OFFICE OF SCIENCE OUTREACH
DEPARTMENT OF BIOLOGY
Obesity, Type 2 Diabetes, and Fructose
Part 2: The Molecular Biology and Biochemistry
With modern high-throughput methods for determining the genes that particular tissues and organs express, it has been possible to look at gene-expression profiles in remarkable detail.
From this, we learn that most organs express the gene for hexokinase, the first enzyme of energy metabolism. The liver does not. Instead, it expresses the genes for two different enzymes, glucokinase and fructokinase. This makes a big difference.
First, a simplified summary of energy metabolism.
First, most cells can metabolize sugars (e.g. glucose), fats (fatty acids), or amino acids. Part of the metabolism occurs in the cytoplasm, and part occurs in the mitochondria. In essence, cytoplasmic enzymes "prepare" sugars and fatty acids to enter mitochondria. Glucose is converted into pyruvate ("compound P" in the diagram on the right), and fatty acids are converted into Acetyl-CoA ("compound A" in the diagram). There is a shuttle system that can move Acetyl-CoA into mitochondria; in the diagram, think of the last part (Compound A → complete metabolism) as the mitochondrial processes. Although it is not shown here, the function of all of this is to re-assemble ATP molecules that are used elsewhere in the cell.
Amino acids can enter mitochondrial metabolism at different points, depending on the particular amino acid. In short, it is possible to use nearly anything as a source of energy. For a more detailed view of these biochemical reactions, click on the lefthand thumbnail on the right. The thumbnail to its right uses the purple highlight to illustrate the "flow" of glucose through these biochemical pathways.
But different types of cells have different types of quirks. The three that are most important are these:
- Neurons (e.g. the brain and other parts of the nervous system) use only glucose.
- The liver can make glucose from amino acids, almost (but not quite) by running the glucose-degradation enzymes backwards.
- The liver performs the first step of sugar metabolism with different enzymes than do other cell types.
This is why it matters so much what your blood-glucose level is. Glucose is what keeps your brain functioning. With too little glucose (hypoglycemia), your brain cannot produce enough ATP to function, and you lose consciousness (and life, if it goes on long enough.) If glucose levels are too high (hyperglycemia), neuronal mitochondria can go into hyperdrive, uncoupling mitochondrial metabolism and oxygen utilization from ATP synthesis. This is a problem because oxygen utilization is imperfect, and creates oxygen radicals that do extensive chemical damage. You really don't want chemical damage to your neurons, because it can kill them. This accounts for the neuropathies(nerve damage) associated with diabetes.
To keep blood-glucose levels from remaining too high for too long, we have insulin. This hormone is secreted into the bloodstream when glucose levels rise above normal. It triggers various target cells to take up glucose. The liver also is triggered to treat glucose differently from what we said above. Instead of metabolizing glucose to produce ATP, glucose is assembled into glycogen. This is partly under hormonal control, and partly a result of feedback regulation. ATP binds to one of the enzymes and decreases its activity. Through this overall mechanism, high glucose levels are reduced to normal.
When blood-glucose levels drop below normal, the hormone glucagon is released. This does several different things. For most cell types, it decreases their ability to take up glucose (by causing the cells to internalize their glucose-transport proteins). These cells must now use fatty acids or amino acids as their source of energy.
For the liver, glucagon triggers the production of glucose from amino acids (gluconeogenesis). As glucose is made, it is exported into the bloodstream. Because other cells' glucose-uptake systems have been down-regulated, they don't use the glucose. Therefore, the glucose is available to the brain and other neurons.
Needless to say, there is constant adjustment of insulin and glucagon levels. As the liver produces glucose, the pancreas is likely to respond by producing insulin. It's somewhat like using both the air-conditioner and the heater at the same time, which is more expensive, but maintains temperature with much less fluctuation than using only one of the systems.
In most cells, fructose is metabolized just the way glucose is. The first enzyme to work on it is hexokinase, which transfers a phosphate from ATP to the sugar. The enzyme attaches the phosphate to the 6th carbon of the sugar molecule, producing glucose-6-phosphate (from glucose) and fructose-6-phosphate (from fructose). The second enzyme of glucose metabolism converts glucose-6-phosphate to fructose-6-phosphate. Consequently, both sugars are metabolized the same way. The thumbnail on the right highlights the processing of fructose by this mechanism.
Liver cells don't work this way. Their metabolism of glucose is the same, since glucokinase performs the same reaction with glucose as does hexokinase. But glucokinase cannot work on fructose. Fructokinase, therefore, is the enzyme that first interacts with fructose in liver cells. It catalyzes the transfer of a phosphate from ATP to fructose, but puts the phosphate onto the first carbon rather than the sixth, producing fructose-1-phosphate.
Fructose-1-phosphate cannot be processed the same way as fructose-6-phosphate. Instead, it follows a somewhat different metabolic path. Eventually, it is converted into one of the intermediates in the normal metabolic pathway, and can be properly run through mitochondria after that.
BUT, this bypasses the enzyme that is subject to feedback regulation. Therefore, while glucose is readily stored as glycogen, fructose is not. Fructose is processed into "compound P" (pyrvate), but since the cells' ATP pool is saturated, it cannot easily be processed my normal mitochondrial metabolism. What happens to it?
Isotope-tracer studies with adult humans indicate that roughly half of consumed fructose is eventually converted to glucose; much of the rest is converted to CO2 and water. Most of this probably occurs in non-liver cells that produce hexokinase. The liver seems more likely to convert compound P (pyruvate) into compound A (acetyl-CoA), which is exported from mitochondria and assembled into fat.
This is, essentially, the same processing pathway followed by ethanol, which the liver converts first to acetaldehyde, then to pyruvate. One of the hallmarks of alcoholism is "fatty liver." When the liver produces fats (triglycerides) faster than it can export them into the bloodstream, they accumulate as fat droplets within the liver itself.
A diet rich in fructose also leads to "fatty liver." Apparently, a high-fructose diet is nutritionally equivalent to a high-fat diet.
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last updated: Dec. 23, 2014