LDLR

The low-density lipoprotein receptor (LDLR) is a cell-surface receptor that mediates the endocytosis of circulating low-density lipoprotein (LDL) particles, playing a central role in cholesterol homeostasis. It is expressed predominantly in the liver but is found in other tissues as well. LDLR binds apolipoprotein B-100 on LDL particles and facilitates their internalization, delivering cholesterol to cells and contributing to systemic lipid balance.

LDLR is a type I transmembrane glycoprotein. Its extracellular region contains ligand-binding repeats that recognize apoB-100 on LDL, followed by epidermal growth factor (EGF)-like domains and an O-linked sugar domain. A single transmembrane helix anchors the receptor, and the cytoplasmic tail contains an NPXY motif that mediates internalization via clathrin-coated pits. LDL binds LDLR at neutral pH; after endocytosis, the complex traffics to endosomes where the acidic environment causes LDL release. The receptor recycles back to the cell surface to bind more LDL.

Regulation and clinical significance: LDLR expression is upregulated when cellular cholesterol is low, controlled in part by sterol regulatory element-binding proteins (SREBP). Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDLR and promotes lysosomal degradation, reducing receptor availability. Mutations in the LDLR gene cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by elevated LDL cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. FH mutations are classified by defects in synthesis, transport to the membrane, ligand binding, internalization, or recycling of LDLR.

Management focuses on increasing surface LDLR activity, including statins, PCSK9 inhibitors, and other lipid-lowering therapies. In severe cases, guidelines may consider more intensive interventions and genetic counseling.