A 55-year-old woman with xanthomas and a strong family history of premature coronary artery disease has total cholesterol of 400 mg/dL and LDL of 330 mg/dL. Genetic testing confirms a point mutation in the LDL receptor gene. In familial hypercholesterolemia, which step in LDL receptor cycling is most commonly defective?
- A Receptor-mediated endocytosis of LDL via clathrin-coated pits ✓
- B Synthesis of ApoB-100 on the LDL particle
- C Activation of ACAT to esterify free cholesterol in lysosomes
- D Binding of LDL to scavenger receptors on macrophages
Explanation
In classical familial hypercholesterolemia (FH), the most common defect is in LDL receptor function. After ApoB-100 on LDL binds to the LDL receptor, internalization occurs via clathrin-coated pits in a process called receptor-mediated endocytosis. Mutations cause defective receptor synthesis, defective ligand binding, defective clustering in coated pits, or recycling defects — all impairing LDL clearance and causing hypercholesterolemia. ApoB-100 synthesis defects cause familial defective ApoB-100, a separate entity. Scavenger receptor uptake by macrophages forms foam cells but is not the primary clearance defect.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.