PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo

Villard, Elise F.; Thedrez, Aurélie; Blankenstein, Jörg; Croyal, Mikaël; Tran, Thi-Thu-Trang; Poirier, Bruno; Bail, Jean-Christophe Le; Illiano, Stéphane; Nobécourt, Estelle; Krempf, Michel; Blom, Dirk; Marais, A. David; Janiak, Philip; Muslin, Anthony J.; Guillot, Etienne; Lambert, Gilles

doi:10.1016/j.jacbts.2016.06.006

Cited by 101 publications

(74 citation statements)

References 24 publications

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“…8 However, another study suggests the LDLR plays no role, but that PCSK9 may potentiate Lp(a) secretion, a pathway inhibited by PCSK9 antibodies. 37 The current data also favor that the LDLR is involved in clearing Lp(a), but that this is also influenced by the underlying APOE genotype that also competes for the same receptor. However, it is not possible to quantitate this effect, or the effect of non-LDLR pathways, such as plasminogen and SRB1 receptors.…”

Section: Discussionmentioning

confidence: 59%

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype

Moriarty

Varvel

Gordts

et al. 2017

ATVB

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Objective Lipoprotein(a) [Lp(a)] levels are genetically determined by hepatocyte apolipoprotein(a) synthesis, but catabolic pathways also influence circulating levels. APOE genotypes have different affinities for the LDL receptor (LDLR) and LDL related protein-1 (LRP-1), with ε2 having the weakest binding to LDLR at <2% relative to ε3 and ε4. Approach and Results APOE genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4 and ε4/ε4), Lp(a) mass, directly-measured Lp(a) cholesterol (Lp(a)-C) levels and a variety of apoB-related lipoproteins were measured in 431,239 patients. The prevalence of APOE traits were: ε2:7.35%, ε3:77.56%, and ε4:15.09%. Mean (SD) Lp(a) levels were 65% higher in ε4/ε4 compared to ε2/ε2 genotypes and increased significantly according to APOE genotype: ε2/ε2: 23.4(29.2), ε2/ε3: 31.3(38.0), ε2/ε4: 32.8(38.5), ε3/ε3: 33.2(39.1), ε3/ε4: 35.5(41.6), and ε4/ε4: 38.5(44.1) mg/dL (P<0.0001). LDL-C, apoB, Lp(a)-C, LDL-C corrected for Lp(a)-C content, LDL particle number and small dense LDL also had similar patterns. Patients with LDL-C ≥250mg/dL, who are more likely to have LDLR mutations and reduced affinity for apoB, had higher Lp(a) levels across all apoE isoforms, but particularly in patients with ε2 alleles, compared to LDL <250mg/dL. The lowest Lp(a) mass levels were present in patients with ε2 isoforms and lowest LDL-C. Conclusions APOE genotypes strongly influence Lp(a) and apoB-related lipoprotein levels. This suggests that differences in affinity of apoE proteins for lipoprotein clearance receptors may affect Lp(a) catabolism, suggesting a competition between Lp(a) and apoE protein for similar receptors.

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Section: Discussionmentioning

confidence: 59%

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype

Moriarty

Varvel

Gordts

et al. 2017

ATVB

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“…The enhanced secretion of Lp(a) from primary human hepatocytes is blunted by PCSK9 inhibition (with alirocumab) [53, 100];…”

Section: Studies Of Pcsk9-inhibition In Patients With High Cardiovascmentioning

confidence: 99%

PCSK9 targets important for lipid metabolism

Schulz

Schlüter

2017

Clin Res Cardiol Suppl

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Ischemic heart disease is the main cause of death worldwide and it is accelerated by increased low-density lipoprotein (LDL) cholesterol (LDL-C) and/or lipoprotein (a) (Lp(a)) concentrations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) alters both LDL-C and in part Lp(a) concentrations through its ability to induce degradation of the LDL receptor (LDLR). PCSK9, however, has additional targets which are potentially involved in lipid metabolism regulation such as the very low density lipoprotein receptor (VLDL), CD36 (cluster of differentiation 36) and the epithelial cholesterol transporter (NPC1L1) and it affects expression of apolipoprotein B48. The PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Many comorbidities (kidney insufficiency, hypothyreoidism, hyperinsulinemia, inflammation) modify PCSK9 expression and release. Two humanized antibodies directed against extracellular PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics (such as silencing RNA) are already in clinical trials. Their results demonstrate a significant reduction in both LDL-C and Lp(a) concentrations – independent of the concomitant medication – and one of them reduced plaque size in high risk cardiovascular patients; results of two ongoing large clinical endpoints studies are awaited. In this review, we summarize and discuss the recent biological data on PCSK9, the regulation of PCSK9, and finally briefly summarize the data of recent clinical studies in the context of lipid metabolism.

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“…This remains contentious, partly because a role for the LDL receptor is suggested by the observable effects of PCSK9 inhibition, but is refuted by the lack of effect by statins. 71,86 In vitro studies have suggested roles for the VLDL, megalin/gp330, asialoglycoprotein and PlgRKT plasminogen receptors in Lp(a) catabolism, [87][88][89][90] but the effect of PCSK9 on most of these pathways is unknown; therefore, the mechanism by which PCSK9 inhibition reduces Lp(a) merits further investigation.…”

Section: Efficacy In Decreasing Lipids Lipoproteins and Apolipopromentioning

confidence: 99%

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease

Page

Watts

2017

Diabetes Obesity Metabolism

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The identification of the critical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has rapidly led to the development of PCSK9 inhibition with monoclonal antibodies (mAbs). PCSK9 mAbs are already in limited clinical use and are the subject of major cardiovascular outcomes trials, which, if universally positive, could see much wider clinical application of these agents. Patients with familial hypercholesterolaemia are the most obvious candidates for these drugs, but other patients with elevated cardiovascular risk, statin intolerance or hyperlipoproteinaemia(a) may also benefit. PCSK9 mAbs, administered once or twice monthly, reduce LDL cholesterol levels by 50% to 70%, and appear to be safe and acceptable to patients over at least 2 years of treatment; however, treatment-emergent adverse effects are not always identified in clinical trials, as well-evidenced by statin myopathy. Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs, but with a much longer duration of action. The cost-effectiveness and long-term safety of therapies targeted at inhibiting PCSK9 remain to be demonstrated if they are to be used widely in coronary prevention.

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PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo

Cited by 101 publications

References 24 publications

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype

PCSK9 targets important for lipid metabolism

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease

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