Cholesterol is exported to the peripheral tissues in LDL and VLDL. About 70 percent of the cholesterol molecules in LDL are esterified with a fatty acid (for example, palmitate) on the OH group (at Carbon 3; see Figure 1). Cells take up cholesterol from the LDL by means of LDL receptors in the outer cell membrane.
The pathway for uptake involves several steps, including the following:
- The assembly of the receptor‐LDL complexes into a coated pit on the cell surface.
- The pit folds into a spherical endosome, which is a small vesicle of cell membrane with receptor‐LDL complexes on the inside.
- The endosome fuses with a lysosome containing a large number of degradative enzymes and a low pH on the inside.
- The receptors separate from the endosome‐lysosome and return to the cell surface.
- The cholesterol esters are hydrolyzed to free cholesterol.
- The free cholesterol inhibits the synthesis and/or causes the degradation of HMG‐CoA reductase and of LDL receptor. This last step ensures that more cholesterol will not be taken up or made than is needed.
- Cholesterol is re‐esterified with a fatty acid for storage inside the cell.
A close connection exists between the regulation of cholesterol biosynthesis and uptake. When HMG‐CoA reductase is inhibited, the cell responds by synthesizing more LDL receptors to ensure the uptake of cholesterol from the serum. When cholesterol is present in a high enough concentration in the cell, LDL receptors are not exported to the cell surface, an example of the phenomenon of down regulation.
The tight regulation of cholesterol metabolism helps explain the pathology of coronary artery disease, a major killer in developed countries. Clearly, diet affects coronary artery disease: Individuals with high intake of saturated fat and cholesterol are most at risk. Furthermore, a high serum concentration of LDL cholesterol is associated with an increased risk of coronary artery disease.
The capability of LDL receptors to remove LDL cholesterol from the circulation can rationalize these clinical observations. If little cholesterol is available in the diet, the cells of the peripheral tissues respond by up‐regulating the number of LDL receptors on the cell surface. The higher concentration of receptors means that more of the cholesterol will be removed from the circulatory system. Because the inappropriate deposition of cholesterol is a major contributor to blocked arteries, if the cholesterol is removed from the circulation, less risk of blockage exists. On the other hand, if a large amount of cholesterol exists in the diet, and the cells have enough for their needs, they will synthesize fewer LDL receptors, less cholesterol will be removed from the circulatory system, and the risk of artery disease increases further.
Several therapies are used to treat individuals with high serum cholesterol levels. The first is a low‐fat, low‐cholesterol diet. If the diet provides less cholesterol, then the cells will synthesize more LDL receptors to meet their needs, which means that more cholesterol will be removed from the circulation. The second therapy—which goes hand in hand with the first—is to decrease the reabsorption of bile acids in the gut, for example, by increasing the amount of soluble fiber in the diet or by administering synthetic bile acid binders. Bile acids bind to these agents. Fiber and the synthetic binders cannot be absorbed by the intestines and are excreted, carrying the bile acids with them. Excess cholesterol is then converted to bile acids and ultimately excreted. The third method is to inhibit HMG‐CoA synthesis with any of several drugs on the market. HMG‐CoA reductase carries out the committed step of cholesterol biosynthesis. Inhibiting this enzyme decreases the amount of cholesterol synthesized intracellularly, and the cells compensate by increasing the number of LDL receptors on the cell surface. This helps remove LDL cholesterol from the circulation.