New developments in proprotein convertase subtilisin–kexin 9's biology and clinical implications

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Purpose of review

High levels of LDL-cholesterol (LDL-C) are directly associated with devastating cardiovascular complications. Statins downregulate cholesterol synthesis and upregulate hepatic mRNA levels of LDL receptor (LDLR) and proprotein convertase subtilisin–kexin 9 (PCSK9), a validated enhancer of LDLR protein degradation. Herein, we summarize recent discoveries of the biological properties of PCSK9 in both health and disease states.

Recent findings

PCSK9 downregulation of the LDLR protein likely explains the observed protective effect of the loss of PCSK9 in reducing lipoprotein(a) and incidence of septic shock. Injectable inhibitory PCSK9 monoclonal antibodies are now prescribed to hypercholesterolemic patients that do not reach target levels of LDL-C with available drugs. PCSK9 also reduces the levels of other receptors, for example, VLDL receptor (VLDLR), ApoER2, CD36, and CD81. The efficacy of the upregulation of LDLR and VLDLR cell surface levels in the absence of PCSK9 is both tissue and sex dependent. As LDLR, CD81, and VLDLR are hepatitis C receptors, PCSK9 may protect against certain viral infections.


New functions of PCSK9 and other receptor targets are beginning to emerge to explain the observed changes in LDL-C and triglycerides. The effect of PCSK9 loss-of-function on glucose metabolism, factors that regulate the expression of PCSK9, and the roles of PCSK9 in other tissues, for example, intestine, kidney, and brain require further investigations.

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