Most of the fat in the human diet is in the form of triacylglycerol (TAG), which consists of three fatty acids linked to glycerol. In the digestive tract, TAG is hydrolyzed by the enzyme pancreatic lipase, to release free fatty acids and monoglycerides.
The key issue in the digestion and absorption of fats is one of solubility: lipids are hydrophobic, and thus are poorly soluble in the aqueous environment of the digestive tract. The digestive enzyme, pancreatic lipase, is water soluble and can only work at the surface of fat globules. Digestion is greatly aided by emulsification, the breaking up of fat globules into much smaller emulsion droplets. Bile salts and phospholipids are amphipathic molecules that are present in the bile. Motility in the small intestine breaks fat globules apart into small droplets that are coated with bile salts and phospholipids, preventing the emulsion droplets from re-associating.
The emulsion droplets are where digestion occurs. Emulsification greatly increases the surface area where water-soluble lipase can work to digest TAG. Another factor that helps is colipase, an amphipathic protein that binds and anchors pancreatic lipase at the surface of the emulsion droplet.
After digestion, monoglycerides and fatty acids
associate with bile salts and phopholipids to form micelles.
Micelles are about 200 times smaller than emulsion droplets (4-7nm
versus 1Ám for emulsion droplets). Micelles are necessary because
they transport the poorly soluble monoglycerides and fatty acids
to the surface of the enterocyte where they can be absorbed. As
well, micelles contain fat soluble vitamins and cholesterol.
The figure at right illustrates that micelles are small enough to
fall between the the microvilli.
Micelles are constantly breaking down and re-forming, feeding a
small pool of monoglycerides and fatty acids that are in solution.
Only freely dissolved monoglycerides and fatty acids can be
absorbed, NOT the micelles. Because of their nonpolar nature,
monoglycerides and fatty acids can just diffuse across the plasma
membrane of the enterocyte. Some absorption may be
facilitated by specific transport proteins (for instance see
below, for cholesterol).
Once inside the enterocyte, monoglycerides and fatty acids are re-synthesized into TAG. The TAG is packaged, along with cholesterol and fat soluble vitamins, into chylomicrons. Chylomicrons are lipoproteins, special particles that are designed for the transport of lipids in the circulation. You can review the structure of lipoproteins by visiting the web page on lipoproteins from fall quarter.
Chylomicrons are released by exocytosis at the basolateral surface of the enterocytes. Because they are particles, they are too large to enter typical capillaries. Instead they enter lacteals, lymphatic capillaries that poke up into the center of each villus. Chylomicrons then flow into the circulation via lymphatic vessels, which drain into the general circulation at the large veins in the chest.
Chylomicrons deliver absorbed TAG to the body's cells. TAG in chylomicrons and other lipoproteins is hydrolyzed by lipoprotein lipase, an enzyme that is found in capillary endothelial cells. Monoglycerides and fatty acids released from digestion of TAG then diffuse into cells.
The figure at the right summarizes the various steps involved in fat absorption.
Intestinal cholesterol absorption is important because of the clinical relevance of cholesterol: high levels of low-density lipoprotein (LDL) cholesterol in the circulation increase the risk for the development of atherosclerosis. As shown in the figure, some of the cholesterol in the small intestine is dietary cholesterol, and some is put there by the liver, arriving via the bile. Of the total cholesterol that passes through the small intestine, only half is typically absorbed, and the rest is eliminated in the feces. Thus, cholesterol in the bile is an example of a substance that is targeted for excretion via the digestive tract.
The drug ezetimibe blocks a protein that specifically
mediates cholesterol transport across the apical plasma membrane
of enterocytes. Ezetimibe has been shown to be effective at
reducing levels of LDL cholesterol, particularly when combined
with a statin, a drug that inhibits cholesterol synthesis
in the liver. The most recent results of a large clinical trial
show that further lowering of LDL cholesterol with a combination
of ezetimibe and a statin provides a modest benefit in lowering
the risk of myocardial infarction and stroke.