The liver is a large, chemically reactant pool of cells that have a high rate of metabolism, sharing substrates and energy from one metabolic system to another, processing and synthesizing multiple substances that are transported to other areas of the body, and performing myriad other metabolic functions. For these reasons, a major share of the entire discipline of biochemistry is devoted to the metabolic reactions in the liver. But here, let us summarize those metabolic functions that are especially important in understanding the integrated physiology of the body.
In carbohydrate metabolism, the liver performs the following functions, as summarized from Chapter 67:
1. Storage of large amounts of glycogen
2. Conversion of galactose and fructose to glucose
4. Formation of many chemical compounds from intermediate products of carbohydrate metabolism The liver is especially important for maintaining a normal blood glucose concentration. Storage of glyco-gen allows the liver to remove excess glucose from the blood, store it, and then return it to the blood when the blood glucose concentration begins to fall too low. This is called the glucose buffer function of the liver. In a person with poor liver function, blood glucose concentration after a meal rich in carbohydrates may rise two to three times as much as in a person with normal liver function.
Gluconeogenesis in the liver is also important in maintaining a normal blood glucose concentration, because gluconeogenesis occurs to a significant extent only when the glucose concentration falls below normal. In such a case, large amounts of amino acids and glyc-erol from triglycerides are converted into glucose, thereby helping to maintain a relatively normal blood glucose concentration.
Although most cells of the body metabolize fat, certain aspects of fat metabolism occur mainly in the liver. Specific functions of the liver in fat metabolism, as summarized from Chapter 68, are the following:
1. Oxidation of fatty acids to supply energy for other body functions
2. Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins
3. Synthesis of fat from proteins and carbohydrates To derive energy from neutral fats, the fat is first split into glycerol and fatty acids; then the fatty acids are split by beta-oxidation into two-carbon acetyl radicals that form acetyl coenzyme A (acetyl-CoA). This can enter the citric acid cycle and be oxidized to liberate tremendous amounts of energy. Beta-oxidation can take place in all cells of the body, but it occurs especially rapidly in the hepatic cells. The liver itself cannot use all the acetyl-CoA that is formed; instead, it is converted by the condensation of two molecules of acetyl-CoA into acetoacetic acid, a highly soluble acid that passes from the hepatic cells into the extracellular fluid and is then transported throughout the body to be absorbed by other tissues. These tissues reconvert the acetoacetic acid into acetyl-CoA and then oxidize it in the usual manner. Thus, the liver is responsible for a major part of the metabolism of fats.
About 80 per cent of the cholesterol synthesized in the liver is converted into bile salts, which are secreted into the bile; the remainder is transported in the lipoproteins and carried by the blood to the tissue cells everywhere in the body. Phospholipids are likewise synthesized in the liver and transported principally in the lipoproteins. Both cholesterol and phospholipids are used by the cells to form membranes, intracellular structures, and multiple chemical substances that are important to cellular function.
Almost all the fat synthesis in the body from carbohydrates and proteins also occurs in the liver. After fat is synthesized in the liver, it is transported in the lipoproteins to the adipose tissue to be stored.
The body cannot dispense with the liver's contribution to protein metabolism for more than a few days without death ensuing.The most important functions of the liver in protein metabolism, as summarized from Chapter 69, are the following:
1. Deamination of amino acids
2. Formation of urea for removal of ammonia from the body fluids
3. Formation of plasma proteins
4. Interconversions of the various amino acids and synthesis of other compounds from amino acids
Deamination of amino acids is required before they can be used for energy or converted into carbohydrates or fats. A small amount of deamination can occur in the other tissues of the body, especially in the kidneys, but this is much less important than the deamination of amino acids by the liver.
Formation of urea by the liver removes ammonia from the body fluids. Large amounts of ammonia are formed by the deamination process, and additional amounts are continually formed in the gut by bacteria and then absorbed into the blood. Therefore, if the liver does not form urea, the plasma ammonia concentration rises rapidly and results in hepatic coma and death. Indeed, even greatly decreased blood flow through the liver—as occurs occasionally when a shunt develops between the portal vein and the vena cava—can cause excessive ammonia in the blood, an extremely toxic condition.
Essentially all the plasma proteins, with the exception of part of the gamma globulins, are formed by the hepatic cells. This accounts for about 90 per cent of all the plasma proteins. The remaining gamma globulins are the antibodies formed mainly by plasma cells in the lymph tissue of the body. The liver can form plasma proteins at a maximum rate of 15 to 50 g/day. Therefore, even if as much as half the plasma proteins are lost from the body, they can be replenished in 1 or 2 weeks.
It is particularly interesting that plasma protein depletion causes rapid mitosis of the hepatic cells and growth of the liver to a larger size; these effects are coupled with rapid output of plasma proteins until the plasma concentration returns to normal. With chronic liver disease (e.g., cirrhosis), plasma proteins, such as albumin, may fall to very low levels, causing generalized edema and ascites, as explained in Chapter 29.
Among the most important functions of the liver is its ability to synthesize certain amino acids and to synthesize other important chemical compounds from amino acids. For instance, the so-called nonessential amino acids can all be synthesized in the liver. To do this, a keto acid having the same chemical composition (except at the keto oxygen) as that of the amino acid to be formed is synthesized. Then an amino radical is transferred through several stages of transamination from an available amino acid to the keto acid to take the place of the keto oxygen.
The Liver Is a Storage Site for Vitamins. The liver has a particular propensity for storing vitamins and has long been known as an excellent source of certain vitamins in the treatment of patients. The vitamin stored in greatest quantity in the liver is vitamin A, but large quantities of vitamin D and vitamin B12 are normally stored as well. Sufficient quantities of vitamin A can be stored to prevent vitamin A deficiency for as long as 10 months. Sufficient vitamin D can be stored to prevent deficiency for 3 to 4 months, and enough vitamin B12 can be stored to last for at least 1 year and maybe several years.
The Liver Stores Iron as Ferritin. Except for the iron in the hemoglobin of the blood, by far the greatest proportion of iron in the body is stored in the liver in the form of ferritin. The hepatic cells contain large amounts of a protein called apoferritin, which is capable of combining reversibly with iron. Therefore, when iron is available in the body fluids in extra quantities, it combines with apoferritin to form ferritin and is stored in this form in the hepatic cells until needed elsewhere. When the iron in the circulating body fluids reaches a low level, the ferritin releases the iron. Thus, the apoferritin-ferritin system of the liver acts as a blood iron buffer, as well as an iron storage medium. Other functions of the liver in relation to iron metabolism and red blood cell formation are considered in Chapter 32.
The Liver Forms a Large Proportion of the Blood Substances Used in Coagulation. Substances formed in the liver that are used in the coagulation process include fibrinogen, prothrombin, accelerator globulin, Factor VII, and several other important factors. Vitamin K is required by the metabolic processes of the liver for the formation of several of these substances, especially prothrombin and Factors VII, IX, and X. In the absence of vitamin K, the concentrations of all these decrease markedly, and this almost prevents blood coagulation.
The Liver Removes or Excretes Drugs, Hormones, and Other Substances. The active chemical medium of the liver is well known for its ability to detoxify or excrete into the bile many drugs, including sulfonamides, penicillin, ampi-cillin, and erythromycin.
In a similar manner, several of the hormones secreted by the endocrine glands are either chemically altered or excreted by the liver, including thyroxine and essentially all the steroid hormones, such as estrogen, cortisol, and aldosterone. Liver damage can lead to excess accumulation of one or more of these hormones in the body fluids and therefore cause overactivity of the hormonal systems.
Finally, one of the major routes for excreting calcium from the body is secretion by the liver into the bile, which then passes into the gut and is lost in the feces.
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