Emerging Roles of PCSK9: More Than a One-Trick Pony.

Abstract

Rare human genetic variations at the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus revealed the role of this protein in regulating plasma levels of low-density lipoprotein-cholesterol (LDL-C), and its promise as a therapeutic target.1,2 PCSK9 promotes the internalization and degradation of the hepatic LDL receptor, thereby reducing the liver’s ability to clear LDL from the circulation and causing LDL-C levels to rise.3,4 Monoclonal antibodies against PCSK9 that disrupt the interaction of this protein with the LDL receptor have been studied in numerous clinical trials, and these agents have been shown to safely reduce LDL-C by 50% to 60%.5 Although large cardiovascular outcomes trials are still being conducted, 2 of these agents were recently approved by regulatory authorities on the basis of their LDL-C reductions alone, for the treatment of patients with familial hypercholesterolemia or those with established cardiovascular disease who require additional lipid-lowering therapy despite maximally tolerated doses of statins. See accompanying article on page 2517 of the December 2015 issue The rapid development of a novel therapeutic can often outpace our understanding of the underlying biology, and this is becoming apparent in the case of PCSK9 function. Although most intensely studied for its interaction with the LDL receptor, it is now evident that PCSK9 can promote the degradation of other cell surface receptors, including close structural homologues of the LDL receptor (eg, the very low-density lipoprotein …