Category: transport
LDL receptor (LDL-R) clears circulating LDL particles by hepatic endocytosis. After internalization, LDL-R normally recycles back to the plasma membrane for hundreds of cycles. PCSK9 binds LDL-R + diverts it to lysosomal degradation, reducing surface receptor density and raising plasma LDL. Statins lower intracellular cholesterol → SREBP-2 activation → upregulates BOTH LDL-R AND PCSK9 (negating part of the LDL-R upregulation). PCSK9 inhibitors (mAb: alirocumab + evolocumab; siRNA: inclisiran with q6-monthly dosing) block PCSK9 → preserve LDL-R recycling → LDL reductions of 50-60% on top of maximal statin. Familial hypercholesterolemia: most often LDL-R loss-of-function mutations (autosomal codominant); gain-of-function PCSK9 mutations produce phenocopy.