The Mammalian Low-Density Lipoprotein Receptor Family

Abstract

The low-density lipoprotein (LDL) receptor (LDL-R) family consists of cell-surface receptors that recognize extracellular ligands and internalize them for degradation by lysosomes. The LDL-R is the prototype of this family, which also contains very-low-density lipoprotein receptors (VLDL-R), apolipoprotein E receptor 2, LRP, and megalin. The family members contain four major structural modules: the cysteine-rich complement-type repeats, epidermal growth factor precursor-like repeats, a transmembrane domain, and a cytoplasmic domain. Each structural module serves distinct and important functions. These receptors bind several structurally dissimilar ligands. It is proposed that instead of a primary sequence, positive electrostatic potential in different ligands constitutes a receptor binding domain. This family of receptors plays crucial roles in various physiologic functions. LDL-R plays an important role in cholesterol homeostasis. Mutations cause familial hypercholesterolemia and premature coronary artery disease. LDL-R-related protein plays an important role in the clearance of plasma-activated alpha 2-macroglobulin and apolipoprotein E-enriched lipoproteins. It is essential for fetal development and has been associated with Alzheimer's disease. Megalin is the major receptor in absorptive epithelial cells of the proximal tubules and an antigenic determinant for Heymann nephritis in rats. Mutations in a chicken homolog of VLDL-R cause female sterility and premature atherosclerosis. This receptor is not expressed in liver tissue; however, transgenic expression of VLDL-R in liver corrects hypercholesterolemia in experiment animals, which suggests that it can be a candidate for gene therapy for various hyperlipidemias. The functional importance of individual receptors may lie in their differential tissue expression. The regulation of expression of these receptors occurs at the transcriptional level. Expression of the LDL-R is regulated by intracellular sterol levels involving novel membrane-bound transcription factors. Other members of the family are not regulated by sterols. All the members are, however, regulated by hormones and growth factors, but the mechanisms of regulation by hormones have not been elucidated. Studies of these receptors have provided important insights into receptor structure-function and mechanisms of ligand removal and catabolism. It is anticipated that increased knowledge about the LDL-R family members will open new avenues for the treatment of many disorders.

Apolipoprotein E knockout mice have accentuated malnutrition with mucosal disruption and blunted insulin-like growth factor I responses to refeeding

“…Early studies identified apoE as a key component of plasma cholesterol homeostatic mechanisms [1,2]. ApoE binds with high affinity to lipoprotein particles in the plasma compartment and acts as a ligand for receptor-mediated endocytosis via multiple members of the low-density lipoprotein receptor family [1,[3][4][5].…”

v-Src induces Shc binding to tyrosine 63 in the cytoplasmic domain of the LDL receptor-related protein 1

“…The LDL receptor-related protein 1 (LRP-1) is a cell surface receptor that mediates internalization of a large number of proteins and lipoproteins including ApoEcontaining lipoproteins, very-low density lipoproteins, chylomicron remnants, activated a 2 macroglobulin, and the amyloid precursor protein (Gliemann et al, 1994;Hussain et al, 1999). LRP-1 is composed of an a chain that contains 3924 amino acids and a b chain that contains 601 amino acids (Herz et al, 1988).…”

Association of low-density lipoprotein receptor polymorphisms and outcome of hepatitis C infection

“…6,7 The LDLR is known to play an important role in cholesterol homeostasis and lipid transport by mediating the cellular uptake of plasma LDL. 8,9 It has been firmly established that mutations and polymorphisms in the LDLR gene are associated with familial hypercholesterolemia (FH), obesity and atherosclerosis. [10][11][12] FH is an autosomal dominant inherited condition charac-terized by raised levels of LDL-cholesterol leading to increased risk of coronary heart disease.…”