Cholesterol and Atherosclerosis

These days, it is very common to see advertisements for drugs that decrease the amount cholesterol in the blood. In addition, various aspects of the media have a lot to say on heart disease and its relationship with cholesterol levels. In this issue of the scribe I wanted to address what cholesterol is, certain aspects of its metabolism and its role in the development of atherosclerosis.
Steroids are a sub class of lipids. Steroids owe their special characteristics to their unique molecular structure. In animals, cholesterol is the most common steroid. In addition to being a precursor for all other steroids, it also serves as a major component of many cellular membranes. Its overall structure, including the presence of a weak polar group at C-3, is implicated in a number of important properties of the plasma membrane, including membrane fluidity. Membrane fluidity, which is the measure of the dynamic nature of cellular membranes, is important for various functions that a cell carries out. Cholesterol, and other lipids such as triacylglycerols and phospholipids circulate in the body as lipoprotein complexes. As their name implies, lipoproteins are complex molecules that contain both proteins and lipids.
Lipoproteins are classified based on their densities, which is a function of the relative amount of protein they contain. The more the protein in the complex, the denser the lipoprotein. Based on this, lipoproteins are named as (in an order of decreasing density) high-density lipoprotein (HDL), low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL) and chylomicrons. About 70% of the circulating cholesterol is in the form of LDL.
The LDL receptor, which is mainly found on the surface of liver cells, removes circulating cholesterol into cells by a receptor-mediated endocytosis. In other words, the receptor, which has an area of recognition to circulating lipoproteins, binds LDL, and moves into the cells as the cellular skeleton that was holding the receptor in place collapses. Through the process of endocytosis, the receptor experiences a change in pH, from neutral to acidic: The LDL that binds at the cell’s surface (pH 7.4) is internalized and released in endosomes (pH 6) to be degraded by enzymes in lysosomes. Lysosomes are small vesicular structures that contain different enzymes for the destruction of unwanted substances in the cell. This pH change induces a change in ionic composition of the LDL receptor. This change is accompanied by a change in the structure of the receptor, inducing the release of the bound LDL, and facilitating the recycling of the receptor back to the cell surface to repeat the same process.
Mutations in the LDL receptor gene cause a common and very severe form of hypercholesterolemia called familial hypercholesterolemia (FH). This condition is characterized by highly elevated amount of serum cholesterol resulting from decreased efficacy of cholesterol removal from the serum. Some people with FH respond to drug treatments and diet while others show little change even under severe treatments.
Accumulation of LDL in the serum of individuals with FH results in atherosclerosis. Atherosclerosis is a gradual process where LDL forms hard plaques. These plaques are deposited in the walls of the blood vessels. The deposits, over a long period of time, cause hardening of the walls of various blood vessels, resulting in the narrowing of the lumen of the arteries and veins. Arteries are vessels that carry blood that is rich in oxygen and nutrients to all organs such as the brain, skin, muscles, bones, heart, kidneys, liver etc… In contrast to healthy arteries that can deliver an ample supply of blood to these organs and tissues, those that are narrowed by atherosclerosis have difficulty delivering blood and result in poor circulation. Partial or total blockage of blood supply to the various organs resulting from atherosclerosis has various health implications. Some of these are pain in the lower extremities, slow wound healing, atrophy and in extreme cases, where arteries supplying the brain and/or the heart are totally blocked, results in deadly stroke and heart attack (myocardial infraction) respectively.