CHOLESTEROL AND CARDIOVASCULAR DISEASE Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis

Low-density lipoprotein (LDL) is the most abundant and the most atherogenic class of cholesterol-carrying lipoproteins in human plasma. The level of plasma LDL is regulated by the LDL receptor, a cell surface glycoprotein that removes LDL from plasma by receptor-mediated endocytosis. Defects in the gene encoding the LDL receptor, which occur in patients with familial hypercholesterolemia, elevate the plasma LDL level and produce premature coronary atherosclerosis. The physiologically important LDL receptors are located primarily in the liver, where their number is regulated by the cholesterol content of the hepatocyte. When the cholesterol content of hepatocytes is raised by ingestion of diets high in saturated fat and cholesterol, LDL receptors fall and plasma LDL levels rise. Conversely, maneuvers that lower the cholesterol content of hepatocytes, such as ingestion of drugs that inhibit cholesterol synthesis (mevinolin or compactin) or prevent the reutilization of bile acids (cholestyramine or colestipol), stimulate LDL receptor production and lower plasma LDL levels. The normal process of receptor regulation can therefore be exploited in powerful and novel ways so as to reverse hypercholesterolemia and prevent atherosclerosis. Circulation 76, No. 3, 504-507, 1987. IN 1913, a Russian scientist named Anitschkow fed pure cholesterol to rabbits and produced a high level of cholesterol in the blood as well as atherosclerosis in the aorta and coronary arteries.1 He therefore proposed that hypercholesterolemia leads to atherosclerosis. This straightforward demonstration set the stage for the next 50 years of epidemiologic, genetic, and experimental research, which has now established a firm causal link between the blood cholesterol level and coronary atherosclerosis in man. After the cholesterol connection had been cemented in the late 1 950s and early 1 960s, the focus of research shifted from measurement of total cholesterol level in blood to mechanistic studies designed to elucidate the factors regulating the level of specific cholesterol-carrying lipoproteins. By the mid 1960s, investigators had established that blood cholesterol is transported in lipoproteins of specific composition.2 The most abundant class of atherogenic lipoproteins in human plasma is low-density lipoprotein (LDL). The 1 970s and 1 980s From the Department of Molecular Genetics, University of Texas Health Science Center at Dallas. Supported by research grants from the National Institutes of Health (HL 20948) and the Moss Heart Foundation. Address for correspondence: Joseph L. Goldstein, M.D., Department of Molecular Genetics, University ofTexas Health Science Center, 5323 Harry Hines Blvd., Dallas, TX 75235. 504 saw the discovery of the LDL receptor and the recognition of its role in regulating the level of LDL in plasma.3 The lower the number of LDL receptors, the higher the plasma LDL level and the more florid the atherosclerosis. In this article, we will briefly review recent studies of the molecular biology and genetics of the LDL receptor. We will also discuss how regulatory changes in this receptor may underlie many forms of hypercholesterolemia in man and how this regulatory system can be stimulated by drugs to lower plasmaLDL levels. Receptor-mediated endocytosis of LDL. Two classes of lipoprotein receptors have been identified: (1) those that bind lipoproteins containing exogenous cholesterol absorbed from the intestine, i.e., chylomicron remnant receptors, and (2) those that bind lipoproteins that carry endogenous cholesterol derived from the liver and other nonintestinal sources, i.e., LDL receptors.4 5 The two classes oflipoprotein receptors are produced by different genes that are subject to different forms of metabolic regulation.4 5 Research on the molecular biology and biochemistry of the chylomicron remnant receptor is in its infancy and will not be discussed further in this article. The LDL receptors were the first lipoprotein receptors to be described; indeed, they are among the best characterized of all mammalian cell surface receptors. CIRCULATION by gest on A ril 0, 2017 http://ciajournals.org/ D ow nladed from CHOLESTEROL AND CARDIOVASCULAR DISEASE These receptors are present on the surface of essentially all cultured mammalian cells, where they mediate the uptake ofplasmaLDL, thereby providing growing cells with the cholesterol that they need for membrane synthesis. In the body, most LDL receptors are expressed in the liver, where they supply cholesterol for secretion into bile, conversion to bile acids, and resecretion into the plasma in newly synthesized lipoproteins. LDL receptors are also present in high concentrations in the adrenal cortex and the ovarian corpus luteum, where they function to provide cholesterol for steroid hormone formation.4 The human LDL receptor is a single-chain transmembrane glycoprotein of 839 amino acids (figure 1). It specifically binds lipoproteins that contain apolipoprotein B-100 or the active form of apolipoprotein E. The ligand-binding domain of the LDL receptor comprises the NH2-terminal 292 amino acids and is composed of a cysteine-rich sequence of40 amino acids that is repeated seven times with minor variations. The cytoplasmic domain, composed of 50 amino acids at the COOH-terminal end of the protein, serves to direct