A 45-year-old woman with corneal arcus, tendon xanthomata, and premature coronary artery disease has LDL-C of 380 mg/dL despite a normal-weight body mass index. Genetic analysis reveals a gain-of-function mutation in PCSK9. The pathophysiology involves:
- A Increased hepatic cholesterol synthesis via upregulation of HMG-CoA reductase
- B Decreased LDL receptor expression due to SREBP-2 suppression
- C Enhanced LDL receptor degradation preventing receptor recycling to the hepatocyte surface ✓
- D Accelerated LDL production from VLDL in peripheral tissues
Correct answer: C. Enhanced LDL receptor degradation preventing receptor recycling to the hepatocyte surface
Explanation
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease that binds to the LDL receptor-PCSK9 complex after endocytosis; normally the receptor recycles back to the hepatocyte surface, but PCSK9 directs the complex to lysosomal degradation. Gain-of-function PCSK9 mutations (as in familial hypercholesterolemia type 3) enhance this degradation, reducing surface LDL receptors and causing LDL accumulation. This is the mechanistic basis for PCSK9 inhibitors (evolocumab, alirocumab) as cholesterol-lowering drugs.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.