Lipid Lowering Therapy and Circulating PCSK9 Concentration

Abstract

Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid-modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events.

Keywords: Familial hypercholesterolemia (FH); Low-density lipoprotein cholesterol (LDL-C); Low-density lipoprotein receptor (LDLR); Proprotein convertase subtilisin/kexin type 9 (PCSK9); Statin.

Fig. 1.

PCSK9 protein structure PCSK9 comprises a signal peptide (1–30 amino acids), a prodomain (amino acids 31–152), a catalytic domain (amino acids 153–421) and a C-terminal domain (amino acids 422–692). The molecular weight of proPCSK9 is 75 kDa, and the mature form is 62 kDa. Following autocatalytic cleavage in the endoplasmic reticulum, the prodomain is separated from the 62 kDa mature PCSK9 protein and both are secreted following the formation of a prosegment-PCSK9 complex. SP, signal peptide; PCSK9, proprotein convertase subtilisin/kexin type 9.

Fig. 2.

SREBP-2-mediated co-expression of LDLR and PCSK9 Statin-induced reduction of the cholesterol pool in hepatocyte activates SREBP-2-medicated LDLR expression, thereby increasing hepatic LDL-C uptake. Concurrently, SREBP-2 up-regulates the expression of PCSK9 and enhances hepatic LDLR degradation. Thus, SREBP-2-mediated co-expression of LDLR and PCSK9 prevent excessive cholesterol uptake in hepatocytes in order to preserve cholesterol homeostasis. SREBP-2, sterol-regulatory element binding protein-2; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9.