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Lipid Metabolism
Several chemical compounds in food and in the body are classified as lipids, including the following: (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 triglycerides and phospholipids is fatty acids , which are long-chain hydrocarbon organic acids. A typical fatty acid, palmitic acid, is the following: CH 3 (CH 2 ) 14 COOH.
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 lipids.
The triglycerides are used in the body mainly to provide energy for the different metabolic processes, a function they share almost equally with carbohydrates. However, some lipids, especially cholesterol, phospholipids, and small amounts of triglycerides, are used to form the membranes of all cells of the body and to perform other essential cellular functions.
Basic Chemical Structure of Triglycerides (Neutral Fat)
Because most of this chapter deals with 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 as follows: (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 66 , 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 69-1 ), whose diameters are between 0.08 and 0.6 micron. A small amount of apolipoprotein , mainly apolipoprotein B, is adsorbed to the outer surfaces of the chylomicrons. The remainder of the protein molecules project into the surrounding water and thereby increase the suspension stability of the chylomicrons in the lymph fluid and prevent their adherence to the lymphatic vessel walls.
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% phospholipids, 3% cholesterol, and 1% apolipoproteins. 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 containing large quantities of fat, the chylomicron concentration in the plasma may rise to 1% to 2% 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 ( Figure 69-2 ).
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, which also 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 transport 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 topic is discussed later in the chapter.
Upon 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 physiological 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% of all the lipids in the plasma are in the form of lipoprotein . These lipids 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 mg per 100 ml of plasma—that is, 700 mg/dl—and 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 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 VLDLs 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 IDLs 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 (≈50%) 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 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. The other lipoproteins are especially important in 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
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.
Adipose Tissue
A major function of adipose tissue is storage of triglycerides until they are needed to provide energy elsewhere in the body. Additional functions are to provide heat insulation for the body, as discussed in Chapter 74 , and secretion of hormones , such as leptin and adiponectin , which affect multiple body functions, including appetite and energy expenditure, as discussed in Chapter 72 .
Fat Cells (Adipocytes) Store Triglycerides
The fat cells (adipocytes) of adipose tissue are modified fibroblasts that store almost pure triglycerides in quantities as great as 80% to 95% 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 characteristic 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.
Tissue Lipases Permit Exchange of Fat Between Adipose Tissue and the Blood
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 during (1) 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 people who are obese or have lipodystrophy, a condition characterized by atrophy or genetic deficiency of adipocytes. In both of these conditions, excess fat that cannot be stored in adipose tissue accumulates in the liver and, to a lesser extent, in other tissues that normally store minimal amounts of lipids.
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 of desaturating fatty acids than are other tissues, and thus 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% of caloric intake in some Asian populations to as much as 35% to 50% 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. In addition, many of the carbohydrates ingested with each meal are converted into triglycerides, stored, and used later in the form of fatty acids released from the triglycerides for energy.
Hydrolysis of Triglycerides Into Fatty Acids and Glycerol
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, upon 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 mitochondria.
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 using carnitine as a carrier. Once inside the mitochondria, fatty acids split away from carnitine and are degraded and oxidized.
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