Cardiovascular disease is the number one killer in the US, 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 (eg, 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’’) express some LDL receptors. LDL receptors, located in specialized indentations in the cell membrane called coated pits, specifically and tightly bind LDL. After binding, the receptor–lipoprotein complex is internalized by the cells via coated pits and vesicles, and the entire LDL particle is delivered to lysosomes, wherein it is disassembled by enzymatic hydrolysis, releasing cholesterol for subsequent cellular metabolism. This whole-particle uptake pathway is called ‘‘receptormediated endocytosis’’(14). Cholesterol-mediated feedback regulation of both the levels of LDL receptors and cellular cholesterol biosynthesis help ensure cellular cholesterol homeostasis. Genetic defects in the LDL receptor in humans result in familial hypercholesterolemia, a disease characterized by elevated plasma LDL cholesterol and premature atherosclerosis and heart attacks (5). One attractive hypothesis for the deleterious effects of excess plasma LDL cholesterol is that the LDL enters the artery wall, is chemically modified, and then is recognized by a special class of receptors, called macrophage scavenger receptors, that mediate the cellular accumulation of the LDL cholesterol in the artery, eventually leading to the formation of an atherosclerotic lesion (15, 16). A major breakthrough in the pharmacologic treatment of hypercholesterolemia has been the development of the ‘‘statin’’class of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitory drugs (17). 3-Hydroxy-3-methylglutaryl-CoA reductase is the rate controlling enzyme in cholesterol biosynthesis, and its inhibition in the liver stimulates LDL receptor expression. As a consequence, both plasma LDL cholesterol levels and the risk for atherosclerosis decrease. The discovery and analysis of the LDL receptor system has had a profound impact …