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Key aspects of PCSK9 inhibition beyond LDL lowering

Ramin-Mangata, Stéphane*; Blanchard, Valentin*; Lambert, Gilles

doi: 10.1097/MOL.0000000000000551
THERAPY AND CLINICAL TRIALS: Edited by Erik S.G. Stroes and Gerald F. Watts

Purpose of review Our primary objective is to review the most recent findings on the biology of PCSK9 and on two key aspects of PCSK9 inhibition beyond LDL control of great clinical relevance: the regulation of lipoprotein (a) circulating levels by PCSK9 inhibitors and the putative diabetogenic effects of these novel therapies.

Recent findings The reality of two distinct extracellular and intracellular pathways by which PCSK9 decreases the abundance of the LDLR at the surface of many cell types, most importantly hepatocytes, has recently been established. In contrast, the exact mechanisms by which PCSK9 inhibitors lower the circulating levels of lipoprotein (a) remain a point of major dispute. Despite strong indications from genetic studies that PCSK9 inhibition should increase diabetes risk, no such effect has been observed in clinical trials, and in-vitro and in-vivo studies do not clarify this issue.

Summary The trafficking pathways by which PCSK9 enhance LDLR degradation via the endolysosomal extracellular route or via the Golgi–lysosomal intracellular route remain to be fully elucidated. The mechanisms by which PCSK9 inhibitors reduce lipoprotein (a) also merit additional research efforts. The role of PCSK9 on glucose metabolism should likewise be studied in depth.

Laboratoire Inserm UMR 1188, DéTROI, Université de La Réunion, Sainte-Clotilde, France

Correspondence to Gilles Lambert, PhD, Inserm UMR 1188, Plateforme CYROI, 2 Rue Maxime Rivière, 97490 Sainte Clotilde, France. Tel: +33 262 692 437 708; fax: +33 262 262 938 237; e-mail:

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PCSK9 plays a pivotal role in lipoprotein metabolism as a potent inhibitor of the LDL receptor (LDLR). Its precursor undergoes intramolecular autocatalytic cleavage and the resulting heterodimer is routed towards the secretory pathway. PCSK9 binds to the epidermal growth factor precursor homology domain of the LDLR and undergoes endocytosis together with the receptor. The affinity between the LDLR and PCSK9 increases with the acidic conditions found in endosomes, which locks the receptor in an ‘open’ conformation. The PCSK9/LDLR complex is subsequently degraded in the lysosome, precluding normal recycling of the LDLR to the plasma membrane (Fig. 1).



Box 1

Box 1

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PCSK9 gene expression is modulated by SREBP2 and HNF1α transcription factors [1]. E2F1, an importsant transcription factor regulating cell cycle, was recently shown to trans-activate PCSK9 promoter synergistically with SREBP2 in vitro as well as in vivo. E2F1 thereby controls LDLR abundance and LDL uptake via a positive regulation of PCSK9 gene expression [2▪]. In addition, three micro-RNAs were shown to finely tune PCSK9 expression posttranscriptionally [3].

It is well established that PCSK9 targets the LDLR for lysosomal degradation. However, the trafficking of the PCSK9/LDLR complex has not been elucidated yet. The presentation of PCSK9 to the LDLR at the cell surface was recently proposed to be mediated by heparan sulfate proteoglycans [4▪]. As a significant proportion of circulating PCSK9 is bound to LDL and appears as such to be less sensitive to furin cleavage and thereby more active [5], it remains to be seen whether heparan sulfate proteoglycans also present the LDL/PCSK9 complex to the receptor.

Noticeably, the PCSK9/LDLR complex can reach the lysosome via the extracellular endosome–lysosome route or alternatively via the Golgi–lysosome pathway that requires a direct interaction between the LDLR and PCSK9 intracellularly. The description of one LDLR mutant insensitive to PCSK9-induced degradation via the extracellular but not via the intracellular route illustrates major differences between both pathways in terms of trafficking dynamics [6]. The extracellular pathway appears to be favored in the liver, since grp94, an endoplasmic reticulum resident protein expressed in this tissue prevents PCSK9 from interacting with the LDLR [7]. In addition, grp74 prevents a direct interaction between PCSK9 loss-of-function variants that are retained in the endoplasmic reticulum (ER) and grp78, a chaperone known to activate ER stress transducers. As a result, these variants do not induce unfolded protein response or apoptosis, as it is the case with numerous mutant proteins retained in the ER [8,9▪]. Even if some PCSK9 variants display altered intracellular trafficking [8], the dynamics of PCSK9 exit from the ER to the Golgi and beyond still remain elusive.

In that respect, PCSK9 gain-of-function variants work by heterogenous mechanisms that all result in enhanced degradation of the LDLR, and promote hypercholesterolemia. For instance, mutations located in its 5’UTR may increase PCSK9 gene expression. Mutations located within the PCSK9 pro-domain usually enhance the intracellular or the extracellular LDLR degradation pathways. Mutations located within the catalytic and the C-terminal domains of PCSK9 can reduce furin-mediated cleavage or increase the binding affinity of PCSK9 for the LDLR [10,11▪]. Similarly, heterogeneous are PCSK9 loss-of-function variants that all reduce the degradation of the LDLR and thereby promote hypocholesterolemia. These mutants may be not produced (e.g. premature stop codons), retained in the ER and poorly secreted, they may present with reduced affinities for the LDLR or an enhanced ability to be inactivated by furin [11▪,12].

From a clinical perspective, the exact mechanisms by which PCSK9 enhance LDLR degradation clearly merit to be elucidated, as they might provide important information regarding potential adverse effects in particular for drugs targeting PCSK9 intracellularly.

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Given that statins do not lower lipoprotein (a) [Lp(a)] [13], it had not been anticipated that PCSK9 inhibitors that also increase the abundance of the LDLR would significantly reduce Lp(a) levels [14]. Lp(a) is a highly atherogenic lipoprotein made of a unique protein structurally similar to plasminogen, apolipoprotein (a) [apo(a)], covalently linked to the apoB100 moiety of an LDL particle [15▪▪]. Elevated Lp(a) is the single most common genetically inherited risk factor for coronary heart disease. It is causative of calcific aortic valve stenosis. Whereas circulating Lp(a) levels are primarily determined genetically, the molecular mechanisms by which PCSK9 inhibitors reduce Lp(a) have not been clearly established and remain a point of controversy [14,16].

In-vitro experiments have provided conflicting evidence regarding the role of the LDLR in Lp(a) cellular uptake. Thus, PCSK9 was shown to reduce the binding and the cellular uptake of Lp(a) via the LDLR in human hepatoma cells, in primary human fibroblasts, and in primary murine hepatocytes, whereas the LDLR-related protein 1 (LRP1) was ruled out as a putative receptor for Lp(a) [17–19]. In another study, the LDLR did not seem to play any significant role in mediating Lp(a) cellular uptake in primary human hepatocytes, in primary human fibroblasts, as well as in human hepatoma cells [14,20,21]. Neither did we observe any significant difference in Lp(a) cellular uptake in primary lymphocytes isolated from controls and homozygous familial hypercholesterolemia patients who totally lack LDLR function (G. Lambert, unpublished observation). Other receptors have been proposed to mediate Lp(a) hepatic uptake, including the scavenger receptor BI (SR-BI), and the plasminogen receptor PlgRKT [20]. In that study conducted in hepatoma cells, Lp(a) is taken up by the plasminogen receptor PlgRKT, and apo(a) is to some extent re-secreted.

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In-vivo experiments have also provided conflicting evidence regarding the role of the LDLR and the effects of PCSK9 inhibitors on Lp(a) turnover, production and catabolism. Thus, PCSK9 inhibition with alirocumab increased, although not significantly, the fractional catabolic rate of Lp(a) in human volunteers [22]. In contrast, PCSK9 neutralization with evolocumab in monotherapy did not alter the fractional catabolic rate but rather enhanced the production rate of Lp(a) in another human study [23▪]. Discrepancies between these studies in terms of Lp(a) kinetic parameters might stem from the facts that the degree of Lp(a) reduction induced by PCSK9 inhibitors substantially differed (−19 vs. −35%, respectively), and that the demographical characteristics of the patients were quite different (mixed race and sex vs. caucasian men only, respectively) [22,24]. On top of statin treatment, however, evolocumab enhanced the catabolism of Lp(a) [23▪]. In addition, alirocumab was recently shown in nonhuman primates to efficiently reduce apolipoprotein B100 primarily by enhancing its catabolism and apolipoprotein (a) primarily by lowering its production [25▪], an observation in line with a previous study in which PCSK9 enhanced apo(a) secretion from human primary hepatocytes [21].

The studies mentioned above have not provided a consensus regarding the mechanism(s) governing Lp(a) clearance. In favor of a role of the LDLR in mediating Lp(a) clearance: familial hypercholesterolemia patients presenting with LDLR defects usually display higher Lp(a) level than their nonaffected relatives, the correlations between changes in LDL (−50/60%) and changes in Lp(a) (−20/30%) following PCSK9 inhibitors treatments are weak but consistently significant [5,25▪,26] and appear independent of apo(a) polymorphisms [27]. In favor of a non-LDLR mediated pathway: PCSK9 inhibitors lower Lp(a) even in receptor-negative homozygous familial hypercholesterolemia patients without modulating LDL-C, up-regulating the LDLR even in the most potent statins does not reduce Lp(a), there is no correlation between the levels of LDLR expression assessed ex vivo and the levels of circulating Lp(a) in familial hypercholesterolemia patients [13,28▪]. More work is, therefore, required to elucidate the exact mechanisms governing Lp(a) production and clearance and their modulation by PCSK9 and PCSK9 inhibitors.

From a clinical point of view, it has not been established whether the reduction in Lp(a) induced by PCSK9 inhibitors per se confers cardiovascular protection. Clinical trials with evolocumab or alirocumab have not shown any incremental benefits in terms of cardiovascular risk (CVD) risk reduction compared with what would have been anticipated from the sole reduction in LDL-C induced by these drugs [29,30]. Nevertheless, it has recently been shown that patients with high baseline Lp(a) levels benefit more from these treatments in terms of absolute cardiovascular risk reduction than patients with low-baseline Lp(a) levels (Dr M O’Donoghue presentation at EAS meeting 2018 and Dr V Bittner presentation at ISA meeting 2018).

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Despite their undisputable beneficial effects in lowering LDL-C and CVD risk, statins have shown to slightly but significantly increase the risk of new-onset diabetes among predisposed individuals. As both statins and PCSK9 inhibitors reduce LDL-C by increasing the abundance of the LDLR at the surface of many cell types, most importantly hepatocytes, a very logical question is to determine whether PCSK9 inhibitors might also increase the risk of diabetes. Whereas enhancing the LDLR pathway in the liver is antiatherogenic and clearly beneficial, activating the same pathway in pancreatic β-cells may lead to LDL cholesterol overload and be harmful to those cells. This hypothesis is underpinned by Mendelian randomization studies showing that genetic variants in HMGCR and PCSK9 that confer lifelong reductions in LDL-C levels and are thus cardioprotective, also additively associate with an increased risk of developing diabetes [31–33]. Further advocating for a role of the LDLR in the development of diabetes, the observation that diabetes prevalence is twice lower in patients with familial hypercholesterolemia compared with their nonaffected relatives (1.75 vs. 2.93%, respectively) [34]. Diabetes risk was further reduced in carriers of the most severe mutations (i.e. negative vs. defective LDLR genetic defects at 1.41 vs. 1.80%, respectively), but also in carriers of familial hypercholesterolemia causing APOB mutations (at 2.42%) [34].

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The LDLR is expressed abundantly at the surface of pancreatic β-cells where it promotes LDL uptake [35▪]. However, β-cell lines exposed to LDL in culture often display increased necrosis or apoptosis as well as reduced insulin secretion ability in response to glucose, indicating that excessive uptake of LDL cholesterol could be detrimental to β-cells [36,37]. Fully in line with its role in most tissues, PCSK9 is involved in the regulation of the LDLR in pancreatic islets. Thus, islet cells from PCSK9 knockout mice show increased LDLR expression, whereas human islets incubated with recombinant PCSK9 display reduced LDLR expression levels [38]. Experiments conducted in rodents have, however, yielded opposite conclusions about the effect of PCSK9-deficiency on glucose homeostasis. There was no alteration in glucose homeostasis in PCSK9 knockout mice, including glucose-stimulated insulin secretion measured in one study [38], whereas another study showed that PCSK9 knockout male mice are glucose intolerant, with an increased rate of β-cell apoptosis [39]. In a more recent study, PCSK9 knockout mice were shown to present with glucose intolerance without any sign of insulin resistance [35▪]. The secretion of insulin appeared impaired in PCSK9 knockout mice, an effect associated with an increased presence of islets of large sizes, and dependent on the presence of a functional LDLR. In contrast, liver-specific PCSK9-knockout mice, a model in which there is no detectable circulating PCSK9, have normal pancreatic LDLR expression and do not show any sign of glucose intolerance [35▪]. In mice, PCSK9 was found to be expressed in Langherans islets δ-cells and proposed to contribute to the limitation of cholesterol overload in neighbouring β-cells [35▪,38]. In humans, however, PCSK9 gene expression appears to occur preferentially in β-cells (Fig. 2). Beyond its role on β-cell function, the role of PCSK9 on insulin sensitivity remains largely unknown. In epidemiological studies, plasma PCSK9 concentrations have been found to be positively correlated with the index of insulin resistance HOMA-IR.



From a clinical point of view, the possibility that PCSK9 inhibition may slightly increase the risk of new onset diabetes is supported by some pathophysiological and genetic studies. However, PCSK9 inhibition did not increase the risk of diabetes in large-scale clinical trials [40▪].

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The successful developments of evolocumab and alirocumab unambiguously demonstrate that PCSK9 is an extremely valuable therapeutic target, given that these novel therapies clearly improve clinical outcomes with extremely limited side effects. The cellular trafficking pathways by which PCSK9 enhance LDLR degradation either via the endolysosomal extracellular route or via the Golgi-lysosomal intracellular route still need to be elucidated. Likewise, the mechanisms by which PCSK9 inhibitors reduce lipoprotein (a) remain a point of controversy and certainly merit additional research efforts. Additional work on the putative role of PCSK9 in the overall metabolism of glucose are also needed, given the paucity of data from long-term follow-up studies with PCSK9 inhibitors. No doubt that these gaps in knowledge will be filled in the coming years.

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We deeply thank Dr Raphaël Scharfmann who shared the information that PCSK9 mRNA is expressed in sorted human beta-cells.

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Financial support and sponsorship

This work was supported by the French national project CHOPIN (CHolesterol Personalized Innovation) granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007).

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Conflicts of interest

G.L. has received research funding and honoraria from Sanofi, Regeneron, Amgen, Affiris, Pfizer, and Nyrada Inc.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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An elegant study showing that the transcription factor E2F1 maintains cellular cholesterol homeostasis through the positive regulation of PCSK9 gene expression.

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A provocative demonstration that the N terminal domain of PCSK9 contains a cluster of basic residues that interact with HSPGs, which is essential for PCSK9 function in vitro and in vivo.

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An elegant study showing that the PCSK9-Q152H loss of function variant retained in the ER does not cause ER stress as it is efficiently degraded in the proteasome.

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A comprehensive review on the mode of action of PCSK9 gain-of-function and PCSK9 loss of-function mutants

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An excellent expert recommendation article on lipoprotein(a) listing the main gaps in knowledge on this understudied lipoprotein.

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A rigorous demonstration showing how PCSK9 inhibition reduces Lp(a) by a series of in-vivo human kinetic studies.

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This cross over study demonstrates that the PCSK9 inhibitor alirocumab reduces Lp(a) production and augments LDL catabolism in vivo.

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A comprehensive study showing that residual LDLR activity is key for PCSK9i-mediated reductions in LDL-C among homozygote familial hypercholesterolemia.

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An elegant study showing that PCSK9 deficiency in mouse models causes impairment in glucose homeostasis as a result of defective pancreatic islets.

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40▪. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5:941–950.

This study demonstrates that the PCSK9 inhibitor evolocumab does not worsen diabetes or cause new onset diabetes.

* Stéphane Ramin-Mangata and Valentin Blanchard Equal contributions.


diabetes; LDL receptor; lipoprotein (a); PCSK9

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