PCSK9 function and LDL receptor regulation
Core concept
- Normal LDL receptor cycle - the receptor is meant to be reused ~150 times
- LDLR binds ApoB-100 -> clathrin-coated endocytosis -> endosomal acidification releases LDL
- LDL -> lysosome; LDLR recycles to the surface
- PCSK9 (proprotein convertase subtilisin/kexin type 9) - secreted by hepatocytes, binds the EGF-A domain of the LDLR on the cell surface
- The complex is internalised together
- PCSK9 locks the receptor in its closed conformation so it cannot release LDL and cannot recycle
- -> LDLR diverted to lysosomal degradation
- -> dec surface LDLR -> inc plasma LDL-C
- Blocking PCSK9 -> more LDLR recycling -> dec LDL-C by ~50-60% on top of statin
- *Statins paradoxically raise PCSK9* - SREBP-2 activation transcribes both LDLR and PCSK9 -> a built-in ceiling on statin efficacy, and the rationale for combining
3 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access