PCSK9 (proprotein convertase subtilisin/kexin type 9) regulates LDL receptor levels. The mechanism by which PCSK9 inhibition lowers LDL-C is:
- A PCSK9 normally promotes lysosomal degradation of LDL receptors; inhibiting PCSK9 allows receptors to recycle to the cell surface, increasing LDL clearance ✓
- B PCSK9 inhibition activates LDLR gene transcription via SREBP-2 pathway
- C PCSK9 normally cleaves LDL particles in the bloodstream; inhibition prevents LDL fragmentation
- D PCSK9 inhibition activates lipoprotein lipase, increasing VLDL-to-LDL conversion
Correct answer: A. PCSK9 normally promotes lysosomal degradation of LDL receptors; inhibiting PCSK9 allows receptors to recycle to the cell surface, increasing LDL clearance
Explanation
After LDL receptor (LDLR) delivers LDL to the cell, LDLR normally dissociates from LDL at endosomal pH and recycles back to the cell surface. PCSK9 binds to the LDLR-LDL complex in the endosome and redirects it to the lysosome for degradation rather than recycling, reducing cell-surface LDLR density. Monoclonal antibodies against PCSK9 (evolocumab, alirocumab) prevent this interaction, allowing receptor recycling and dramatically increasing LDL clearance. Gain-of-function PCSK9 mutations cause familial hypercholesterolaemia.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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