LDLR (low density lipoprotein receptor; HGNC:6547, NCBI Gene ID 3949) is a human locus mapped to chromosome band 19p13.2 that encodes cell-surface single-pass transmembrane LDL receptor glycoprotein (860 aa). LDLR acts in clathrin-mediated endocytosis of ApoB-100 LDL & ApoE remnant lipoproteins, together with PCSK9 (LDLR Degrader Gene), APOB (Apolipoprotein B Gene), and APOE (Apolipoprotein E Gene). Encodes the hepatic low-density lipoprotein receptor discovered by Brown and Goldstein, clearing cholesterol-rich LDL from plasma.
Clathrin-mediated endocytosis of ApoB-100 LDL & ApoE remnant lipoproteins
Clinical / Therapeutic Role
Over 3,000 pathogenic variants cause Autosomal Dominant Familial Hypercholesterolemia (FH1); up-regulated by statins & PCSK9 inhibitors
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 18-exon gene spanning 45 kb on chromosome 19p13.2 whose promoter is controlled by sterol regulatory element-binding protein 2 (SREBP-2), with exons modularly encoding five functional domains: seven N-terminal cysteine-rich complement-type ligand-binding repeats (R1–R7), an EGF precursor homology domain (EGF-A, EGF-B, beta-propeller, EGF-C), an O-linked sugar domain, a transmembrane helix, and a cytoplasmic NPxY clathrin-sorting tail.
Cellular & Tissue Expression Profile: Expressed on the sinusoidal basolateral surface of hepatic hepatocytes (which clear ~70–80% of circulating plasma LDL) as well as steroidogenic adrenal cortical cells and ovarian/testicular cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Binds the single ApoB-100 molecule on LDL or multiple ApoE molecules on VLDL/chylomicron remnants at neutral pH, internalizes via LDLRAP1 (ARH)-dependent clathrin-coated pits, releases its lipoprotein cargo in the acidic sorting endosome (pH 5.0) via intramolecular folding of the beta-propeller onto the ligand-binding repeats, and recycles to the plasma membrane ~150 times during its 20-hour lifespan unless bound by PCSK9 or ubiquitylated by IDOL (MYLIP).
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Discovered by Michael Brown and Joseph Goldstein (1985 Nobel Prize in Physiology or Medicine); over 3,000 loss-of-function mutations across five functional classes cause Familial Hypercholesterolemia Type 1 (heFH ~1 in 250 births; hoFH ~1 in 300,000 births with extreme premature coronary atherosclerosis).
Therapeutic & Clinical Pharmacology: Every major LDL-lowering therapy acts through LDLR: statins (inhibiting HMGCR) and bempedoic acid deplete hepatocyte sterols to activate SREBP-2 and up-regulate LDLR transcription, while PCSK9 antibodies/inclisiran prevent LDLR lysosomal degradation and AAV8-hLDLR gene therapy targets homozygous FH.