The “best” of cholesterols, the “worst” of cholesterols: A tale of two receptors

Abstract

Cardiovascular disease is the number one killer in the U.S., and atherosclerosis is the major cause of heart disease and stroke (1). It is widely appreciated that cholesterol plays an important role in atherogenesis. Normally, most cholesterol serves as a structural element in the walls of cells, whereas much of the rest is in transit through the blood or functions as the starting material for the synthesis of bile acids in the liver, steroid hormones in endocrine cells (e.g., adrenal gland, ovary, testes), and vitamin D in skin. The transport of cholesterol and other lipids through the circulatory system is facilitated by their packaging into lipoprotein carriers. These spherical particles comprise protein and phospholipid shells surrounding a core of neutral lipid, including unesterified (“free”) or esterified cholesterol and triglycerides. Risk for atherosclerosis increases with increasing concentrations of low density lipoprotein (LDL) cholesterol whereas risk is inversely proportional to the levels of high density lipoprotein (HDL) cholesterol (2, 3). The receptor-mediated control of plasma LDL levels has been well-defined (4, 5), and very recent studies have now provided new insights into HDL metabolism (6–11). In 1974, Michael Brown, Joseph Goldstein, and colleagues began publishing a classic series of papers that described the receptor-mediated cellular metabolism of LDL (4, 12). Their work defined how the LDL receptor influences LDL metabolism in the body and helps to determine blood LDL levels. Fig. 1 summarizes in a simplified form the role of LDL in cholesterol transport. In brief, the liver synthesizes a precursor lipoprotein (very low density lipoprotein, VLDL) that is converted during circulation to intermediate density lipoprotein (IDL) and then to LDL (13). The majority of the LDL receptors expressed in the body are on the surfaces of liver cells, although virtually all other tissues (“peripheral tissues”) …