Overview of the LDL receptor: relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease

Abstract

Since the discovery of the low-density lipoprotein (LDL) receptor over 30 years ago manipulation of its activity has been pursued through dietary and pharmacological means with the goal of reducing LDL cholesterol levels. This has proven to be one of the most widely implemented and beneficial interventions to reduce LDL cholesterol levels and the incidence of cardiovascular death. This review provides an overview of the LDL receptor and its role in regulating whole body cholesterol homeostasis and LDL cholesterol levels. New findings on regulation of the LDL receptor are discussed and how they can be used to develop novel therapeutics to reduce cardiovascular risk. Overview of the LDL receptor Cholesterol is an essential component of cellular membranes, as well as an essential substrate for steroid hormones and bile acid synthesis. However, cholesterol is toxic when accumulated in excess in cellular membranes 1 and elaborate pathways have evolved to control its synthesis, uptake and storage. 2 Cells can obtain cholesterol either from de novo synthesis, or uptake from circulating lipoproteins. The low-density lipoprotein (LDL) receptor (LDLR) is the primary pathway for removal of cholesterol from the circulation, 3 and its activity is meticulously governed by intracellular cholesterol levels. 4 The discovery of the LDLR had its roots in the study of the molecular mechanism responsible for familial hypercholesterolemia (FH), an autosomal dominant metabolic disorder in which patients present with plasma cholesterol levels ranging from 300 mg/dL to as high as 1500 mg/dL. 5 Patients with FH are at increased risk of cardiovascular disease and those with the highest cholesterol levels often have advanced atherosclerosis before 10 years of age. 6 FH was first recognized as a genetic disorder over 70 years ago when it was observed that extreme hypercholesterolemia that was accompanied by xanthomas (cholesterol deposits in tendons and skin) and angina was an inherited disorder. 7 In the early 1970s Goldstein and Brown demonstrated that fibroblasts isolated from patients with homozygous FH had defective feedback inhibition of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme for cholesterol synthesis. 8 In 1974 they were able to demonstrate the existence of a LDLR by showing that fibroblasts from patients with homozygous FH were unable to bind LDL at the cell surface. 9 The following year they showed that the LDLR regulated HMGCR activity by controlling the cellular uptake of exogenous cholesterol 10