LDL receptor

The LDL receptor is expressed primarily on hepatocyte surfaces and binds apolipoprotein B-100 (ApoB-100) on LDL particles, and ApoE on remnant lipoproteins. After binding, the LDLR-LDL complex is internalized via clathrin-coated pits, delivered to endosomes, and the LDL is degraded in lysosomes releasing free cholesterol. The receptor itself typically recycles back to the cell surface. Intracellular cholesterol suppresses HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis) and downregulates LDLR expression via SREBP pathway inhibition, providing feedback control.

Familial Hypercholesterolemia (FH) is caused by autosomal dominant mutations in LDLR (most common cause), leading to reduced receptor number or function. Heterozygotes have LDL-C ~2x normal with tendon xanthomas, corneal arcus, and premature CAD (men <45, women <55). Homozygotes have LDL-C 4-6x normal (>500 mg/dL) with severe atherosclerosis and MI possible in childhood/adolescence. Other genetic causes of FH-like phenotypes include mutations in ApoB (ligand defect), PCSK9 (gain-of-function increases LDLR degradation), and LDLRAP1 (autosomal recessive, impairs receptor internalization).

Clinically, statins work by inhibiting HMG-CoA reductase, decreasing intracellular cholesterol, which upregulates SREBP-2 and increases LDLR expression, enhancing LDL clearance from plasma. PCSK9 normally binds LDLR and targets it for lysosomal degradation after endocytosis, reducing receptor recycling; PCSK9 inhibitors (evolocumab, alirocumab) prevent this degradation, increasing LDLR availability and further lowering LDL-C—particularly useful in statin-intolerant patients or those with FH.