|
Proteins & Amino Acids / How the Liver Works
Page: 1
The liver is one of the most important organs in the human body. Our largest organ, the liver is located in a central position of the abdomen, and is intimately involved in almost every aspect of the body's processes. Because of its central role, liver disease strikes at the very heart of the body's functions and processes - and can be extremely life-threatening. You cannot live without a liver.
While the liver serves a variety of functions, the most crucial is its role in the body's metabolism. There is no organ that is more important to healthy metabolism than the liver - in many ways, it is as central to metabolism as the heart is to the circulation of blood. The liver plays a critical role in four key areas of metabolism: fuel management, nitrogen excretion, the regulation water distribution between the blood and tissues, and the detoxification of foreign substances.
Because of the crucial importance of healthly metabolism to overall health, diseases of the liver, such as hepatitis C, can be devastating, leading to fatigue, malaise, and even to death.
Our society depends on energy derived from burning fuels of various kinds in "engines" designed to release, capture, and deliver that energy in a useful form. Typically, wood, oil or coal are burned in the presence of oxygen (air) to liberate energy with the production of CO2 and water. These combustion processes typically occur quite rapidly and generally require relatively high temperatures.
Biological systems operate on the basis of similar energetic principles. There are three types of fuel consumed by a living cell, carbohydrate, fat, and protein and living cells derive large amounts of energy from the "burning" (oxidation) of these fuels. These biological fuels are closely related to those used in mechanical engines and their consumption produces the same waste products, CO2 and water. Carbohydrate and wood are very similar (starch and cellulose are both composed entirely of glucose), fat and oil are both hydrocarbons, and protein is converted to a complex set of carbon based molecules.
While the overall energetics are similar, the molecular processes of energy production in living cells are profoundly different. Unlike mechanical engines, living cells can produce energy very efficiently at temperatures of less than 100 degrees F while capturing that energy and coupling it to systems that carry out useful work with very little waste or loss.
|
|
|
|
Mitochondria in a human liver cell. |
A detailed treatment of the reactions involved in energy production is not necessary for our purposes here. However, it is useful to note that all biological fuels ultimately are converted to one of a small number of intermediates in what is known as the Tricarboxylic Acid Cycle (TCA cycle; sometimes called the Citric Acid Cycle.) The name TCA was given to this cycle because a key intermediate is citric acid, a molecule that contains three carboxylic acid (COOH) groups.
The TCA cycle can be viewed as starting with a reaction in which a four carbon molecule (oxaloacetate) combines with a two carbon molecule (acetyl- CoA) to form a six carbon molecule (citrate). The following steps of the cycle involve a series of reactions in which two carbons are released as carbon dioxide (CO2) and the remaining four carbons are used to reform the original four carbon starting material, oxaloacetate. With every turn of the cycle, two carbons are oxidized to CO2 and the material (oxaloacetate) needed for another turn of the cycle is regenerated.
The oxidation of carbon to CO2 is coupled to the reduction of other compounds. These in turn are oxidized (donate electrons) by a series of reactions coupled to a final step that consumes molecular oxygen to produce water. These reactions are all carried out in a small subcellular "organelle," the mitochondrion, and taken together lead to the production of a great deal of useful energy.
|
|
|
|
During a several hour period following a meal, there is a progressive shift to the fasting state as the various nutrients are taken up by cells for storage, the synthesis of needed cell components, and for use as fuel in the production of energy to support a broad range of cellular processes. Thus fed and fasting are not distinct states, but rather represent two ends of a continuum. As the fasting state becomes more established, the blood levels of glucose, fat, and amino acids progressively fall. |
We derive our energy and build our cells and tissues using energy derived from the metabolic breakdown of three major classes of nutrients; carbohydrates (simple and complex sugars), lipids (various fats and oils), and protein (very large nitrogen containing molecules found in plant and animal tissues; meat is the clearest representative.)
We will consider each of these three classes of nutrient and the role of the liver in their metabolism in two different states, "fed" and "fasting." The fed state refers to the period following a meal and is characterized by high levels of nutrients in the blood. There are high circulating levels of a family of simple sugars, the most important being glucose. In addition, typically there are high levels of fat packaged in relatively large (but not visible to naked eye) structures called chylomicrons. A chylomicron is composed of a small droplet of fat (triglyceride) at its center surrounded by a family of detergent- like molecules and protein that make the structure stable in the aqueous (water based) environment of the blood. Finally there are relatively high levels of amino acids derived from the breakdown of protein in the diet.
During a several hour period following a meal, there is a progressive shift to the fasting state as the various nutrients are taken up by cells for storage, the synthesis of needed cell components, and for use as fuel in the production of energy to support a broad range of cellular processes.
The fed state is signaled by the presence of high levels of insulin, an important endocrine system hormone secreted in response to high blood sugar levels. The major signal indicating that the body is fasting is provided when blood glucose levels fall to a low level and there is resulting fall in the circulating level of insulin. Low levels of insulin, accompanied by elevated levels of other hormone signals such as glucogon, provide a signal that the circulating level of fuels in the blood are inadequate. The body responds by releasing free fatty acids from fat stored in specialized cells known as adipose cells making up the fatty tissue of the body. At the same time the liver begins to make glucose available to the body by synthesizing and by producing free glucose from storage. This glucose is released to the blood for use by other tissues. Similarly, amino acids are produced by the onset of protein degradation in many tissues, primarily muscle, for use within the cell in the synthesis of new needed protein or fuel. Amino acid that is not used by the cell is released to the blood and taken up by the liver as a source of carbon molecules in the synthesis of glucose.
Given adequate fluid intake, the body is able to maintain the fasting state so long as fat stores exist, a period of approximately 10-15 weeks in an initially well nourished adult. Once the fat reserves are exhausted, starvation begins and there is a rapid loss of protein as the body invades the structural components of cells for needed fuel. Starvation progresses quickly to death as proteins needed for critical activities of cells are degraded and the ability of the body to maintain itself is compromised.
As described above, glucose plays a central role in whole body metabolism as the concentration of glucose in the blood provides an important signal to the master system, the endocrine system, that regulates overall metabolic activity.
Glucose is a critical fuel for the function of some specialized tissues, particularly the central nervous system (CNS). Under normal circumstances the CNS uses only glucose as a source of energy, and is therefore completely depended on blood glucose. As described above, blood glucose levels rise following a meal and fall as the body enters the fasting state. Because of the essential role of glucose in supporting CNS function, it is vital that these changes in blood glucose concentration be managed in a way that prevents excessively low levels of glucose (hypoglycemia). Liver plays a unique role in achieving this goal.
Glucose is stored in many tissues, generally for meeting the need for glucose during fasting, or when extra fuel is needed as during intense muscle activity. Storage is achieved through the synthesis of a large, highly branched complex carbohydrate molecule named glycogen. Glycogen is composed entirely of glucose molecules linked to one another is a highly regular way. It provides a compact storage molecule that can be quickly broken down when glucose is needed.
Glycogen synthesis is limited in most tissues by means of an inhibitory feedback mechanism that limits the amount of glucose that is taken up by the cell. This is achieved by limiting the rate of conversion of glucose to glucose- 6-phosphate. This is the first step in the metabolism of glucose and the addition of a phosphate group "traps" glucose inside the cell. Glucose-6- Phosphate (G-6-P) can enter any one of three major pathways (three different series of biochemical reactions) involved in the overall metabolism of glucose. One of these pathways leads to the formation of glycogen.
Unlike all other tissues, liver has not one but two ways of making G-6-P, each catalyzed by a different enzyme. One of these is identical to that of most other tissues and is feedback inhibited. The other is not regulated and, under conditions where the blood glucose levels are high (fed state), actively supports the formation of G-6-P. Together, these two mechanisms assure that the liver has lots of G-6-P available, and thus assure that glycogen synthesis in the liver is very active. Indeed, the liver accounts for approximately half of the total synthesis of glycogen in the human body with half of the total glucose stored being contained in liver.
During the transition from fed to fasting, the concentration of glucose in the blood falls, signaling the need for additional fuel (fatty acid from adipose tissue) and signaling the need to prevent glucose levels from becoming too low. Once again, the liver plays a unique and critical role as it works to maintain blood glucose at a stable level. Two processes come into action; the breakdown of glycogen that was accumulated in the fed state, and the actual synthesis of more glucose.
All cells capable of making glycogen (most cells of the body) can also break glycogen down, forming G-6-P. However, as mentioned above, so long as the glucose has a phosphate attached, it is trapped within the cell. In these cells, G-6-P is used as a fuel, used to support the production of energy from other fuels (fatty acids and ketone bodies), or used in other parts of metabolism.
In the context of glycogen breakdown, once again the liver has a unique ability. Like other cells, the liver breaks glycogen down to glucose-6- phosphate. But only the liver has the ability to removing the phosphate group from G-6-P, forming free glucose. This free glucose easily leaves the liver and enters the blood. Since liver is the only tissue that can support blood glucose levels during fasting, it is easy to understand the importance of the ability of the liver to store large amounts of glucose as glycogen during fed periods when blood glucose is plentiful.
In most tissues, glucose is eventually degraded as part of cellular metabolism. However, during the fasting state when there is an ongoing demand for glucose by other cells, the liver is capable of synthesizing G-6-P from a variety of carbohydrates and from the carbon "skeletons" of many of the amino acids. This process, termed "gluconeogenesis," occurs at a high rate in liver and is, again, unique to liver cells. As above, the removal of the phosphate from G- 6-P forms free glucose, allowing this newly synthesized glucose to enter the blood.
The release of glucose from stored liver glycogen and the synthesis of glucose by the liver acts to keep the blood glucose concentration stable during the fasting state. Taken together, these processes maintain blood glucose at a level adequate to support the activities of other tissues in the body, particularly the central nervous system. It is difficult to overstate the importance of the role of the liver in glucose storage and release to the healthy functioning of the whole body.
|
