acids, without using any carbohydrates or proteins for energy.
2. Conditions that increase the rate of utilization of fat for cellular energy also increase the free fatty acid concentration in the blood; in fact, the concentration sometimes increases fivefold to eightfold. Such a large increase occurs especially in cases of starvation and in diabetes mellitus; in both these conditions, the person derives little or no metabolic energy from carbohydrates.
Under normal conditions, only about 3 molecules of fatty acid combine with each molecule of albumin, but as many as 30 fatty acid molecules can combine with a single albumin molecule when the need for fatty acid transport is extreme. This shows how variable the rate of lipid transport can be under different physiologic conditions.
Lipoproteins—Their Special Function in Transporting Cholesterol and Phospholipids
In the postabsorptive state, after all the chylomicrons have been removed from the blood, more than 95 percent of all the lipids in the plasma are in the form of lipoprotein. These are small particles—much smaller than chylomicrons, but qualitatively similar in composition—containing triglycerides, cholesterol, phospholipids, and protein. The total concentration of lipoproteins in the plasma averages about 700 milligrams per 100 milliliters of plasma—that is, 700 mg/dl. This can be broken down into the following individual lipoprotein constituents:
|
mg/dl of Plasma |
|
|
Cholesterol |
180 |
|
Phospholipids |
160 |
|
Triglycerides |
160 |
|
Protein |
200 |
Types of Lipoproteins
Aside from the chylomicrons, which are themselves very large lipoproteins, there are four major types of lipoproteins, classified by their densities as measured in the ultracentrifuge: (1) very low density lipoproteins (VLDLs), which contain high concentrations of triglycerides and moderate concentrations of both cholesterol and phospholipids; (2) intermediate-density lipoproteins (IDLs), which are very low density lipoproteins from which a share of the triglycerides has been removed, so the concentrations of cholesterol and phospholipids are increased; (3) low-density lipoproteins (LDLs), which are derived from intermediate-density lipoproteins by the removal of almost all the triglycerides, leaving an especially high concentration of cholesterol and a moderately high concentration of phospholipids; and (4) high-density lipoproteins (HDLs), which contain a high concentration of protein (about 50 percent) but much smaller concentrations of cholesterol and phospholipids.
Formation and Function of Lipoproteins
Almost all the lipoproteins are formed in the liver, which is also where most of the plasma cholesterol, phospholipids, and triglycerides are synthesized. In addition, small quantities of HDLs are synthesized in the intestinal epithelium during the absorption of fatty acids from the intestines.
The primary function of the lipoproteins is to transport their lipid components in the blood. The VLDLs transport triglycerides synthesized in the liver mainly to the adipose tissue, whereas the other lipoproteins are especially important in the different stages of phospholipid and cholesterol transport from the liver to the peripheral tissues or from the periphery back to the liver. Later in the chapter, we discuss in more detail special problems of cholesterol transport in relation to the disease atherosclerosis, which is associated with the development of fatty lesions on the insides of arterial walls.
Fat Deposits
Adipose Tissue
Large quantities of fat are stored in two major tissues of the body, the adipose tissue and the liver. The adipose tissue is usually called fat deposits, or simply tissue fat.
The major function of adipose tissue is storage of triglycerides until they are needed to provide energy elsewhere in the body. A subsidiary function is to provide heat insulation for the body, as discussed in Chapter 73.
Fat Cells (Adipocytes)
The fat cells (adipocytes) of adipose tissue are modified fibroblasts that store almost pure triglycerides in quantities as great as 80 to 95 percent of the entire cell volume. Triglycerides inside the fat cells are generally in a liquid form. When the tissues are exposed to prolonged cold, the fatty acid chains of the cell triglycerides, over a period of weeks, become either shorter or more unsaturated to decrease their melting point, thereby always allowing the fat to remain in a liquid state. This is particularly important because only liquid fat can be hydrolyzed and transported from the cells.
Fat cells can synthesize very small amounts of fatty acids and triglycerides from carbohydrates; this function supplements the synthesis of fat in the liver, as discussed later in the chapter.
Exchange of Fat Between the Adipose Tissue and the Blood—Tissue Lipases
As discussed earlier, large quantities of lipases are present in adipose tissue. Some of these enzymes catalyze the deposition of cell triglycerides from the chylomicrons and lipoproteins. Others, when activated by hormones, cause splitting of the triglycerides of the fat cells to release free fatty acids. Because of the rapid exchange of fatty acids, the triglycerides in fat cells are renewed about once every 2 to 3 weeks, which means that the fat stored in the tissues today is not the same fat that was stored last month, thus emphasizing the dynamic state of storage fat.
Liver Lipids
The principal functions of the liver in lipid metabolism are to (1) degrade fatty acids into small compounds that can be used for energy; (2) synthesize triglycerides, mainly from carbohydrates, but to a lesser extent from proteins as well; and (3) synthesize other lipids from fatty acids, especially cholesterol and phospholipids.
Large quantities of triglycerides appear in the liver (1) during the early stages of starvation, (2) in diabetes mellitus, and (3) in any other condition in which fat instead of carbohydrates is being used for energy. In these conditions, large quantities of triglycerides are mobilized from the adipose tissue, transported as free fatty acids in the blood, and redeposited as triglycerides in the liver, where the initial stages of much of fat degradation begin. Thus, under normal physiological conditions, the total amount of triglycerides in the liver is determined to a great extent by the overall rate at which lipids are being used for energy.
The liver may also store large amounts of lipids in lipodystrophy, a condition characterized by atrophy or genetic deficiency of adipocytes.
The liver cells, in addition to containing triglycerides, contain large quantities of phospholipids and cholesterol, which are continually synthesized by the liver. Also, the liver cells are much more capable than other tissues of desaturating fatty acids, so liver triglycerides normally are much more unsaturated than the triglycerides of adipose tissue. This capability of the liver to desaturate fatty acids is functionally important to all tissues of the body because many structural elements of all cells contain reasonable quantities of unsaturated fats and their principal source is the liver. This desaturation is accomplished by a dehydrogenase in the liver cells.
Use of Triglycerides for Energy: Formation of Adenosine Triphosphate
The dietary intake of fat varies considerably in persons of different cultures, averaging as little as 10 to 15 percent of caloric intake in some Asian populations to as much as 35 to 50 percent of the calories in many Western populations. For many persons the use of fats for energy is therefore 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 Beta-Oxidation
The fatty acid molecule is degraded in the mitochondria by progressive release of two-carbon segments in the form of acetyl coenzyme A (acetyl-CoA). This process, which is shown in Figure 68-2, is called the beta-oxidation process for degradation of fatty acids.
Figure 68-2 Beta-oxidation of fatty acids to yield acetyl coenzyme A.
To understand the essential steps in the beta-oxidation 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:
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).
Large Amounts of ATP Are Formed by Oxidation of Fatty Acids
In Figure 68-2, note that the four 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. Therefore, 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 nine 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 nine 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:
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 concentrationin 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, 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 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 acid 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 β-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 mainly on a fat diet, do not develop ketosis. Undoubtedly, several factors, none of which is clear, enhance the rate of aceto- acetic 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 percent of their energy from fats.
Synthesis of Triglycerides from Carbohydrates
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 VLDLs 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 68-3, using malonyl-CoA and NADPH as the principal intermediates in the polymerization process.
Figure 68-3 Synthesis of fatty acids.
Combination of Fatty Acids with α-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 68-4, the glycerol portion of triglycerides is furnished by α-glycerophosphate, which is another product derived from the glycolytic scheme of glucose degradation. This mechanism is discussed in Chapter 67.
Figure 68-4 Overall schema for synthesis of triglycerides from glucose.
Efficiency of Carbohydrate Conversion into Fat
During triglyceride synthesis, only about 15 percent of the original energy in the glucose is lost in the form of heat; the remaining 85 percent is transferred to the stored triglycerides.
Importance of Fat Synthesis and Storage
Fat synthesis from carbohydrates is especially important for two reasons:
1. The ability of the different cells of the body to store carbohydrates in the form of glycogen is generally slight; a maximum of only a few hundred grams of glycogen can be stored in the liver, the skeletal muscles, and all other tissues of the body put together. In contrast, many kilograms of fat can be stored in adipose tissue. Therefore, fat synthesis provides a means by which the energy of excess ingested carbohydrates (and proteins) can be stored for later use. Indeed, the average person has almost 150 times as much energy stored in the form of fat as stored in the form of carbohydrate.
2. Each gram of fat contains almost two and a half times the calories of energy contained by each gram of glycogen. Therefore, for a given weight gain, a person can store several times as much energy in the form of fat as in the form of carbohydrate, which is exceedingly important when an animal must be highly motile to survive.
Failure to Synthesize Fats from Carbohydrates in the Absence of Insulin
When insufficient insulin is available, as occurs in serious diabetes mellitus, fats are poorly synthesized, if at all, for the following reasons: First, when insulin is not available, glucose does not enter the fat and liver cells satisfactorily, so little of the acetyl-CoA and NADPH needed for fat synthesis can be derived from glucose. Second, lack of glucose in the fat cells greatly reduces the availability of α-glycerophosphate, which also makes it difficult for the tissues to form triglycerides.
Synthesis of Triglycerides from Proteins
Many amino acids can be converted into acetyl-CoA, as discussed in Chapter 69. The acetyl-CoA can then be synthesized into triglycerides. Therefore, when people have more proteins in their diets than their tissues can use as proteins, a large share of the excess is stored as fat.
Regulation of Energy Release from Triglycerides
Carbohydrates Are Preferred over Fats for Energy When Excess Carbohydrates Are Available
When excess quantities of carbohydrates are available in the body, carbohydrates are used preferentially over triglycerides for energy. There are several reasons for this “fat-sparing” effect of carbohydrates. One of the most important is the following: The fats in adipose tissue cells are present in two forms: stored triglycerides and small quantities of free fatty acids. They are in constant equilibrium with each other. When excess quantities of α-glycerophosphateare present (which occurs when excess carbohydrates are available), the excess α-glycerophosphate binds the free fatty acids in the form of stored triglycerides. As a result, the equilibrium between free fatty acids and triglycerides shifts toward the stored triglycerides; consequently, only minute quantities of fatty acids are available to be used for energy. Because α-glycerophosphate is an important product of glucose metabolism, the availability of large amounts of glucose automatically inhibits the use of fatty acids for energy.
Second, when carbohydrates are available in excess, fatty acids are synthesized more rapidly than they are degraded. This effect is caused partially by the large quantities of acetyl-CoA formed from the carbohydrates and by the low concentration of free fatty acids in the adipose tissue, thus creating conditions appropriate for the conversion of acetyl-CoA into fatty acids.
An even more important effect that promotes the conversion of carbohydrates to fats is the following: The first step, which is the rate-limiting step, in the synthesis of fatty acids is carboxylation of acetyl-CoA to form malonyl-CoA. The rate of this reaction is controlled primarily by the enzyme acetyl-CoA carboxylase, the activity of which is accelerated in the presence of intermediates of the citric acid cycle. When excess carbohydrates are being used, these intermediates increase, automatically causing increased synthesis of fatty acids.
Thus, an excess of carbohydrates in the diet not only acts as a fat-sparer but also increases fat stores. In fact, all the excess carbohydrates not used for energy or stored in the small glycogen deposits of the body are converted to fat for storage.
Acceleration of Fat Utilization for Energy in the Absence of Carbohydrates
All the fat-sparing effects of carbohydrates are lost and actually reversed when carbohydrates are not available. The equilibrium shifts in the opposite direction, and fat is mobilized from the adipose cells and used for energy in place of carbohydrates.
Also important are several hormonal changes that take place to promote rapid fatty acid mobilization from adipose tissue. Among the most important of these is a marked decrease in pancreatic secretion of insulin caused by the absence of carbohydrates. This not only reduces the rate of glucose utilization by the tissues but also decreases fat storage, which further shifts the equilibrium in favor of fat metabolism in place of carbohydrates.
Hormonal Regulation of Fat Utilization
At least seven of the hormones secreted by the endocrine glands have significant effects on fat utilization. Some important hormonal effects on fat metabolism—in addition to insulin lack, discussed in the previous paragraph—are noted here.
Probably the most dramatic increase that occurs in fat utilization is that observed during heavy exercise. This results almost entirely from release of epinephrine and norepinephrine by the adrenal medullae during exercise, as a result of sympathetic stimulation. These two hormones directly activate hormone-sensitive triglyceride lipase, which is present in abundance in the fat cells, and this causes rapid breakdown of triglycerides and mobilization of fatty acids. Sometimes the free fatty acid concentration in the blood of an exercising person rises as much as eightfold, and the use of these fatty acids by the muscles for energy is correspondingly increased. Other types of stress that activate the sympathetic nervous system can also increase fatty acid mobilization and utilization in a similar manner.
Stress also causes large quantities of corticotropin to be released by the anterior pituitary gland, and this causes the adrenal cortex to secrete extra quantities of glucocorticoids. Both corticotropin and glucocorticoids activate either the same hormone-sensitive triglyceride lipase as that activated by epinephrine and norepinephrine or a similar lipase. When corticotropin and glucocorticoids are secreted in excessive amounts for long periods, as occurs in the endocrine condition called Cushing’s syndrome, fats are frequently mobilized to such a great extent that ketosis results. Corticotropin and glucocorticoids are then said to have a ketogenic effect. Growth hormone has an effect similar to but weaker than that of corticotropin and glucocorticoids in activating hormone-sensitive lipase. Therefore, growth hormone can also have a mild ketogenic effect.
Finally, thyroid hormone causes rapid mobilization of fat, which is believed to result indirectly from an increased overall rate of energy metabolism in all cells of the body under the influence of this hormone. The resulting reduction in acetyl-CoA and other intermediates of both fat and carbohydrate metabolism in the cells is a stimulus to fat mobilization.
The effects of the different hormones on metabolism are discussed further in the chapters dealing with each hormone.
Obesity
Obesity means deposition of excess fat in the body. This subject is discussed in Chapter 71 in relation to dietary balances, but briefly, it is caused by the ingestion of greater amounts of food than can be used by the body for energy. The excess food, whether fats, carbohydrates, or proteins, is then stored almost entirely as fat in the adipose tissue, to be used later for energy.
Several strains of rodents have been found in which hereditary obesity occurs. In at least one of these, the obesity is caused by ineffective mobilization of fat from the adipose tissue by tissue lipase, while synthesis and storage of fat continue normally. Such a one-way process causes progressive enhancement of the fat stores, resulting in severe obesity.
Phospholipids and Cholesterol
Phospholipids
The major types of body phospholipids are lecithins, cephalins, and sphingomyelin; their typical chemical formulas are shown in Figure 68-5. Phospholipids always contain one or more fatty acid molecules and one phosphoric acid radical, and they usually contain a nitrogenous base. Although the chemical structures of phospholipids are somewhat variant, their physical properties are similar because they are all lipid soluble, transported in lipoproteins, and used throughout the body for various structural purposes, such as in cell membranes and intracellular membranes.
Figure 68-5 Typical phospholipids.
Formation of Phospholipids
Phospholipids are synthesized in essentially all cells of the body, although certain cells have a special ability to form great quantities of them. Probably 90 percent are formed in the liver cells; substantial quantities are also formed by the intestinal epithelial cells during lipid absorption from the gut.
The rate of phospholipid formation is governed to some extent by the usual factors that control the overall rate of fat metabolism because, when triglycerides are deposited in the liver, the rate of phospholipid formation increases. Also, certain specific chemical substances are needed for the formation of some phospholipids. For instance, choline, either obtained in the diet or synthesized in the body, is necessary for the formation of lecithin, because choline is the nitrogenous base of the lecithin molecule. Also, inositol is necessary for the formation of some cephalins.
Specific Uses of Phospholipids
Several functions of the phospholipids are the following: (1) Phospholipids are an important constituent of lipoproteins in the blood and are essential for the formation and function of most of these; in their absence, serious abnormalities of transport of cholesterol and other lipids can occur. (2) Thromboplastin, which is necessary to initiate the clotting process, is composed mainly of one of the cephalins. (3) Large quantities of sphingomyelin are present in the nervous system; this substance acts as an electrical insulator in the myelin sheath around nerve fibers. (4) Phospholipids are donors of phosphate radicals when these radicals are necessary for different chemical reactions in the tissues. (5) Perhaps the most important of all the functions of phospholipids is participation in the formation of structural elements—mainly membranes—in cells throughout the body, as discussed in the next section of this chapter in connection with a similar function for cholesterol.
Cholesterol
Cholesterol, the formula of which is shown in Figure 68-6, is present in the diets of all people, and it can be absorbed slowly from the gastrointestinal tract into the intestinal lymph. It is highly fat soluble but only slightly soluble in water. It is specifically capable of forming esters with fatty acids. Indeed, about 70 percent of the cholesterol in the lipoproteins of the plasma is in the form of cholesterol esters.
Figure 68-6 Cholesterol.
Formation of Cholesterol
Besides the cholesterol absorbed each day from the gastrointestinal tract, which is called exogenous cholesterol, an even greater quantity is formed in the cells of the body, called endogenous cholesterol. Essentially all the endogenous cholesterol that circulates in the lipoproteins of the plasma is formed by the liver, but all other cells of the body form at least some cholesterol, which is consistent with the fact that many of the membranous structures of all cells are partially composed of this substance.
The basic structure of cholesterol is a sterol nucleus. This is synthesized entirely from multiple molecules of acetyl-CoA. In turn, the sterol nucleus can be modified by means of various side chains to form (1) cholesterol; (2) cholic acid, which is the basis of the bile acids formed in the liver; and (3) many important steroid hormones secreted by the adrenal cortex, the ovaries, and the testes (these hormones are discussed in later chapters).
Factors That Affect Plasma Cholesterol Concentration—Feedback Control of Body Cholesterol
Among the important factors that affect plasma cholesterol concentration are the following:
1. An increase in the amount of cholesterol ingested each day increases the plasma concentration slightly. However, when cholesterol is ingested, the rising concentration of cholesterol inhibits the most essential enzyme for endogenous synthesis of cholesterol, 3-hydroxy-3-methylglutaryl CoA reductase, thus providing an intrinsic feedback control system to prevent an excessive increase in plasma cholesterol concentration. As a result, plasma cholesterol concentration usually is not changed upward or downward more than ±15 percent by altering the amount of cholesterol in the diet, although the response of individuals differs markedly.
2. A highly saturated fat diet increases blood cholesterol concentration 15 to 25 percent, especially when this is associated with excess weight gain and obesity. This results from increased fat deposition in the liver, which then provides increased quantities of acetyl-CoA in the liver cells for the production of cholesterol. Therefore, to decrease the blood cholesterol concentration, it is usually just as important, if not more important, to maintain a diet low in saturated fat as to maintain a diet low in cholesterol.
3. Ingestion of fat containing highly unsaturated fatty acids usually depresses the blood cholesterol concentration a slight to moderate amount. The mechanism of this effect is unknown, despite the fact that this observation is the basis of much present-day dietary strategy.
4. Lack of insulin or thyroid hormone increases the blood cholesterol concentration, whereas excess thyroid hormone decreases the concentration. These effects are probably caused mainly by changes in the degree of activation of specific enzymes responsible for the metabolism of lipid substances.
5. Genetic disorders of cholesterol metabolism may greatly increase plasma cholesterol levels. For example, mutations of the LDL receptor gene prevent the liver from adequately removing the cholesterol-rich LDLs from the plasma. As discussed later, this causes the liver to produce excessive amounts of cholesterol. Mutations of the gene that encodes apolipoprotein B, the part of the LDL that binds to the receptor, also cause excessive cholesterol production by the liver.
Specific Uses of Cholesterol in the Body
By far the most abundant nonmembranous use of cholesterol in the body is to form cholic acid in the liver. As much as 80 percent of cholesterol is converted into cholic acid. As explained in Chapter 70, this is conjugated with other substances to form bile salts, which promote digestion and absorption of fats.
A small quantity of cholesterol is used by (1) the adrenal glands to form adrenocortical hormones, (2) the ovaries to form progesterone and estrogen, and (3) the testes to form testosterone. These glands can also synthesize their own sterols and then form hormones from them, as discussed in the chapters on endocrinology.
A large amount of cholesterol is precipitated in the corneum of the skin. This, along with other lipids, makes the skin highly resistant to the absorption of water-soluble substances and to the action of many chemical agents because cholesterol and the other skin lipids are highly inert to acids and to many solvents that might otherwise easily penetrate the body. Also, these lipid substances help prevent water evaporation from the skin; without this protection, the amount of evaporation can be 5 to 10 liters per day (as occurs in burn patients who have lost their skin) instead of the usual 300 to 400 milliliters.
Cellular Structural Functions of Phospholipids and Cholesterol—Especially for Membranes
The previously mentioned uses of phospholipids and cholesterol are of only minor importance in comparison with their function of forming specialized structures, mainly membranes, in all cells of the body. In Chapter 2, it was pointed out that large quantities of phospholipids and cholesterol are present in both the cell membrane and the membranes of the internal organelles of all cells. It is also known that the ratio of membrane cholesterol to phospholipids is especially important in determining the fluidity of the cell membranes.
For membranes to be formed, substances that are not soluble in water must be available. In general, the only substances in the body that are not soluble in water (besides the inorganic substances of bone) are the lipids and some proteins. Thus, the physical integrity of cells everywhere in the body is based mainly on phospholipids, cholesterol, and certain insoluble proteins. The polar charges on the phospholipids also reduce the interfacial tension between the cell membranes and the surrounding fluids.
Another fact that indicates the importance of phospholipids and cholesterol for the formation of structural elements of the cells is the slow turnover rates of these substances in most nonhepatic tissues—turnover rates measured in months or years. For instance, their function in brain cells to provide memory processes is related mainly to their indestructible physical properties.
Atherosclerosis
Atherosclerosis is a disease of the large and intermediate-sized arteries in which fatty lesions called atheromatous plaques develop on the inside surfaces of the arterial walls. Arteriosclerosis, in contrast, is a general term that refers to thickened and stiffened blood vessels of all sizes.
One abnormality that can be measured very early in blood vessels that later become atherosclerotic is damage to the vascular endothelium. This, in turn, increases the expression of adhesion molecules on endothelial cells and decreases their ability to release nitric oxide and other substances that help prevent adhesion of macromolecules, platelets, and monocytes to the endothelium. After damage to the vascular endothelium occurs, circulating monocytes and lipids (mostly LDLs) begin to accumulate at the site of injury (Figure 68-7A). The monocytes cross the endothelium, enter the intima of the vessel wall, and differentiate to become macrophages, which then ingest and oxidize the accumulated lipoproteins, giving the macrophages a foamlike appearance. These macrophage foam cells then aggregate on the blood vessel and form a visible fatty streak.
Figure 68-7 Development of atherosclerotic plaque. A, Attachment of a monocyte to an adhesion molecule on a damaged endothelial cell of an artery. The monocyte then migrates through the endothelium into the intimal layer of the arterial wall and is transformed into a macrophage. The macrophage then ingests and oxidizes lipoprotein molecules, becoming a macrophage foam cell. The foam cells release substances that cause inflammation and growth of the intimal layer. B, Additional accumulation of macrophages and growth of the intima cause the plaque to grow larger and accumulate lipids. Eventually, the plaque could occlude the vessel or rupture, causing the blood in the artery to coagulate and form a thrombus.
(Modified from Libby P: Inflammation in atherosclerosis. Nature 420:868, 2002.)
With time, the fatty streaks grow larger and coalesce, and the surrounding fibrous and smooth muscle tissues proliferate to form larger and larger plaques (see Figure 68-7B). Also, the macrophages release substances that cause inflammation and further proliferation of smooth muscle and fibrous tissue on the inside surfaces of the arterial wall. The lipid deposits plus the cellular proliferation can become so large that the plaque bulges into the lumen of the artery and greatly reduces blood flow, sometimes completely occluding the vessel. Even without occlusion, the fibroblasts of the plaque eventually deposit extensive amounts of dense connective tissue; sclerosis (fibrosis) becomes so great that the arteries become stiff and unyielding. Still later, calcium salts often precipitate with the cholesterol and other lipids of the plaques, leading to bony-hard calcifications that can make the arteries rigid tubes. Both of these later stages of the disease are called “hardening of the arteries.”
Atherosclerotic arteries lose most of their distensibility, and because of the degenerative areas in their walls, they are easily ruptured. Also, where the plaques protrude into the flowing blood, their rough surfaces can cause blood clots to develop, with resultant thrombus or embolus formation (see Chapter 36), leading to a sudden blockage of all blood flow in the artery.
Almost half of all deaths in the United States and Europe are due to vascular disease. About two thirds of these deaths are caused by thrombosis of one or more coronary arteries. The remaining one third are caused by thrombosis or hemorrhage of vessels in other organs of the body, especially the brain (causing strokes), but also the kidneys, liver, gastrointestinal tract, limbs, and so forth.
Basic Causes of Atherosclerosis—the Roles of Cholesterol and Lipoproteins
Increased Low-Density Lipoproteins
An important factor in causing atherosclerosis is a high blood plasma concentration of cholesterol in the form of low-density lipoproteins. The plasma concentration of these high-cholesterol LDLs is increased by several factors, including eating highly saturated fat in the daily diet, obesity, and physical inactivity. To a lesser extent, eating excess cholesterol may also raise plasma levels of LDLs.
An interesting example occurs in rabbits, which normally have low plasma cholesterol concentrations because of their vegetarian diet. Simply feeding these animals large quantities of cholesterol as part of their daily diet leads to serious atherosclerotic plaques throughout their arterial systems.
Familial Hypercholesterolemia
This is a disease in which the person inherits defective genes for the formation of LDL receptors on the membrane surfaces of the body’s cells. In the absence of these receptors, the liver cannot absorb either intermediate-density or low-density lipoprotein. Without this absorption, the cholesterol machinery of the liver cells goes on a rampage, producing new cholesterol; it is no longer responsive to the feedback inhibition of too much plasma cholesterol. As a result, the number of VLDLs released by the liver into the plasma increases immensely.
Patients with full-blown familial hypercholesterolemia may have blood cholesterol concentrations of 600 to 1000 mg/dl, levels that are four to six times normal. Many of these people die before age 20 because of myocardial infarction or other sequelae of atherosclerotic blockage of blood vessels throughout the body.
Heterozygous familial hypercholesterolemia is relatively common and occurs in about one in 500 people. The more severe form of this disorder caused by homozygous mutations is much rarer, occurring in only about one of every million births on average.
Role of High-Density Lipoproteins in Preventing Atherosclerosis
Much less is known about the function of HDLs compared with that of LDLs. It is believed that HDLs can actually absorb cholesterol crystals that are beginning to be deposited in arterial walls. Whether this mechanism is true or not, HDLs do help protect against the development of atherosclerosis. Consequently, when a person has a high ratio of high-density to low-density lipoproteins, the likelihood of developing atherosclerosis is greatly reduced.
Other Major Risk Factors for Atherosclerosis
In some people with perfectly normal levels of cholesterol and lipoproteins, atherosclerosis still develops. Some of the factors that are known to predispose to atherosclerosis are (1) physical inactivity and obesity, (2) diabetes mellitus, (3) hypertension, (4) hyperlipidemia, and (5) cigarette smoking.
Hypertension, for example, increases the risk for atherosclerotic coronary artery disease by at least twofold. Likewise, a person with diabetes mellitus has, on average, more than a twofold increased risk of developing coronary artery disease. When hypertension and diabetes mellitus occur together, the risk for coronary artery disease is increased by more than eightfold. And when hypertension, diabetes mellitus, and hyperlipidemia are all present, the risk for atherosclerotic coronary artery disease is increased almost 20-fold, suggesting that these factors interact in a synergistic manner to increase the risk of developing atherosclerosis. In many overweight and obese patients, these three risk factors do occur together, greatly increasing their risk for atherosclerosis, which in turn may lead to heart attack, stroke, and kidney disease.
In early and middle adulthood, men are more likely to develop atherosclerosis than are women of comparable age, suggesting that male sex hormones might be atherogenic or, conversely, that female sex hormones might be protective.
Some of these factors cause atherosclerosis by increasing the concentration of LDLs in the plasma. Others, such as hypertension, lead to atherosclerosis by causing damage to the vascular endothelium and other changes in the vascular tissues that predispose to cholesterol deposition.
To add to the complexity of atherosclerosis, experimental studies suggest that excess blood levels of iron can lead to atherosclerosis, perhaps by forming free radicals in the blood that damage the vessel walls. About one quarter of all people have a special type of LDL called lipoprotein(a), containing an additional protein, apolipoprotein(a), that almost doubles the incidence of atherosclerosis. The precise mechanisms of these atherogenic effects have yet to be discovered.
Prevention of Atherosclerosis
The most important measures to protect against the development of atherosclerosis and its progression to serious vascular disease are (1) maintaining a healthy weight, being physically active, and eating a diet that contains mainly unsaturated fat with a low cholesterol content; (2) preventing hypertension by maintaining a healthy diet and being physically active, or effectively controlling blood pressure with antihypertensive drugs if hypertension does develop; (3) effectively controlling blood glucose with insulin treatment or other drugs if diabetes develops; and (4) avoiding cigarette smoking.
Several types of drugs that lower plasma lipids and cholesterol have proved to be valuable in preventing atherosclerosis. Most of the cholesterol formed in the liver is converted into bile acids and secreted in this form into the duodenum; then, more than 90 percent of these same bile acids is reabsorbed in the terminal ileum and used over and over again in the bile. Therefore, any agent that combines with the bile acids in the gastrointestinal tract and prevents their reabsorption into the circulation can decrease the total bile acid pool in the circulating blood. This causes far more of the liver cholesterol to be converted into new bile acids. Thus, simply eating oat bran, which binds bile acids and is a constituent of many breakfast cereals, increases the proportion of liver cholesterol that forms new bile acids rather than forming new LDLs and atherogenic plaques. Resin agents can also be used to bind bile acids in the gut and increase their fecal excretion, thereby reducing cholesterol synthesis by the liver.
Another group of drugs called statins competitively inhibits hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the synthesis of cholesterol. This inhibition decreases cholesterol synthesis and increases LDL receptors in the liver, usually causing a 25 to 50 percent reduction in plasma levels of LDLs. The statins may also have other beneficial effects that help prevent atherosclerosis, such as attenuating vascular inflammation. These drugs are now widely used to treat patients who have increased plasma cholesterol levels.
In general, studies show that for each 1 mg/dl decrease in LDL cholesterol in the plasma, there is about a 2 percent decrease in mortality from atherosclerotic heart disease. Therefore, appropriate preventive measures are valuable in decreasing heart attacks.
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