Introduction to lipids - Lipids are a diverse group of fats and fatlike substances. Lipids are organic molecules that are insoluble in water. Because of this water insolubility, lipids tend to gather together. This pattern of aggregation can be seen in the membrane (outer portion of cells) lipids of cells and lipoproteins and in other areas. There are many different types of lipids, each with certain characteristics. The group lipids includes fatty acids, neutral fats, waxes and steroids. Compound lipids comprise lipoproteins, glycolipids and phospholipids.
Lipids are essential to life. Practically every function in the human body is in some way dependant on lipids. Structurally, lipids compose the membrane in the outer portion of our cells. Without this membrane, the contents of a cell would just drift away. And with the average person having more than 170 trillion cells, we can see the importance lipids serve in this respect. Lipids serve as energy stores. The energy content of fat is more than twice that of carbohydrates and protein. Excess sugar can be converted to a lipid and stored for future use. Excess lipids in the diet can also be stored. Lipids provide padding and insulation for us and other animals to keep warm. Some lipids act as hormones, affecting the function of a target tissue. Lipids even perform functions that we take for granted, such as serving as attractants to another person in courting (eg., the curves you may find attractive on a female)
Certain lipids can also cause illness. Lipid A, the glycolipid portion of lipopolysaccharide in certain bacteria is responsible for causing endotoxic shock. Toxic shock syndrome, which is caused by certain bacteria multiplying on tampons, causes life threatening decreases in blood pressure and other dangerous signs and symptoms. This life-threatening condition is also caused by a type of lipid produced by bacteria.
Increased intake of dietary lipids increases the risk of developing type II diabetes, cardiovascular problems, such as heart attacks and strokes, organ failure, and other health problems. From this short introduction we can see that fats are essential, and at the same time we must learn to balance intake of lipids and their specific types.
The lipid highway
The best way to understand lipids is to follow their journey from their entry into the body, to their metabolism throughout.
We have divided lipid metabolism into several sections.
Dietary lipid metabolism of Triacylglycerols
Dietary lipid metabolism of Phospholipids
Dietary lipid metabolism of Glycolipids
Cholesterol and steroids
Classes of lipids
Dietary Lipid Metabolism
Dietary lipid digestion in chemical terms does not occur in the mouth or stomach. Chewing, of course, is very important, as larger pieces of fat as well as other nutrients are broken down into smaller pieces. As food reaches the stomach, its muscular grinding action helps to further prepare the food for delivery to its main destination for digestion, the small intestine. In the the first portion of the small intestine, the duododenum, emulsification of fats occurs. By the time dietary fats reach the duodenum, they exist in smaller droplets. Since enzymes cannot penetrate the lipid droplet, they must hydrolyze fats from the surface of the droplet. This would take quite some time, if allowed to proceed unaided. Emulsification speedens this process. Emulsification is the process by which individual fats are made available to be hydrolyzed by enzymes from the surface of the lipid droplet. Emulsification is possible by the detergent action of bile salts. Bile salts are producted by the liver and stored in the gallbladder. When a meal with fat is consumed, the gallbladder is stimulated to release bile into the duodenum. Bile mixes readily with fats, increasing the surface area and thereby helping facilitate enzyme action on them. The enzymes are produced in the pancreas. These enzymes are also released into the duodenum, and together, help to break apart lipid droplets. This enzyme action and the peristaltic action of the muscular duododenum, help in releasing individual fats, so that they can be transported out of the intestinal lumen and into the bloodstream.
Bile salts are derivatives of cholesterol. This is accomplished by adding A molecule of glycine or taurine to cholesterol. The result is a molecule that can act as an emulsifying agent not only with fats, but also with water or aqueous solutions in the intestine. This dual function molecule is useful because as the fatty tissue (eg., of a meal) is broken down into smaller particles, the emulsifying bile salt prevents the fats from coalescing (gathering together).
As the lipids are emulsified, they can easily be degraded by enzymes. These enzymes are produced and stored in the pancreas. When the pancreas is stimulated, it secretes the needed enzymes into the lumen of the intestine. The secretion of enzymes from the pancreas is in turn stimulated by a hormone called cholecystokinin (also called pancreozymin). Cholecystokinin is produced by intestinal cells when they in turn are stimulated from fats and proteins entering the duodenum (1st part of small intestine) and jejunum (2nd part). The cholecystokinin released from the intestinal cells, not only stimulates the pancreas to secrete digestive enzymes, but also stimulates the gallbladder to secrete bile. As mentioned earlier, the bile emulsifies lipids while the pancreatic enzymes digest the lipids. Basically, the enzymes and bile salts work together as a team, one emulsifying the lipids, while the other (enzyme) digests. Cholecystokinin also slows emptying of stomach contents into the intestines. This insures more complete digestion, rather than moving an entire meal into the small intesting at once.
The same intestinal cells producing cholecystokinin also produce a second hormone called secretin. Secretin is produced and secreted in response to a decrease in pH (acidity) from chyme (food that has just entered the intestine). Secretin stimulates the pancreas to release an aqueous bicarbonate solution, which helps neutralize the acidic contents of the intestine. This corrects the acidity, so that the enzymes responsible for digesting lipids can work correctly. Keep in mind that enzymes are sensitive to temperature, acidity, and other factors.
Let’s take a look at the figure below. This is an example of a common lipid, called a fat.
A "free" fatty acid. A free fatty acid is a solitary molecule which remains (by itself) after emulsification and digestion in the intestinal lumen. Fats need to be free or solitary in order to pass through the intestinal wall and into circulation for use by the body.
Nutritional fats are all quite similar. They have a carbon chain of varying length and a head, as ilustrated above. Since the illustrated fat above is solitary, or "free", it is called a free fatty acid. The name free fatty acid is simply descriptive of this molecule. "Free", because it is solitary (on its own), "fatty", because it is a fat, and "acid" because this word describes some of its chemical attributes. It would be nice if all the fats that we obtained in our diet were free fatty acids. If this were the case, our intestines would be able to simply absorb them immediately, to be used for metabolism in the body. However, fats that we obtain in the diet are not usually in this form.
Triacyglycerol
When we consume food, the way fats are presented can vary. Keep in mind that fat structure is similar, as we discussed above. The difference in fat presentation is how they are stored or arranged in a food source. For example, if we consume animal flesh, some of the tissue will no doubt be fat. Even in the leanest of meats, we cannot escape eating fat. This is because the membranes of the muscle cells are composed of fat. There is also stores of excess fat which the animal uses to store energy. Much of this is what we see in the skin of the animal. And as you may note, this fat layer in the skin is usually thicker in the winter. We refer to this tissue as adipose tissue. The free fatty acids that we need are not usually free in the food source we consume, but rather, are bonded to other molecules. It is up to our digestive enzymes to separate these fats from other molecules, so that free fatty acids are available to be absorbed for use.
Fats can be bonded in several ways. Depending on the fat and the type of molecule that the fatty acid is bonded to, dictates the name, and hence, class of the resulting molecule. One type of molecule we consume and digest to release fats is called triglyceride, or triacylglycerol. Don’t let these terms scare you, they are simply descriptive. In the word triglyceride, "tri"=three and "glyceride" is another word for glycerol. Glycerol is simply a molecule that can hold three free fatty acids (see illustration below).
A triacylglycerol molecule. Three fatty acids bonded to a glycerol "backbone". A glycerol molecule can hold up to 3 fatty acids. As we can see, a triglyceride is a large molecule, and cannot pass through the gut without first being disassembled in the doudenum and jejunum with the assistance of pancreatic enzymes and bile. Once these fats are removed from the glycerol, they are then free to pass through the intestines as free fatty acids. To disassemble a triacylglycerol in the intestine, the pancrease liberates an enzyme called pancreatic lipase. Pancreatic lipase removes the fatty acids at positions 1 and 3 (see illustration below).
The enzyme pancreatic lipase acts on positions 1 and 3 of the triacyglycerol, releasing the bound fatty acids. Note that H2O (water) is required for this reaction to occur.
Once the reaction with pancreatic lipase and water occur on positions 1 and 3 of the triacylglycerol, the result is 2 free fatty acids and a glycerol backbone with 1 remaining bonded fatty acid. This molecule of glycerol and one fatty acid is now called 2-monoacylglycerol (2-monoglyceride, old name). Like the other terms we’ve reviewed, 2-monoacylglycerol is a descriptive term as well. The number "2" indicates the position of the remaining fatty acid on the glycerol, "mono" denotes a "single ("mono"=1) fatty acid, and "glycerol" indicates the backbone in which the fatty acid is attached. The "acyl" is a chemical description of a chemical group in the molecule (see illustration below). Another enzyme called colipase is liberated by the pancreas during this process. Colipase functions in stabilising the pancreatic lipase in the area of the aqueous-lipid interface.
2-monoacylglycerol. As we can see, 2-monoglycerol is composed of a single remaining fatty acid bonded to the number 2 position of the glycerol backbone. The fatty acids at positions 1 and 3 were already removed by pancreatic lipase. The remaining fatty acid can now be removed by another pancreatic enzyme called acylglycerol lipase.
There are other enzymes which help to digest the various types of lipids as well. The remaining 2-monoacylglycerol is acted upon by another pancreatic enzyme called acylgycerol lipase. This enzyme cleaves the remaining fatty acid from the second position of the glycerol backbone. The result is a single free fatty acid, and a "free" glycerol backbone. The free fatty acids are now able to pass through the intestinal wall into circulation for use.
Digestion of dietary phospholipids
In the previous section we discussed the digestion of the class of lipids known as triacylglycerols. In this section, we shall discuss phospholipids, the major form of lipid in all cell membranes. Phospholipids, like triacylglycerols, contain fatty acids, as discussed in triacylglycerol metabolism. Phospolipids are different because, as the name implies, they also contain phosphorus.
The phospholipid, lecithin (also called phosphatidylcholine) . This phosphorus containing lipid is composed of 2 fatty acids bonded to a glycerol backbone, phosphorus and choline.
Digestion of phospolipids occurs in the small intestine. The pancreas liberates the pro-enzyme phospholipase A2 into the small intestine. Phospholipase A2 is then converted into the active enzyme from trypsin (another pancreatic enzyme). Phospholipase A2 removes the fatty acid at position 2 of the phospholipid.
Once the fatty acid is removed, the remaining molecule is called a lysophospholipid. If we remove the the fatty acid from position 2 in the phospholipid lecithin, above, it becomes lysolecithin. The prefix "lyso" simply gives us an indication of the type of structural change.
Since the fatty acid at position 2 on the glycerol backbone has been removed, there is only one remaining fatty acid. The remaining fatty acid resides at position 1. This fatty acid is removed by lysophospholipase, another pancreatic enzyme. Once both fatty acids are removed, all that remains is a glyceroylphosphoryl base. This may pass through in the faeces or further metabolized and absorbed and used.
Glycolipid metabolism
Introduction to glycolipids and their metabolism in the human
In the previous sections we discusses phospolipids, as well as other types of lipids. The glycolipids are yet another division of lipids that is utilised by the human as well as other forms of life. Glycolipids are named in reference to their chemical structure: practically all glycolipids are derivatives of ceramides. Ceremides are a fatty acid bonded or connected to the amino alcohol sphingosine. In fact, although the class of lipids we discussed called phospholipids, are chemically different from glycolipids, the phospholipid we call sphingomyelin, also is derived from ceramides. Glycolipids, however, are different as well, because they contain no phosphates in comparison to phospholipids. What also puts glycolipids in a class of their own is the fact that the fat is connected to a sugar molecule. Hence, the name glycolipid (glyco=sugar, lipid=fat). Therefore, glycolipids are simply fats that are bonded to sugars. So, since glycolipids are built from sphingosine, fat, and a sugar, we can be more exact in our naming and call them "glycosphingolipids".
Functions of glycolipids
In common with the phospholipids, the glycolipids are an essential part of cell membranes. Glycolipids also help determine the blood group of an individual. In regards to blood grouping, glycolipids act as receptors at the surface of the red blood cell. This is important as we can use this principle to classify our blood type, which is critical during transfusions, etc. If we give the incorrect type of blood to an individual, the recipients immune system detects these differences and treats the donated blood cells as foreign, and can cause death. Glycolipids also play a "hormonal" funtion during embryonic development. In microorgansims, certain glycolipids even help ensure their survival by "tricking" our immune system into thinking they are not foreign. This helps them to evade immune survelllence. On the other hand, some viruses, bacteria (eg., cholera) use glycolipids on their cell surface as well. This helps the immune system destroy and clear the pathogen from the body.
Examining the illustration above, we can see that there are single bonds between each carbon in the tail. Although in each section of the tail, a ’zig-zag’ pattern exists, overall, the tail has a straight appearance. If we were remove one of the single bonds between carbon atoms, and replace it with a double bond the molecule would no longer have an overall straight appearance as illustrated below.
Types of glycolipids
Cerebrosides-Cerebroside (from cerebro=brain) are glycolipids that are found primarily in the brain and peripheral (other areas of the body) nervous tissue. Cerebrosides in the nervous tissue are found in the myelin sheath. The myelin sheath in the protective coating surrounding each nerve, and this coating acts as an insulator and aids in the proper conduction of a nervous impoulse. We can see how important this fatty coating is when we look at the disease process known as Multiple Sclerosis. There are different types of glycolipids, each characterised by the sugar that they are bonded to and the type of fatty acid that is used to bond to the sugar. Sugars such as galactose and glucose are bonded to the lipid. When a galactose or glucose molecule is bonded to the lipid, the glycolipid is called a galactocerebroside or glucocerebroside, respectively.
Ceramide oligosaccharides-Just as we discussed ceremides, another group of glycolipids is termed the ceremide oligosaccharides (ceremide="ceremide", oligo="short", saccharide="sugar"). Basically, these are ceremides with short chains of sugars, in comparison to cerebrosides with only "one" sugar attached. Examples are listed below.
Gangliosides-Above we discussed ceramides. These glycolipids (aka glycosphingolipids) are neutral (uncharged). The gangliosides on the other hand, are acidic in pH, and they are the more complex of the glycolipids. Basically, gangliosides are ceramide oligosaccharides (discussed above) with an extra substance attached. This substabce is called N-acetylneuraminic acid (abbreviated NANA), and it’s this NANA that gives the glycolipid its negative charge and hence, acidic quality. Gangliosides are medically significant because some of these accumulate in an individual in certain genetically inherited diseases. For example, ganglioside GM 2, a ganglioside with several NANA groups attached, accumulates in the individual with Tay-Sachs disease. Tay-Sachs is but one of the several diseases in which a genetic lack or inefficiency of an enzyme needed to metabolize a glycolipid can cause catastrophic consequences. Hopefully, through genetic engineering, or suitable pharmacological (drug) therapy, we can find more helpful means to support anyone with these enzyme deficiencies.
Sulfoglycosphingolipids-These cerebrosides are also called sulfatides, They are simply cerebrosides with a sulfate residue on the sugar portion of glycolipid. This long name simply implies a cerebroside that contains a sulfated galactose. As you can see, galactosyl, contains the word "galact" meaning the sugar galactose. The difference here, is that the galactose has sulfate added to it, and this extra chemical group causes it to have a negative charge. Now that you know the chemical aspects, what does this have to do with our health? These are but one of the many types of lipids. However, this particular lipid is found primarily in the medulated nerve fibres and can accumulate in the white matter of the brain in metachromatic leukodystrophy.
Synthesis and degradation of glycolipids
Synthesis of glycolipids occurs with the help of enzymes that sequentially add sugars to the lipid. When the lipids are required to be broken down, enzymes in the lysosome of the cell help to remove the sugar subunits. This is important medically, because a deficiency of any of the enzymes involved in these processes cause an accumulation of a particular glycolipid that cannot be further broken down. When this accumulation occurs, the excess lipid remains trapped in the plasma or the cells and deposits in various organ/tissue systems and unfortunately, damages them.
