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Digestion / How the Liver Works
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submitted by Dr. Gary Farr - Contact the author here.
Last Updated September, 23, 2011
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Management of Fat Metabolism
We are all aware that it is possible to become fat by eating excess amounts of any kind of food. One would expect that excess calories taken in as fat would be stored as fat. In fact, that is the case as fat is transported from the intestinal cells through the blood for deposit in adipose tissue by a elaborate process involving the breakdown and resynthesis of the fat molecule (triglyceride) each time it is necessary to move from one cell or tissue to another.
Excess calories in the form of carbohydrate (sugars, starches) and protein (both animal and vegetable) are converted to fat in a complex series of reactions that occur in the liver. The biochemical reactions that underlie these conversions are too complex and ornate to consider here. As described earlier, the TCA cycle is the point at which the carbon skeletons derived from fuels of all types, carbohydrate, protein, and fat, are converted into common intermediates and released as carbon dioxide with the production of energy. Recall that this series of reactions occurs in a subcellular organelle, the mitochondrion, and lies at the very core of metabolism.
One of the intermediates of the TCA cycle is a six carbon molecule known as citrate or citric acid. Under fed conditions where there are adequate levels of fuel, citric acid serves as key intermediate in the conversion of excess carbohydrate and protein to fat. The carbon based structures in sugar and amino acids (the building blocks of carbohydrates and proteins, respectively) are passed through individual pathways of biochemical reactions that progressively convert them to one, and in some cases more than one, of the compounds of the TCA cycle. These are in turn converted to citrate as part of the cycle itself. Citrate is then removed from the mitochondria and used to form a critical intermediate, Malony CoA, needed for fat synthesis.
During the fed state, the liver is actively synthesizing fat as a way of storing excess calories for use at a later time. While fat is synthesized in the liver, a healthy liver does not store fat. Instead, newly synthesized fat is converted to a transport form similar to the chylomicron described earlier. Known as Very Low Density Lipoprotein (VLDL), these transport vesicles contain a core composed of a small droplet of triglyceride (fat), surrounded by protein and detergent- like molecules (amphipathic molecules, largely phospholipids) that make them stable in the water-based environment of the cells and the blood. The VLDLs are released from the liver to the blood, transporting the triglyceride for storage in various tissues of the body, primarily adipose (fat) tissue and, to a lesser extent, muscle.
As mentioned above, low blood glucose levels are interpreted by the endocrine system as a signal that the body has inadequate levels of fuel in the blood. The endocrine system responds by decreasing the release of insulin and increasing the release of other hormones, particularly glucagon. Taken together, these changes produce a set of metabolic adjustments as the body accommodates to the decreasing availability of fuels characteristic of the fasting state.
Because of the central role of the liver in managing fuels, many of the central adjustments act to alter liver function. In the context of fat metabolism, as a consequence of the transition from fed to fasting the liver stops the synthesis of fat and VLDL. In the fasting state fat (triglyceride) storage is turned off and triglyceride stored in adipose tissue begins to be broken down. In this process, each triglyceride molecule is disassembled to form three molecules of free fatty acid and the three carbon glycerol molecule and these are released to the blood.
The liver has the richest blood supply of any organ, and as a consequence has excellent access to circulating fuels. During fasting, free fatty acids are the body's major fuel while glycerol provides some of the carbon necessary for glucose synthesis. As described above, the liver carries out gluconeogenesis. In that process the liver actively converts two molecules of glycerol (two three carbon molecules) into one molecule of glucose (one six carbon molecule) and releases that glucose to the blood for use by other tissues.
Fatty acid breakdown occurs within a subcellular structure, the mitochondrion, a kind of cellular organ and thus termed an "organelle." The mitochondria serve as a kind of "powerhouse" for the cell where the final stage of fuel consumption and energy production occurs. Typically, a single cell has many mitochondria to assure that the cell's energy requirements are met. Detailed information regarding the mitochondria and cell function can be found here.
Fatty acid is the preferred cellular fuel in the fasting state. Fatty acids are composed of a long chain of carbon atoms, with sixteen being the most common number. In all tissues of the body except the liver free fatty acid is degraded in two stages. The first phase of fatty acid degradation involves the progressive breakdown of the long carbon chain into a set of two carbon units known as acetyl-CoA. Thus a sixteen carbon fatty acid is broken down into eight molecules of acetyl-CoA. In the second stage, acetyl-CoA enters the TCA cycle.
As described above, this cycle of reactions starts with a reaction in which a four carbon molecule (oxaloacetate, abbreviated as OAA) 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, OAA. With every turn of the cycle, two carbons are oxidized to CO2 and the material needed for another turn of the cycle is regenerated. Through this biochemical process, coupled to a final sequence that consumes molecular oxygen, fuels are oxidized to CO2 and water with the production of a great deal of useful energy.
It is important to recognize that oxaloacetate is regenerated with each turn of the TCA cycle. For this reason, a central feature of the cycle is that one OAA molecule can support the oxidation of a large number of acetyl-CoA molecules.
There is a powerful intersection between glucose metabolism and the production of energy from fat. Since one molecule of glucose can be directly converted into two molecules of OAA, a very small amount of glucose can support the oxidation of a very large amount of fat. With that in mind, it is easy to understand why it is important to maintain blood glucose during the fasting state, a state in which fat is the principle fuel. The presence of adequate levels of glucose assures that the cell can derive energy from fatty acids circulating in the blood.
Once again, the liver fulfills a unique function. Because of its preferred access to fuels, the liver is able to meet its energy needs by carrying out only the first stage of fatty acid breakdown in which free fatty acids to are degraded to acetyl- CoA. The metabolic posture of the liver is such that the TCA cycle is relatively inactive and acetyl-CoA is produced in quantities far in excess of what is needed by the liver cell for energy production. As a consequence, the clears the excess through a series of reactions in which two molecules of acetyl-CoA are combined into four carbon molecules, known collectively as "ketone bodies" and releases these substances to the blood.
Ketone bodies synthesized by the liver are an important fuel for other tissues. In particular, the heart and other muscle tissues use ketone bodies as a preferred fuel. Thus, while meeting its own energy needs to sustain the production of glucose, and to fulfill a number of other important needs not considered here, the liver uses free fatty acid in a way that produces an optimum fuel for other tissues of the body.
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