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.

A. Synthesis of Fat During the Fed State

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.

B. Fat Breakdown During the Fasting State

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.