The LDL receptor and the regulation of cellular cholesterol metabolism.

I N T R O D U C T I O N Cholesterol is a structural component of the plasma membrane that surrounds animal cells. It is absolutely essential for cell growth and survival. Yet, excessive amounts of cholesterol can also be lethal as when massive amounts of cholesterol deposit in cells of the artery wall producing atherosclerosis. Thus, animal cells have evolved a highly ordered mechanism for regulating their cholesterol content. In this article, we review some of the recent studies that have been carried out by our group on the cellular and molecular biology of the cell surface receptor for low density lipoprotein, or LDL, the major transport protein for cholesterol in human plasma. The LDL receptor has turned out to be an exciting system in several ways. First, the LDL receptor has served as a prototype for the study of receptor-mediated endocytosis, a general biological process in which cells bind hormones and other macromolecules at the surface and take them into the cell for nutritional and regulatory processes. And second, the LDL receptor studies have taught us a great deal about how genes regulate cholesterol metabolism. Mutations occurring in the gene for the receptor disrupt the regulation of blood cholesterol levels, producing hypercholesterolaemia and atherosclerosis. The LDL receptor is a member of a class of membrane glycoproteins called lipoprotein receptors (Goldstein & Brown, 1977). These receptors remove choles­ terol-carrying lipoproteins from the circulation through the process of receptormediated endocytosis (Goldstein, Anderson & Brown, 1979). They are present on the surface of essentially all cultured mammalian cells, where they mediate the uptake of plasma LDL, thereby providing cells with the cholesterol that they need for growth. In the body, most LDL receptors are expressed in the liver, where they supply cholesterol for secretion into bile, for conversion to bile acids, and for re­ secretion into the plasma in newly synthesized lipoproteins (Brown & Goldstein, 1983; Mahley & Innerarity, 1983). LDL receptors are also present in high con­ centrations in the adrenal cortex and the ovarian corpus luteum, where they function to provide cholesterol for steroid hormone formation (Brown, Kovanen & Goldstein, 1979).