LDLreceptoner

LDL receptors (LDLRs) are cell-surface receptors that mediate the selective uptake of cholesterol-rich low-density lipoprotein (LDL) particles. They play a central role in cholesterol homeostasis by delivering cholesterol to cells and by regulating intracellular sterol synthesis through feedback mechanisms.

The human LDLR gene encodes a single-pass transmembrane glycoprotein of about 860 amino acids. The extracellular portion contains multiple ligand-binding repeats that recognize apolipoprotein B-100 on LDL particles, followed by EGF precursor–like repeats, a beta-propeller domain, and a short cytoplasmic tail with NPXY motifs important for endocytosis.

LDL particles bind to LDLR, cluster in clathrin-coated pits, and are internalized via endocytosis. In endosomes, protons cause release of LDL due to decreased pH, the receptor is recycled to the cell surface, and LDL is delivered to lysosomes for cholesterol ester hydrolysis. The liberated cholesterol then participates in cellular processes and helps regulate SREBP-mediated gene expression, maintaining cholesterol balance within the cell.

Mutations in LDLR cause familial hypercholesterolemia (FH), an inherited disorder characterized by high LDL cholesterol and early cardiovascular disease. FH can be heterozygous or homozygous. Other factors influencing LDLR function include PCSK9-mediated degradation of the receptor; statins increase LDLR expression; PCSK9 inhibitors or siRNA therapies lower LDL-C by preserving or reducing receptor degradation.

The LDLR family includes related receptors such as LRP1; they share structural domains and contribute to lipoprotein metabolism. Understanding LDLR biology informs treatments for hypercholesterolemia and atherosclerosis.