PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells

Abstract

Purpose of review: Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to LDL receptor (LDLR) and targets it for lysosomal degradation in cells. Decreased hepatic clearance of plasma LDL-cholesterol is the primary gauge of PCSK9 activity in humans; however, PCSK9's evolutionary role may extend to other lipoprotein classes and processes. This review highlights studies that are providing novel insights into physiological regulation of PCSK9 transcription and plasma PCSK9 activity.

Recent findings: Recent studies indicate that circulating PCSK9 binds to apolipoprotein B100 on LDL particles, which in turn inhibits PCSK9's ability to bind to cell surface LDLRs. Negative feedback of secreted PCSK9 activity by LDL could serve to increase plasma excursion of triglyceride-rich lipoproteins and monitor lipoprotein remodeling. Recent findings have identified hepatocyte nuclear factor-1α as a key transcriptional regulator that cooperates with sterol regulatory element-binding protein-2 to control PCSK9 expression in hepatocytes in response to nutritional and hormonal inputs, as well as acute inflammation.

Summary: PCSK9 is an established target for cholesterol-lowering therapies. Further study of PCSK9 regulatory mechanisms may identify additional control points for pharmacological inhibition of PCSK9-mediated LDLR degradation. PCSK9 function could reflect ancient roles in the fasting-feeding cycle and in linking lipoprotein metabolism with innate immunity.

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FIGURE 1

Regulation of PCSK9-mediated LDLR degradation by plasma apolipoprotein B100. Two pathways exist in hepatic cells for degradation of LDLR directed by PCSK9 (red arrows). PCSK9 can bind to LDLR in the luminal secretory compartment and target LDLR to lysosomes in vesicles emanating from the trans-Golgi. Alternatively, secreted PCSK9 can bind to LDLR on the cell surface and be internalized with LDLRs in endocytic vesicles. Unlike ligands LDL (apoB100) and VLDL (apoE) that release from the LDLR within acidic early endosomes, PCSK9 remains bound and prevents LDLR recycling to the cell surface, redirecting the receptor to lysosomes in which both PCSK9 and LDLR are degraded. Within the circulation PCSK9 can bind to apoB100 on LDL particles, but not to apoB100 on VLDL particles. The binding site on apoB100 may be unmasked by lipolysis of triglycerides on VLDL particles or other lipid modifications and conversion of VLDL to the short-lived IDL, which is further converted to LDL. IDL, intermediate density lipoprotein.

FIGURE 2

Model of proprotein convertase subtilisin/kexin type-9 dysregulation under conditions of elevated plasma proprotein convertase subtilisin/kexin type-9 concentration. At low concentrations of plasma PCSK9 (top panel), such as may be present in a low nutrient environment, PCSK9 senses the conversion of VLDL to LDL in the plasma compartment through its ability to bind to LDL. When plasma LDL is low relative to hepatic VLDL production and PCSK9 secretion, the majority of circulating PCSK9 is in a free active form and directs hepatic LDLR degradation. As the LDL/VLDL ratio increases, and as plasma PCSK9 levels decline in fasting, a progressively higher percentage of plasma PCSK9 becomes LDL-bound and inactive, thereby promoting hepatic clearance of LDL. At high concentrations of plasma PCSK9 and LDL (lower panel) PCSK9 activity is less sensitive to the VLDL-to-LDL conversion, and the regulatory pool of LDL-apoB100 is mainly a function of hepatic LDL clearance. Due to a relatively low binding affinity to LDL (Kd∼ 300 nM) [^▪▪], negative feedback control of PCSK9 activity becomes dysregulated at high PCSK9 levels. Although a higher percentage of total plasma PCSK9 may bind to LDL under conditions of hypercholesterolemia, because of increased hepatic PCSK9 secretion there remains a large component of free and active PCSK9 in the circulation.