Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other

Butkinaree, Chutikarn; Canuel, Maryssa; Essalmani, Rachid; Poirier, Steve; Benjannet, Suzanne; Asselin, Marie‐Claude; Roubtsova, Anna; Hamelin, Josée; Marcinkiewicz, Jadwiga; Chamberland, Ann; Guillemot, Johann; Mayer, Gaétan; Sisodia, Sangram S.; Jacob, Yves; Prat, Annik; Seidah, Nabil G.

doi:10.1074/jbc.m115.647180

Cited by 50 publications

(59 citation statements)

References 62 publications

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“…Recently, two proteins were suggested to enhance PCSK9-mediated degradation of the LDL receptor: one is sortilin, which binds to PCSK9 in the trans-Golgi network and possibly facilitates its secretion 37) , and the other is amyloid precursor-like protein 2 (APLP2), which facilitates trafficking of the PCSK9-LDL receptor complex to endosomes/lysosomes 38) . However, Butkinaree et al 39) reported that PCSK9 enhanced LDL receptor degradation independent of sortilin or APLP2 ex vivo The present study has several limitations. First, it was a post hoc analysis of the TRUTH trial and all subjects had CAD.…”

Section: Discussionmentioning

confidence: 62%

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Nozue

Hashimoto

Ogawa

et al. 2016

JAT

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Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein (LDL) cholesterol levels, and sortilin is linked to lipoprotein metabolism. Although statin therapy increases PCSK9 levels, effects of this therapy on plasma sortilin levels have not been evaluated. The purpose of the present study was to examine the effects of statins on plasma PCSK9 and sortilin levels, and association of statin-induced increase in PCSK9 levels with sortilin. Methods: Serum lipid levels and plasma PCSK9 and sortilin levels were measured at baseline and 8 months after statin therapy in 90 statin-naive patients with coronary artery disease (CAD). Pitavastatin 4 mg/day was used to treat 44 patients and pravastatin 20 mg/day to treat the remaining 46 patients. Results: For both statin groups, significant increases in hetero-dimer PCSK9 levels (pitavastatin: 31%, p 0.0001; pravastatin: 34%, p 0.03) and decreases in sortilin levels (pitavastatin: 8%, p 0.02; pravastatin: 16%, p 0.002) were observed. Although a reduction in LDL cholesterol was greater in the pitavastatin group than in the pravastatin group, no significant differences were observed in percentage changes in hetero-dimer PCSK9 and sortilin levels. A significant positive correlation was observed between percentage changes in hetero-dimer PCSK9 levels and those in sortilin levels (pitavastatin: r 0.359, p 0.02; pravastatin: r 0.276, p 0.06). Conclusions: Use of pitavastatin and pravastatin increased plasma PCSK9 and decreased sortilin levels. Statin-induced increases in PCSK9 were associated with changes in sortilin in statin-naive patients with CAD. J Atheroscler Thromb, 2016; 23: 848-856.

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Section: Discussionmentioning

confidence: 62%

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Nozue

Hashimoto

Ogawa

et al. 2016

JAT

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“…7D ) but remained stable in WT livers. A similar observation was done with Pcsk9 +/ Ϫ (heterozygote) mice that presented a 70% drop in circulating PCSK9 levels, likely due to a concomitant increase in LDLR levels ( 42 ). Whether this unexpected accumulation of surface LDLR in WT mice fed a high-cholesterol diet contributes to the protection of vessel walls by clearing the excess of circulating cholesterol remains to be verifi ed.…”

Section: Synergistic Effect Of Ovariectomy and Pcsk9 Defi Ciency On Pmentioning

confidence: 74%

PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice

Roubtsova

Chamberland

Marcinkiewicz

et al. 2015

Journal of Lipid Research

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These PCs are encoded by genes designated PCSK1 to PCSK9 , except for the third and eighth members furin and SKI-1/S1P, whose genes were named FURIN and MBTPS1 , respectively. PCSK9 was the third gene known to be involved in autosomal dominant hypercholesterolemia ( 2 ) after those encoding the LDL receptor (LDLR) and apolipoprotein B. PCSK9 binds to the LDLR and directs it to the endosomal/lysosomal pathway for degradation ( 3, 4 ). Gain-of-function mutations in PCSK9 were shown to enhance the degradation of the LDLR ( 2, 4 ), with ensuing increased LDL-cholesterol levels in plasma. Conversely, PCSK9 loss-of-function mutations result in hypocholesterolemia ( 5 ). Low concentrations of active PCSK9 are also associated with a lower incidence of atherosclerosis ( 6 ), myocardial infarction ( 7 ), and stroke ( 8 ). Individuals entirely lacking functional PCSK9 are healthy and have extremely low levels of LDL-cholesterol ( ‫ف‬ 0.4 mM) ( 9-11 ). Accordingly, monoclonal antibodies directed against PCSK9 that disrupt the PCSK9-LDLR interaction are effi cient in reducing LDL-cholesterol levels (by >50%) and are commercially available (reviewed in Ref. 12 ).Like all other PCs, PCSK9 is synthesized as a precursor (proPCSK9; 74 kDa) that undergoes an autocatalytic cleavage at the VFAQ 152 ↓ site, allowing it to exit the endoplasmic reticulum ( 4, 13 ). However, the inhibitory prosegment remains tightly bound to PCSK9 ( 14,15 ), and the complex is secreted. Thus, mature PCSK9 has no catalytic activity in trans but acts as a binding protein to specifi c receptors.Abstract Proprotein convertase subtilisin kexin type 9 (PCSK9), the last member of the family of Proprotein Convertases related to Subtilisin and Kexin, regulates LDL-cholesterol by promoting the endosomal/lysosomal degradation of the LDL receptor (LDLR). Herein, we show that the LDLR cell surface levels dramatically increase in the liver and pancreatic islets of PCSK9 KO male but not female mice. In contrast, in KO female mice, the LDLR is more abundant at the cell surface enterocytes, as is the VLDL receptor (VLDLR) at the cell surface of adipocytes. Ovariectomy of KO female mice led to a typical KO male pattern, whereas 17 ␤ -estradiol (E2) treatment restored the female pattern without concomitant changes in LDLR adaptor protein 1 (also known as ARH), disabled-2, or inducible degrader of the LDLR expression levels. We also show that this E2-mediated regulation, which is observed only in the absence of PCSK9, is abolished upon feeding the mice a high-cholesterol diet. The latter dramatically represses PCSK9 expression and leads to high surface levels of the LDLR in the hepatocytes of all sexes and genotypes. In conclusion, the absence of PCSK9 results in a sex-and tissue-specifi c subcellular distribution of the LDLR and VLDLR, which is determined by E2 levels. 82946 and 102741 (N.G.S. and A.P.) and 5605 (J.J.B.), by the Leducq Foundation (N.G.S. and A.P.), and by a Canada Research Chair (N.G.S.). 18 August 2015. Published, JLR Papers in Press, August 31, 2015...

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“…was challenged in a recent report, which found APLP2 was not involved in PCSK9-mediated degradation of LDLR ( 37 ). The fi nding of DeVay and coworkers ( 34,35 ) of most relevance to our work was that an anti-PCSK9 antibody was transported with PCSK9 to lysosomes by the APLP2-mediated pathway.…”

Section: Proteolytic Cleavage Of Pcsk9 Slows the CL Of Ly From Serummentioning

confidence: 41%

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

Schroeder

Beyer

Hansen

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org atherosclerosis ( 7,8 ). Conversely, loss-of-function mutations are associated with reduced LDL-C and reduced risk of cardiovascular diseases ( 9-11 ).PCSK9 is expressed in multiple tissues, including liver, intestine, kidney, and cerebellum, of which the liver appears to be the major source of the circulating protein (12)(13)(14). It is synthesized as a 74 kDa proprotein, which is activated prior to secretion by the autocatalytic cleavage of its N-terminal prodomain ( 15 ). PCSK9 that is secreted from cells is comprised of the 14 kDa prodomain associated noncovalently with a 60 kDa mature domain, the latter consisting of an N-terminal catalytic domain and a cysteine-and histidine-rich C-terminal domain. In addition to this 74 kDa form (intact PCSK9), a smaller form (truncated PCSK9) is found in serum in which the N terminus of the catalytic domain is truncated by 7-8 kDa. This truncated PCSK9 represents up to 40% of the total circulating PCSK9 in humans (16)(17)(18). The site of cleavage in PCSK9 was identifi ed as Arg218 of the catalytic domain ( 16,17 ). Furin appears to be responsible for most of the cleavage in vivo, based on studies in mice with hepatocytespecifi c inactivation of the protease ( 18 ). The observation of reduced plasma levels of the truncated PCSK9 in humans heterozygous for the R218S gain-of-function mutation is also consistent with furin-mediated cleavage, as this mutation disrupts the RXXR sequence recognized by furin ( 18 ).Several reports have addressed the question of whether the truncated PCSK9 is active in the regulation of LDL-C. Studies in furin knockout mice found reduced circulating levels of truncated PCSK9 and less hepatic LDLR than in Abstract Lilly PCSK9 antibody LY3015014 (LY) is a monoclonal antibody (mAb) that neutralizes proprotein convertase subtilisin-kexin type 9 (PCSK9). LY decreases LDL cholesterol in monkeys and, unlike other PCSK9 mAbs, does not cause an accumulation of intact PCSK9 in serum. Comparing the epitope of LY with other clinically tested PCSK9 mAbs, it was noted that the LY epitope excludes the furin cleavage site in PCSK9, whereas other mAbs span this site. In vitro exposure of PCSK9 to furin resulted in degradation of PCSK9 bound to LY, whereas cleavage was blocked by other mAbs. These other mAbs caused a signifi cant accumulation of serum PCSK9 and displayed a shorter duration of LDL-cholesterol lowering than LY when administered to mice expressing the WT human PCSK9. In mice expressing a noncleavable variant of human PCSK9, LY behaved like a cleavage-blocking mAb, in that it caused signifi cant PCSK9 accumulation, its duration of LDL lowering was reduced, and its clearance (CL) from serum was accelerated. Thus, LY neutralizes PCSK9 and allows its proteolytic degradation to proceed, which limits PCSK9 accumulation, reduces the CL rate of LY, and extends its duration of action.PCSK9 mAbs with this property are likely to achieve longer durability and require lower doses than mAbs that cause antigen...

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Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other

Cited by 50 publications

References 62 publications

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

Effects of Statin Therapy on Plasma Proprotein Convertase Subtilisin/kexin Type 9 and Sortilin Levels in Statin-Naive Patients with Coronary Artery Disease

PCSK9 deficiency unmasks a sex- and tissue-specific subcellular distribution of the LDL and VLDL receptors in mice

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

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