New Insights Into the Regulation of Lipoprotein Metabolism by PCSK9: Lessons From Stable Isotope Tracer Studies in Human Subjects

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.

Keywords: LDL-cholesterol; PCSK9; PCSK9 inhibitor; lipoprotein metabolism; lipoprotein(a); stable isotope tracer study.

FIGURE 1

Postulated mechanisms for the effect of statin and PCSK9 mAb on lipoprotein kinetics. (A) Placebo: VLDLs, IDLs, and LDLs are preferentially cleared by the LDLR compared with Lp(a). (B) Statin (Atorvastatin): LDLR activity is approximately two-fold elevated, resulting in increase in catabolism of VLDLs, IDLs, and LDLs, but no effect on Lp(a) kinetics. (C) PCSK9 mAb (Evolocumab): Increased catabolism leads to reduced VLDL concentration; IDL and LDL concentrations decreased due to two-fold elevation in LDLR activity and reduced production of these lipoproteins; PCSK9 mAb reduces Lp(a) concentration by decreasing hepatic production of Lp(a) particles. (D) Statin and PCSK9 mAb: VLDL concentration falls due to a doubling in the rate of VLDL catabolism; IDL concentration also falls owing to a doubling in catabolism and reducing in production of IDL; LDL concentration markedly reduced owing to a four-fold elevation in catabolism and halving in the production of LDL; Lp(a) concentration falls due to elevated hepatic clearance of Lp(a) particles (Watts et al., 2017, 2018).