A patient with familial hypercholesterolaemia (FH) has markedly elevated LDL despite high-dose statin therapy. Genetic testing reveals homozygous gain-of-function mutation in PCSK9. The mechanism by which this PCSK9 mutation elevates LDL is:

• A PCSK9 binds LDL receptors and targets them for lysosomal degradation, reducing hepatic LDL clearance ✓
• B PCSK9 directly inhibits HMG-CoA reductase, increasing de novo cholesterol synthesis
• C PCSK9 activates IDOL, an E3 ubiquitin ligase that ubiquitinates apoB-100 on LDL particles
• D PCSK9 stimulates CETP activity, transferring cholesterol from HDL to LDL

Explanation

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a hepatic protease that binds to the EGF-A domain of the LDL receptor. After LDL-receptor internalisation, PCSK9 promotes lysosomal degradation of the receptor instead of its recycling to the cell surface — reducing hepatic LDL uptake and elevating plasma LDL. Gain-of-function PCSK9 mutations cause FH; loss-of-function mutations give lifelong low LDL and cardiovascular protection. PCSK9 inhibitors (evolocumab, alirocumab) are monoclonal antibodies targeting this mechanism.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.