The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index; 6 of the 19 sources its claims cite were checked for support.
GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation
Open accessAbstract
Clearance of circulating low-density lipoprotein cholesterol (LDLc) by hepatic LDL receptors (LDLR) is central for vascular health. Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels. Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR. Herein, we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein. Depletion of GRP94 did not affect calcium homeostasis, induce ER stress, nor did it alter PCSK9 processing or its secretion but greatly increased its capacity to induce LDLR degradation. Accordingly, we found that hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels correlated with ∼ 80% reduction in hepatic LDLR protein levels. Thus, we provide evidence that, in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER.
Overview
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Written from the paper’s full text.
TL;DR
This study identifies the ER-resident chaperone GRP94 as an endogenous PCSK9-binding protein that shields hepatic LDLR from PCSK9-induced degradation, thereby limiting circulating LDL cholesterol. Hepatocyte-specific Grp94 deletion in mice raises plasma PCSK9 and LDLc while nearly abolishing hepatic LDLR protein, and the GRP94 C-terminal client-binding domain (CBD-CT) is sufficient to block PCSK9–LDLR interaction.
Key findings
- PCSK9 co-immunoprecipitated with GRP94 (and, upon GRP94 knockdown, GRP78) from HepG2/Huh-7 cells and co-localized with GRP94 but not LDLR in Huh-7 cells and normal human hepatocytes; interaction mapped to the GRP94 CBD-CT domain (aa 652–678), with CBD mutations abolishing PCSK9 binding.
- GRP94 is not an obligatory PCSK9 chaperone: geldanamycin treatment or GRP94 knockdown did not alter proPCSK9 autocatalytic cleavage, furin processing, or secretion, and conditioned media retained full capacity to degrade LDLR in naive HepG2 cells.
- Hepatocyte-specific Grp94-deficient mice (cGrp94f/f) showed elevated circulating PCSK9 and a 14-fold increase in circulating LDLc, with LDLR protein levels severely decreased in liver (abstract reports ∼80% reduction) while Ldlr mRNA and other surface proteins (P-cadherin, CD36) were unchanged.
- GRP94 knockdown rendered LDLR more sensitive to PCSK9-induced degradation (not blocked by MG132), and recombinant GRP94 or CBD-CT reversed PCSK9-induced LDLR degradation dose-dependently and reduced PCSK9 endocytosis; HepG2 cells secrete ~5 nM endogenous GRP94.
Methods
- Biochemical interaction mapping: immunoprecipitation of PCSK9 from HepG2/Huh-7 cells under physiological and overexpression conditions, silver staining, and mass spectrometry; coIP with GRP94/GRP78 knockdown; confocal co-localization in Huh-7 cells and human hepatocytes.
- Cell-based functional assays: geldanamycin inhibition and siRNA knockdown of GRP94 in HepG2/HEK293 cells, PCSK9 (WT and D374Y) processing/secretion and media-swap LDLR degradation assays, LDLR-EGFP/PCSK9-mCherry imaging, thapsigargin ER-stress and ER Ca2+ measurements, and recombinant GRP94/CBD-CT competition assays including a solid-phase PCSK9-LDLR(EGF-AB) binding assay.
- In vivo: hepatocyte-specific Grp94 knockout mice generated by crossing Alb-Cre with Grp94f/f mice (Chen et al., 2014), with Alb-Cre-negative littermates as WT controls; plasma PCSK9 and LDLc measured and liver LDLR protein assessed by western blot. Data presented as mean ± SD, representative of at least three independent experiments in duplicate; Student's t test, p < 0.05.
Limitations
- The paper states no explicit limitations section; the text notes that detailed methods are in Supplemental Experimental Procedures and that some data (e.g., LDLR mRNA) are "not shown."
- Evident from the text: the in vivo evidence rests on a single hepatocyte-specific knockout model with no rescue or PCSK9-loss-of-function cross, so causality of the PCSK9–GRP94 axis for the LDLc phenotype is inferred rather than directly tested; the therapeutic proposal for GRP94/CBD-CT fragments is presented as a perspective without in vivo administration data.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
6 of 19 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured
- Findingown data§ Results and Discussion
No activation of ER stress was observed in livers of cGrp94f/f mice.
“no activation of ER stress were observed in livers of cGrp94f/f”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The GRP94 N-terminal domain is not involved in PCSK9 interaction and subsequent inhibition of LDLR degradation.
“Molecular characterization revealed that GRP94 is not an obligatory chaperone for PCSK9 and that, unlike CBD domain, the GRP94 N-terminal domain, important for folding of its client proteins, is not involved in PCSK9 interaction and subsequent inhibition of LDLR degradation.”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
LDLR protein levels were severely decreased in livers of cGrp94f/f mice.
“LDLR protein levels were severely decreased in livers of cGrp94f/f mice”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
There was a 14-fold increase in circulating LDLc in cGrp94f/f mice.
“we also observed a 14-fold increase in circulating LDLc in cGrp94f/f mice”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Knockdown of GRP94 rendered LDLR much more sensitive to PCSK9-induced degradation.
“Interestingly, KD of GRP94 rendered LDLR much more sensitive to PCSK9-induced degradation (Figure 3I, lane 5 and right top panel).”
Quote in the paperSubstantial claim
- Findingown data§ Results and Discussion
PCSK9-mCherry endocytosis was significantly reduced in LDLR-EGFP-expressing cells in the presence of recombinant GRP94.
“Confocal microscopy revealed that PCSK9-mCherry endocytosis was significantly reduced in LDLR-EGFP-expressing cells in the presence of recombinant GRP94 (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Hepatocyte-specific deletion of Grp94 severely increased plasma PCSK9 and LDLc levels.
“Accordingly, hepatocyte-specific deletion of Grp94 severely increased plasma PCSK9 and LDLc levels (Figure 3A), which is correlated with almost undetectable hepatic LDLR protein levels (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Overexpression of secretable FL GRP94 or CBD-CT significantly blocked LDLR degradation induced by PCSK9 in Huh-7 and HepG2 cells.
“Similar to recombinant GRP94 (Figure 4E), overexpression of secretable FL GRP94 or CBD-CT significantly blocked LDLR degradation induced by PCSK9 in Huh-7 (Figure 4G) and HepG2 cells (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
LDLR was much more sensitive to degradation in the absence of GRP94 in PCSK9-expressing cells and liver.
“Moreover, we showed that LDLR was much more sensitive to degradation in the absence of GRP94 in PCSK9-expressing cells and liver (Figures 3B, 3I, and 4G).”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
PCSK9-induced LDLR degradation was reversed in a dose-dependent manner by addition of GRP94.
“immunoblot data revealed that PCSK9-induced LDLR degradation was reversed in a dose-dependent manner by addition of GRP94 (Figure 4E, lanes 2–6).”
Quote in the paperSubstantial claim - Findingown data§ 3 ∙ Gaetan Mayer
GRP94 is a PCSK9-LDLR inhibitory binding protein.
“we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Thapsigargin induced expression of GRP78 and ER stress marker CHOP in MEFs.
“TG induced expression of GRP78 and ER stress marker CHOP in MEFs”
Quote in the paperNot a substantial claim - Findingown data§ Results and Discussion
PCSK9 maintained its full capacity to induce LDLR degradation following media swap on naive HepG2 cells.
“PCSK9 maintained its full capacity to induce LDLR degradation following media swap on naive HepG2 cells”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
GRP94 and GRP78 also interacted with the catalytically inactive PCSK9-H226A-V5 mutant retained in the ER.
“GRP94 and GRP78 also interacted with the catalytically inactive PCSK9-H226A-V5 mutant”
Quote in the paperNot a substantial claim - Findingown data§ Results and Discussion
GRP94 knockdown did not affect intracellular ER Ca2+ homeostasis.
“GRP94 KD did not affect intracellular ER Ca2+ homeostasis”
- Also stated in: § 3 ∙ Gaetan Mayer · plain
“Depletion of GRP94 did not affect calcium homeostasis”
Quote in the paperSubstantial claim - Also stated in: § 3 ∙ Gaetan Mayer · plain
- Findingown data§ Results and Discussion
Both proPCSK9-V5 and mature PCSK9-V5 were immunoprecipitated using either anti-GRP94 or anti-GRP78.
“both proPCSK9-V5 and mature PCSK9-V5 were IP using either anti-GRP94 or anti-GRP78”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
GRP94 is highly expressed in hepatocytes.
“In contrast, GRP94 is highly expressed in hepatocytes and its interaction with PCSK9 involves the catalytic domain and directly competes for binding with LDLR-EGF-A domain (Figure 4I).”
Quote in the paperSubstantial claim - Findingown data§ 3 ∙ Gaetan Mayer
Hepatocyte-specific Grp94-deficient mice have ∼80% reduction in hepatic LDLR protein levels.
“correlated with ∼80% reduction in hepatic LDLR protein levels”
Quote in the paperSubstantial claim - Findingown data§ 3 ∙ Gaetan Mayer
Depletion of GRP94 greatly increased PCSK9's capacity to induce LDLR degradation.
“but greatly increased its capacity to induce LDLR degradation”
- Also stated in: § 3 ∙ Gaetan Mayer · plain
“In the absence of GRP94, LDLR is more sensitive to PCSK9-mediated degradation”
Quote in the paperSubstantial claim - Also stated in: § 3 ∙ Gaetan Mayer · plain
- Findingown data§ Results and Discussion
The proteasome inhibitor MG132 did not block PCSK9-induced LDLR degradation following knockdown of GRP94.
“Moreover, the proteasome inhibitor MG132 did not block PCSK9-induced LDLR degradation following KD of GRP94, eliminating rerouting of the PCSK9/LDLR complex to the ER-associated degradation pathway (Figure 3I, lane 6 and right bottom).”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
PCSK9-V5, but not LDLR-V5, specifically interacts in complex with GRP94 and GRP78.
“PCSK9-V5, but not LDLR-V5, specifically interacts in complex with GRP94 and GRP78”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Endogenous GRP78 interacted with PCSK9 only upon GRP94 knockdown.
“endogenous GRP78 interacted with PCSK9 only upon GRP94 KD”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Endogenous PCSK9 and GRP94 were found associated in the ER of normal human hepatocytes.
“were found associated in the ER of normal human hepatocytes”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Hepatocyte-specific deletion of Grp94 is correlated with almost undetectable hepatic LDLR protein levels.
“Accordingly, hepatocyte-specific deletion of Grp94 severely increased plasma PCSK9 and LDLc levels (Figure 3A), which is correlated with almost undetectable hepatic LDLR protein levels (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data§ 3 ∙ Gaetan Mayer
The client-binding C-terminal domain of GRP94 is the PCSK9-LDLR inhibitory binding domain.
“we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Geldanamycin did not perturb intracellular proPCSK9 to PCSK9 autocatalytic activation and PCSK9 secretion.
“it did not perturb intracellular proPCSK9 to PCSK9 autocatalytic activation and PCSK9 secretion”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Mass spectrometry revealed GRP78 as the major ∼76-kDa protein interacting with overexpressed PCSK9-V5 together with the uncleaved proPCSK9 precursor present in the ER.
“The analysis also revealed GRP78 as the major ∼76-kDa protein interacting with overexpressed PCSK9-V5 together with the uncleaved proPCSK9 precursor present in the ER”
Quote in the paperNot a substantial claim - Findingown data§ Results and Discussion
The CBD-CT construct was ∼5-fold less produced and secreted by HEK293 cells than full-length GRP94.
“Whereas the CBD-CT construct was ∼5-fold less produced and secreted by HEK293 cells, its interaction with PCSK9 was significantly enhanced as compared to full-length (FL) GRP94 (Figure 4C), reinforcing the major role of CBD for GRP94-PCSK9 interaction.”
Quote in the paperNot a substantial claim - Findingown data§ 3 ∙ Gaetan Mayer
PCSK9 interacts with the ER-resident chaperone GRP94.
“PCSK9 interacts with the ER-resident chaperone GRP94”
- Also stated in: § Results and Discussion · plain
“Mass spectrometry data from the excised bands revealed human GRP94 as the major ∼100-kDa migrating protein in complex with PCSK9 in both conditions”
Quote in the paperSubstantial claim - Also stated in: § Results and Discussion · plain
- Findingown data§ Results and Discussion
Addition of recombinant CBD-CT significantly increased total LDLR protein levels in a PCSK9-dependent manner.
“Furthermore, addition of recombinant CBD-CT significantly increased total LDLR protein levels in a PCSK9-dependent manner (Figure 4H), most likely via a direct competition with LDLR-EGF-A domain for PCSK9 (Figure 4I).”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Overnight treatment with thapsigargin did not affect overexpressed PCSK9 processing and secretion.
“without affecting overexpressed PCSK9 processing and secretion”
Quote in the paperSubstantial claim - Findingown data§ 3 ∙ Gaetan Mayer
Knockdown of GRP94 did not alter PCSK9 secretion.
“or its secretion”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Circulating PCSK9 levels were elevated in the plasma of cGrp94f/f mice.
“circulating PCSK9 levels were elevated in the plasma of cGrp94f/f mice”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
GRP94's interaction with PCSK9 involves the catalytic domain.
“In contrast, GRP94 is highly expressed in hepatocytes and its interaction with PCSK9 involves the catalytic domain and directly competes for binding with LDLR-EGF-A domain (Figure 4I).”
Quote in the paperSubstantial claim - Findingown data§ 3 ∙ Gaetan Mayer
Hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels.
“hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
GRP94 knockdown did not alter LDLR protein levels in naturally PCSK9-deficient HEK293 cells.
“did not alter LDLR protein levels in naturally PCSK9-deficient HEK293 cells”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Both WT and PCSK9-D374Y mutant similarly and specifically interacted with GRP94.
“Both WT and PCSK9-D374Y mutant similarly and specifically interacted with GRP94”
Quote in the paperSubstantial claim - Findingown data§ 3 ∙ Gaetan Mayer
The higher plasma LDLc levels in hepatocyte-specific Grp94-deficient mice correlate with the reduction in hepatic LDLR protein levels.
“higher plasma LDLc levels correlated with ∼80% reduction in hepatic LDLR protein levels”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
The CBD-CT construct's interaction with PCSK9 was significantly enhanced compared to full-length GRP94.
“Whereas the CBD-CT construct was ∼5-fold less produced and secreted by HEK293 cells, its interaction with PCSK9 was significantly enhanced as compared to full-length (FL) GRP94 (Figure 4C), reinforcing the major role of CBD for GRP94-PCSK9 interaction.”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
GRP78 is not an intermediate in the PCSK9-GRP94 complex formation.
“GRP78 is not an intermediate in the PCSK9-GRP94 complex formation”
Quote in the paperNot a substantial claim - Findingown data§ Results and Discussion
There was no significant difference for other cell surface transmembrane proteins such as P-cadherin and CD36 in livers of cGrp94f/f mice.
“we did not observe any significant difference for other cell surface transmembrane proteins such as P-cadherin and CD36 in livers of cGrp94f/f mice”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Ldlr mRNA expression was not affected in cGrp94f/f mice.
“Ldlr mRNA expression was not affected”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Overnight treatment with thapsigargin significantly reduced LDLR levels in HEK293 cells or MEFs.
“Overnight treatment with thapsigargin (TG), a sarco/ER Ca2-ATPase inhibitor and ER stress inducer, in HEK293 cells or mouse embryonic fibroblasts (MEFs) significantly reduced LDLR levels”
Quote in the paperSubstantial claim - Findingown data§ Results and Discussion
Endogenous PCSK9 and GRP94, but not LDLR, co-localized in Huh-7 cells.
“endogenous PCSK9 and GRP94, but not LDLR, co-localized in Huh-7 cells”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
PCSK9 encodes for a natural inducer of LDLR degradation.
“PCSK9 encodes for a natural inducer of LDLR degradation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Maxwell and Breslow, 2004 source
- Interpretationown data§ Results and Discussion
Exogenous GRP94 inhibits PCSK9-induced LDLR degradation likely by blocking PCSK9 interaction and LDLR-mediated internalization.
“These data demonstrate that exogenous GRP94 efficiently inhibits PCSK9-induced LDLR degradation likely by blocking PCSK9 interaction and LDLR-mediated internalization and also suggest that GRP94 could block the PCSK9-LDLR interaction in the ER.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Results and Discussion
GRP94 could block the PCSK9-LDLR interaction in the ER.
“These data demonstrate that exogenous GRP94 efficiently inhibits PCSK9-induced LDLR degradation likely by blocking PCSK9 interaction and LDLR-mediated internalization and also suggest that GRP94 could block the PCSK9-LDLR interaction in the ER.”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
GRP94 regulates LDLc by modulating LDLR protein levels.
“demonstrating that GRP94 regulates LDLc by modulating LDLR protein levels”
- Also stated in: § 3 ∙ Gaetan Mayer · plain
“GRP94 regulates LDLc levels by maintaining LDLR protein levels”
Quote in the paperSubstantial claim - Also stated in: § 3 ∙ Gaetan Mayer · plain
- Interpretationown data§ Results and Discussion
The failure of MG132 to block PCSK9-induced LDLR degradation after GRP94 knockdown eliminates rerouting of the PCSK9/LDLR complex to the ER-associated degradation pathway.
“Moreover, the proteasome inhibitor MG132 did not block PCSK9-induced LDLR degradation following KD of GRP94, eliminating rerouting of the PCSK9/LDLR complex to the ER-associated degradation pathway (Figure 3I, lane 6 and right bottom).”
Quote in the paperSubstantial claim - Interpretationown data§ 3 ∙ Gaetan Mayer
GRP94 is not an obligatory chaperone for PCSK9.
“GRP94 is not an obligatory chaperone for PCSK9”
- Also stated in: § Results and Discussion · plain
“Molecular characterization revealed that GRP94 is not an obligatory chaperone for PCSK9 and that, unlike CBD domain, the GRP94 N-terminal domain, important for folding of its client proteins, is not involved in PCSK9 interaction and subsequent inhibition of LDLR degradation.”
Quote in the paperSubstantial claim - Also stated in: § Results and Discussion · plain
- Interpretationreasoning§ 3 ∙ Gaetan Mayer
The protection of LDLR from degradation by PCSK9 binding to GRP94 is likely by preventing early binding of PCSK9 to LDLR within the ER.
“likely by preventing early binding of PCSK9 to LDLR within the ER”
Quote in the paperNot a substantial claim - Interpretationown data§ Results and Discussion
Recombinant CBD-CT increases total LDLR protein levels most likely via direct competition with LDLR-EGF-A domain for PCSK9.
“Furthermore, addition of recombinant CBD-CT significantly increased total LDLR protein levels in a PCSK9-dependent manner (Figure 4H), most likely via a direct competition with LDLR-EGF-A domain for PCSK9 (Figure 4I).”
Quote in the paperSubstantial claim - Interpretationreasoning§ 3 ∙ Gaetan Mayer
In physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation.
“in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
The interaction of PCSK9 with GRP94 and GRP78 might not be exclusively linked to zymogen activation and/or folding of PCSK9 during de novo synthesis.
“suggesting that the interaction of PCSK9 with those chaperones might not be exclusively linked to zymogen activation and/or folding of PCSK9 during de novo synthesis”
Quote in the paperSubstantial claim - Premisecitation§ Results and Discussion
Deletion or alanine-scan mutations in the CBD of GRP94 prevented interaction with its client proteins.
“Deletion or alanine-scan mutations in the CBD of GRP94 did not alter its overall structure or its ATPase activity but prevented interaction with its client proteins (Wu et al., 2012”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wu et al., 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data§ Results and Discussion
The CBD domain plays a major role in GRP94-PCSK9 interaction.
“reinforcing the major role of CBD for GRP94-PCSK9 interaction.”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
GRP94 directly competes with LDLR-EGF-A domain for binding to PCSK9.
“In contrast, GRP94 is highly expressed in hepatocytes and its interaction with PCSK9 involves the catalytic domain and directly competes for binding with LDLR-EGF-A domain (Figure 4I).”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
Exogenous GRP94 efficiently inhibits PCSK9-induced LDLR degradation.
“These data demonstrate that exogenous GRP94 efficiently inhibits PCSK9-induced LDLR degradation likely by blocking PCSK9 interaction and LDLR-mediated internalization and also suggest that GRP94 could block the PCSK9-LDLR interaction in the ER.”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
PCSK9-GRP94 complex formation, and more specifically its CBD-CT domain, has a direct inhibitory effect on the binding of PCSK9 to LDLR and its subsequent degradation.
“Overall, these data demonstrated that PCSK9-GRP94 complex formation, and more specifically its CDB-CT domain, has a direct inhibitory effect on the binding of PCSK9 to LDLR and its subsequent degradation.”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
GRP94 is not an essential chaperone for PCSK9 in immortalized mammalian cells.
“we conclude that GRP94 is not an essential chaperone for PCSK9 in immortalized mammalian cells”
Quote in the paperSubstantial claim - Interpretationown data§ Results and Discussion
GRP94 is not an obligatory chaperone for PCSK9 processing and secretion by hepatocytes in vivo.
“which substantiate in vivo that GRP94 is not an obligatory chaperone for PCSK9 processing and secretion by hepatocytes”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 12
- It may state two separate claims as one. 16
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ IntroductionGRP94 is a highly abundant ER-resident protein recognized primarily as a luminal molecular chaperone but also as a potent calcium- and peptide-binding protein.
“GRP94, also known as gp96, is a highly abundant ER-resident protein recognized primarily as a luminal molecular chaperone but also as a potent calcium- and peptide-binding protein”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Lee, 2014 source
The Introduction identifies GRP94 as gp96, describes GRPs as ER chaperones with calcium-binding functions, and discusses their traditional residence in the ER lumen. The Vaccination strategies section describes a GRP94–peptide complex, supporting peptide binding. Our copy does not establish that GRP94 is highly abundant or characterize its calcium- and peptide-binding as potent. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ IntroductionFolding and secretion of a very restrictive number of client proteins are solely dependent on GRP94.
“folding and secretion of a very restrictive number of client proteins were solely dependent on GRP94”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Marzec et al., 2012 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ IntroductionAnnexin A2 is an endogenous PCSK9-binding protein and extrahepatic inhibitor of PCSK9-enhanced LDLR degradation.
“annexin A2 as an endogenous PCSK9-binding protein and extrahepatic inhibitor of PCSK9-enhanced LDLR degradation”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ IntroductionPCSK9 is a sterol-regulated gene mainly expressed in liver and to a lesser extent in kidney and intestine.
“PCSK9 is a sterol-regulated gene mainly expressed in liver and to a lesser extent in kidney and intestine”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Maxwell et al., 2003 source
The passage labeled Abstract reports that mouse Pcsk9 expression was strongly downregulated by dietary cholesterol and upregulated in SREBP transgenic mice, supporting sterol regulation in liver. The paper’s liver measurements do not establish that PCSK9 is expressed mainly in liver or at lower levels in kidney and intestine; searches for tissue expression and those organs found no supporting passage. No page number is available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites Seidah et al., 2003 source
The Results report NARC-1 expression in adult rat liver and small intestine, and to a lesser extent in kidney; the Discussion also identifies liver and intestinal tissue as major expression sites. Our copy does not establish that intestinal expression is lower than liver expression, and the passages on regulation concern liver regeneration, not sterols. The tissue-expression part is supported, but the sterol-regulation and relative-intestinal-expression parts are not. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Findingcitation§ Results and DiscussionHepG2 cells secrete a small amount of endogenous GRP94 (∼5 nM).
“Although HepG2 cells secrete a small amount of endogenous GRP94 (∼5 nM; Figure 4E, lane 1; Mangrum et al., 2015”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mangrum et al., 2015 source
It may state two separate claims as one.
Findingown data§ Results and DiscussionKnockdown of GRP94 did not alter PCSK9 protein levels, autocatalytic cleavage, or furin-regulated processing.
“KD of GRP94 did not alter PCSK9 protein levels, autocatalytic cleavage, furin-regulated processing”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ Results and DiscussionGRP94 is an ER-resident PCSK9-interacting protein and inhibitor of PCSK9-LDLR complex formation.
“In the present study, we identified GRP94 as an ER-resident PCSK9-interacting protein (Figures 1A, 1G, and 1H) and inhibitor of PCSK9-LDLR complex formation (Figure 4I).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ Results and DiscussionPCSK9 and CBD-CT were completely co-localized in a diffuse structure reminiscent of the ER and in the perinuclear Golgi-like compartment, whereas PCSK9 and FL GRP94 mainly co-localized in the ER-like compartment.
“PCSK9 and CBD-CT were completely co-localized in a diffuse structure reminiscent of the ER (Figure 4F, solid arrows) and in the perinuclear Golgi-like compartment (Figure 4F, dashed arrows), whereas PCSK9 and FL GRP94 mainly co-localized in the ER-like compartment.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown data§ Results and DiscussionA slight interaction between GRP94 and GRP78 was observed.
“we observed a slight interaction between GRP94 and GRP78”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data§ Results and DiscussionMutations within the CBD domain (AA1 or AA2) abrogated binding to PCSK9, although expressed at similar levels to WT.
“Although expressed at similar levels to WT, mutations within CBD domain (AA1 or AA2) abrogated binding to PCSK9 (Figure 4B).”
Quote in the paperSubstantial claimProbably not a substantial claim.
Premisecitation§ IntroductionPatients harboring gain-of-function mutations in PCSK9 have high levels of circulating LDLc.
“patients harboring gain-of-function mutations have high levels of circulating LDLc”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Abifadel et al., 2003 source
It may state two separate claims as one.
Premisecitation§ Results and DiscussionHepatocytes regulate clearance of plasma LDLc via cell surface LDLR and are the main cell type expressing PCSK9.
“Hepatocytes regulate clearance of plasma LDLc via cell surface LDLR in addition to being the main cell type expressing PCSK9”
Quote in the paperSubstantial claim0 of 2 sources checkedIt may state two separate claims as one.
Premisecitation§ 3 ∙ Gaetan MayerSecreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels.
“Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ Results and DiscussionThe CBD and CT domains of GRP94 are sufficient for interaction with client proteins.
“resulting in a small secretable ∼20-kDa protein encoding the CBD and CT domains sufficient for interaction with client proteins (Wu et al., 2012”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wu et al., 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data§ Results and DiscussionGRP94 regulates circulating LDLc and sustains LDLR protein levels likely by preventing PCSK9-LDLR binding in the ER of hepatocytes.
“As a physiological mechanism, we propose that GRP94 regulates circulating LDLc and sustains LDLR protein levels likely by preventing PCSK9-LDLR binding in the ER of hepatocytes.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ Results and DiscussionDeletion or alanine-scan mutations in the CBD of GRP94 did not alter its overall structure or its ATPase activity.
“Deletion or alanine-scan mutations in the CBD of GRP94 did not alter its overall structure or its ATPase activity but prevented interaction with its client proteins (Wu et al., 2012”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wu et al., 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data§ Results and DiscussionThese data imply a direct involvement of PCSK9 rather than chaperoning or calcium-buffering effects of GRP94 on LDLR.
“these data imply a direct involvement of PCSK9 rather than chaperoning or calcium-buffering effects of GRP94 on LDLR”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone given§ Results and DiscussionAll data are presented as mean ± SD and are representative of at least three independent experiments analyzed in duplicate.
“All data are presented as mean ± SD and are representative of at least three independent experiments analyzed in duplicate.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ Results and DiscussionThe absence of GRP94 did not affect cell viability or the general expression of surface protein in isolated mammalian cells.
“the absence of GRP94 did not affect cell viability or the general expression of surface protein in isolated mammalian cells”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Randow and Seed, 2001 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ Results and DiscussionA 27-aa C-terminal hydrophobic loop structure within the GRP94 client-binding domain (CBD) (aa 652-678) is important for folding and interaction with Toll-like receptors and integrins.
“It was reported that a 27-aa C-terminal hydrophobic loop structure within the GRP94 client-binding domain (CBD) (aa 652–678; Figure 4A) is important for folding and interaction with Toll-like receptors and integrins (Wu et al., 2012”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wu et al., 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ Results and DiscussionAnnexin A2 is an endogenous PCSK9-CTD-binding protein and potent extrahepatic inhibitor of PCSK9-mediated LDLR degradation.
“We previously identified annexin A2 as an endogenous PCSK9-CTD-binding protein and potent extrahepatic inhibitor of PCSK9-mediated LDLR degradation (Mayer et al., 2008; Seidah et al., 2012”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mayer et al., 2008; Seidah et al., 2012
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data§ Results and DiscussionGRP94 could prevent PCSK9 binding to LDLR and thus limit its subsequent degradation.
“Therefore, GRP94 could prevent PCSK9 binding to LDLR and thus limit its subsequent degradation.”
Quote in the paperSubstantial claim
The paper relies on this without support.
It remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR.
“Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR.”
The paper relies on this without support.
No other endogenous PCSK9 inhibitor has been identified at the cell surface or within the secretory pathway of hepatocytes.
“So far, no other such endogenous PCSK9 inhibitor has been identified at the cell surface or within the secretory pathway of hepatocytes.”
The paper relies on this without support.
Hepatic LDLR remains abundant and not completely degraded by PCSK9.
“Whereas the liver is by far the richest source of PCSK9, it remains intriguing why hepatic LDLR remains abundant and not completely degraded by PCSK9.”
Citations
Cites
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
Abifadel, M., Varret, M., Rabès, J.-P., Allard, D., Ouguerram, K., Devillers, M., Cruaud, C., Benjannet, S., Wickham, L., Erlich, D., et al. (2003) · Nature Genetics · doi:10.1038/ng1161 · Cited by 2,985
Nordestgaard, B. G., Chapman, M. J., Humphries, S. E., Ginsberg, H. N., Masana, L., Descamps, O. S., Wiklund, O., Hegele, R. A., Raal, F. J., Defesche, J. C., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht273 · Cited by 2,761
Cohen, J., Pertsemlidis, A., Kotowski, I. K., Graham, R., Garcia, C. K., & Hobbs, H. H. (2005) · Nature Genetics · doi:10.1038/ng1509 · Cited by 1,381
Stebbins, C. E., Russo, A. A., Schneider, C. B., Rosen, N. X., Hartl, F. U., & Pavletich, N. P. (1997) · Cell · doi:10.1016/s0092-8674(00)80203-2 · Cited by 1,370
Seidah, N. G., Benjannet, S., Wickham, L., Marcinkiewicz, J., Jasmin, S. B., Stifani, S., Basak, A., Prat, A., & Chrétien, M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0335507100 · Cited by 1,191
ER chaperones in mammalian development and human diseases
Ni, M., & Lee, A. S. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.04.045 · Cited by 746
Self-citationMaxwell, K. N., & Breslow, J. L. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402133101 · Cited by 613
Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential
Lee, A. S. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3701 · Cited by 587
Self-citationStructural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia
Cunningham, D., Danley, D. E., Geoghegan, K. F., Griffor, M. C., Hawkins, J. L., Subashi, T. A., Varghese, A. H., Ammirati, M. J., Culp, J. S., Hoth, L. R., et al. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1235 · Cited by 409
Marzec, M., Eletto, D., & Argon, Y. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.10.013 · Cited by 390
Maxwell, K. N., Soccio, R. E., Duncan, E. M., Sehayek, E., & Breslow, J. L. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m300203-jlr200 · Cited by 329
Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability
Randow, F., & Seed, B. (2001) · Nature Cell Biology · doi:10.1038/ncb1001-891 · Cited by 316
Bu, G., Geuze, H. J., Strous, G. J., & Schwartz, A. L. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb07221.x · Cited by 274
The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A
Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., & Seidah, N. G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606495200 · Cited by 263
Poirier, S., Mayer, G., Poupon, V., McPherson, P. S., Desjardins, R., Ly, K., Asselin, M.-C., Day, R., Duclos, F. J., Witmer, M., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.037085 · Cited by 254
Self-citationMcNutt, M. C., Lagace, T. A., & Horton, J. D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c700095200 · Cited by 251
Colloidal Gold Post-Embedding Immunocytochemistry
Bendayan, M. (1995) · Progress in Histochemistry and Cytochemistry · doi:10.1016/s0079-6336(11)80027-6 · Cited by 160
Mayer, G., Poirier, S., & Seidah, N. G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805971200 · Cited by 139
Self-citationGoldstein, J. L., & Brown, M. S. (1987) · Circulation · doi:10.1161/01.cir.76.3.504 · Cited by 127
Culi, J., & Mann, R. S. (2003) · Cell · doi:10.1016/s0092-8674(02)01279-5 · Cited by 119
Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation
Seidah, N. G., Poirier, S., Denis, M., Parker, R., Miao, B., Mapelli, C., Prat, A., Wassef, H., Davignon, J., Hajjar, K. A., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041865 · Cited by 117
Self-citationAn Interaction Map of Endoplasmic Reticulum Chaperones and Foldases
Jansen, G., Määttänen, P., Denisov, A. Y., Scarffe, L. A., Schade, B., Balghi, H., Dejgaard, K., Chen, L. Y., Muller, W. J., Gehring, K., et al. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.016550 · Cited by 102
Wu, S., Hong, F., Gewirth, D. T., Guo, B., Liu, B., & Li, Z. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.309526 · Cited by 95
Mayer, G., & Poirier, S. (2013) · Drug Design Development and Therapy · doi:10.2147/dddt.s36984 · Cited by 89
Self-citationChen, W., Tseng, C.-C., Pfaffenbach, K. T., Kanel, G. C., Luo, B., Stiles, B. L., & Lee, A. S. (2013) · Hepatology · doi:10.1002/hep.26711 · Cited by 66
Self-citationGRP78/BiP is a novel downstream target of IGF‐1 receptor mediated signaling
Pfaffenbach, K. T., Pong, M., Morgan, T. E., Wang, H., Ott, K., Zhou, B., Longo, V. D., & Lee, A. S. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24090 · Cited by 50
Self-citationThe epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism
Poirier, S., Samami, S., Mamarbachi, M., Demers, A., Chang, T. Y., Vance, D. E., Hatch, G. M., & Mayer, G. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.563650 · Cited by 47
Self-citationSupino‐Rosin, L., Yoshimura, A., Yarden, Y., Elazar, Z., & Neumann, D. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001834200 · Cited by 44
Mayer, G., Boileau, G., & Bendayan, M. (2004) · Cell and Tissue Research · doi:10.1007/s00441-004-0866-x · Cited by 17
Self-citationIntact stable isotope labeled plasma proteins from the SILAC-labeled HepG2 secretome
Mangrum, J. B., Martin, E. J., Brophy, D. F., & Hawkridge, A. M. (2015) · PROTEOMICS · doi:10.1002/pmic.201400369 · Cited by 8
Chen, W.-T., Tseng, C.-C., Pfaffenbach, K., Kanel, G., Luo, B., Stiles, B. L., & Lee, A. S. (2014) · Cancer Research · doi:10.1158/1538-7445.fbcr13-b09
Self-citation
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PCSK9: From Basic Science Discoveries to Clinical Trials
Shapiro, M. D., Tavori, H., & Fazio, S. (2018) · Circulation Research · doi:10.1161/circresaha.118.311227 · Cited by 285
The Multifaceted Biology of PCSK9
Seidah, N. G., & Prat, A. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab035 · Cited by 232
PCSK9 Biology and Its Role in Atherothrombosis
Barale, C., Melchionda, E., Morotti, A., & Russo, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115880 · Cited by 180
Lrp1 is a host entry factor for Rift Valley fever virus
Ganaie, S. S., Schwarz, M. M., McMillen, C. M., Price, D. A., Feng, A., Albe, J. R., Wang, W., Miersch, S., Orvedahl, A., Cole, A. R., et al. (2021) · Cell · doi:10.1016/j.cell.2021.09.001 · Cited by 142
Inhibiting PCSK9 — biology beyond LDL control
Stoekenbroek, R. M., Lambert, G., Cariou, B., & Hovingh, G. K. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0110-5 · Cited by 141
VLDLR and ApoER2 are receptors for multiple alphaviruses
Clark, L. E., Clark, S. A., Lin, C., Liu, J., Coscia, A., Smith, K. N., Yang, P., Neel, D. V., Lee, H., Brusic, V., et al. (2021) · Nature · doi:10.1038/s41586-021-04326-0 · Cited by 135
Seidah, N. G., Abifadel, M., Prost, S., Boileau, C., & Prat, A. (2017) · Pharmacological Reviews · doi:10.1124/pr.116.012989 · Cited by 116
Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease
Glerup, S., Schulz, R., Laufs, U., & Schlüter, K. (2017) · Basic Research in Cardiology · doi:10.1007/s00395-017-0619-0 · Cited by 95
Lee, S., Kim, S.-H., Hwang, S., Cherrington, N. J., & Ryu, D. (2017) · Oncotarget · doi:10.18632/oncotarget.18812 · Cited by 95
Karagiannis, A. D., Liu, M., Toth, P. P., Zhao, S., Agrawal, D. K., Libby, P., & Chatzizisis, Y. S. (2018) · Current Atherosclerosis Reports · doi:10.1007/s11883-018-0718-x · Cited by 93
Small molecules as inhibitors of PCSK9: Current status and future challenges
Xu, S., Luo, S., Zhu, Z., & Xu, J. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.11.011 · Cited by 85
Expanding biology of PCSK9: roles in atherosclerosis and beyond
Seidah, N. G., & Garçon, D. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01057-z · Cited by 76
PCSK9 at the crossroad of cholesterol metabolism and immune function during infections
Paciullo, F., Fallarino, F., Bianconi, V., Mannarino, M. R., Sahebkar, A., & Pirro, M. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25767 · Cited by 74
de Boer, J. F., de Vries, H. D., Palmiotti, A., Li, R., Doestzada, M., Hoogerland, J. A., Fu, J., Rose, A. M. L., Westerterp, M., Mulder, N. L., et al. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.12.004 · Cited by 69
PCSK9 targets important for lipid metabolism
Schulz, R., & Schlüter, K. (2017) · Clinical Research in Cardiology Supplements · doi:10.1007/s11789-017-0085-0 · Cited by 67
Hendershot, L. M., Buck, T. M., & Brodsky, J. L. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168418 · Cited by 65
Cationic switchable lipids: pH-triggered molecular switch for siRNA delivery
Viricel, W., Poirier, S., Mbarek, A., Derbali, R. M., Mayer, G., & Chain, J. L. (2016) · Nanoscale · doi:10.1039/c6nr06701h · Cited by 56
Self-citationRecent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment
Ahamad, S., & Bhat, S. A. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01290 · Cited by 55
Lebeau, P. F., Al‐Hashimi, A., Sood, S. K., Lhoták, Š., Yu, P., Gyulay, G., Paré, G., Chen, S. R. W., Trigatti, B. L., Prat, A., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.744235 · Cited by 52
Proprotein convertase subtilisin/kexin type 9 and lipid metabolism
Spolitu, S., Dai, W., Zadroga, J. A., & Özcan, L. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000601 · Cited by 51
PCSK9 in metabolism and diseases
Ajoolabady, A., Pratico, D., Mazidi, M., Davies, I. G., Lip, G. Y. H., Seidah, N., Libby, P., Kroemer, G., & Ren, J. (2025) · Metabolism · doi:10.1016/j.metabol.2024.156064 · Cited by 49
PCSK9: from biology to clinical applications
Blanchard, V., Khantalin, I., Ramin‐Mangata, S., Chemello, K., Nativel, B., & Lambert, G. C. (2018) · Pathology · doi:10.1016/j.pathol.2018.10.012 · Cited by 47
Lebeau, P. F., Wassef, H., Byun, J. H., Platko, K., Ason, B. L., Jackson, S. M., Dobroff, J., Shetterly, S., Richards, W. G., Al‐Hashimi, A., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci128650 · Cited by 42
Lavoie, J.-M. (2016) · World Journal of Hepatology · doi:10.4254/wjh.v8.i23.961 · Cited by 39
Weider, E., Susan‐Resiga, D., Essalmani, R., Hamelin, J., Asselin, M.-C., Nimesh, S., Ashraf, Y., Wycoff, K. L., Zhang, J., Prat, A., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.717736 · Cited by 36
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Wang, W., Agellon, L. B., & Michalak, M. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a038265 · Cited by 36
Poirier, S., Hamouda, H. A., Villeneuve, L. R., Demers, A., & Mayer, G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157230 · Cited by 35
Self-citationEmma, M. R., Giannitrapani, L., Cabibi, D., Porcasi, R., Pantuso, G., Augello, G., Giglio, R. V., Re, N. L., Capitano, A., Montalto, G., et al. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2020.158792 · Cited by 34
Lebeau, P. F., Platko, K., Al‐Hashimi, A., Byun, J. H., Lhoták, Š., Holzapfel, N. T., Gyulay, G., Igdoura, S. A., Cool, D. R., Trigatti, B. L., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001049 · Cited by 33
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Rogers, M. A., Hutcheson, J. D., Okui, T., Goettsch, C., Singh, S. A., Halu, A., Schlotter, F., Higashi, H., Wang, L., Whelan, M. C., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab034 · Cited by 32
Seidah, N. G., Chrétien, M., & Mbikay, M. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000484 · Cited by 31
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Guo, S., Xia, X.-D., Gu, H.-M., & Zhang, D. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-6082-8_9 · Cited by 30
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Admin, A., Roger, C., Buch, C., Muller, T., Leemput, J., Demizieux, L., Passilly‐Degrace, P., Çınar, R., Iyer, M. R., Kunos, G., et al. (2020) · Diabetes · doi:10.2337/db20-0078 · Cited by 26
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Sánchez-Hernández, R. M., Taranto, M. D. D., Benito‐Vicente, A., Uribe, K. B., Lamíquiz-Moneo, I., Larrea, A., Jebari‐Benslaiman, S., Galicia-García, U., Nóvoa, F. J., Boronat, M., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.020 · Cited by 24
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RetractedLebeau, P. F., Platko, K., Byun, J. H., Makda, Y., & Austin, R. C. (2022) · Metabolites · doi:10.3390/metabo12030215 · Cited by 20
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Jiang, Y., Zhu, X., Jordan, K. L., Li, Y., Conley, S. M., Tang, H., Lerman, A., Eirin, A., Ou, T., & Lerman, L. O. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100610 · Cited by 18
Katsuki, S., Jha, P. K., Aïkawa, E., & Aikawa, M. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1431398 · Cited by 18
Ly, K., Essalmani, R., Desjardins, R., Seidah, N. G., & Day, R. W. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.746883 · Cited by 17
Kehinde, I. O., Akawa, O. B., Adewumi, A. T., Rabbad, A. H., & Soliman, M. E. S. (2024) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30581 · Cited by 15
Segura, É., Bourdin, B., Tétreault, M.-P., Briot, J., Allen, B. G., Mayer, G., & Parent, L. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.784355 · Cited by 14
Self-citationKey aspects of PCSK9 inhibition beyond LDL lowering
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Tcheoubi, S. E. R., Akpovi, C. D., Coppée, F., Declèves, A., Laurent, S., Agbangla, C., & Burtéa, C. (2022) · Journal of drug targeting · doi:10.1080/1061186x.2022.2092622 · Cited by 13
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Mann, M. J., Melendez-Suchi, C., Vorndran, H. E., Sukhoplyasova, M., Flory, A. R., Irvine, M. C., Iyer, A. R., Guerriero, C. J., Brodsky, J. L., Hendershot, L. M., et al. (2024) · Molecular Biology of the Cell · doi:10.1091/mbc.e24-01-0012 · Cited by 13
Safaeian, L., Vaseghi, G., Jabari, H., & Dana, N. (2019) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2018-0542 · Cited by 13
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Deng, S., Alabi, A., Gu, H.-M., Adijiang, A., Qin, S., & Zhang, D. (2019) · Journal of Lipid Research · doi:10.1194/jlr.m089193 · Cited by 12
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Mnasri, N., Mamarbachi, M., Allen, B. G., & Mayer, G. (2018) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2017.11.010 · Cited by 12
Self-citationOommen, D., Kizhakkedath, P., Jawabri, A. A., Varghese, D. S., & Ali, B. R. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.570355 · Cited by 12
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Loaiza, N., Oldoni, F., & Kuivenhoven, J. A. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000416 · Cited by 10
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Vachon, L., Smaani, A., Tessier, N., Jean, G., Demers, A., Milasan, A., Ardo, N., Jarry, S., Villeneuve, L. R., Alikashani, A., et al. (2022) · Theranostics · doi:10.7150/thno.58780 · Cited by 10
Self-citationXu, H., & Blagg, B. S. J. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117713 · Cited by 9
Varghese, D. S., Oommen, D., John, A., & Ali, B. R. (2023) · Lipids in Health and Disease · doi:10.1186/s12944-023-01835-x · Cited by 9
Wang, X., Xin, H., Zhang, C., Gu, X., & Hao, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214059 · Cited by 7
Benito‐Vicente, A., Uribe, K. B., Larrea, A., Palacios, L., Cenarro, A., Calle, X., Galicia-García, U., Jebari‐Benslaiman, S., Sánchez-Hernández, R. M., Stef, M. A., et al. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.315499 · Cited by 6
Zhang, A. M. C., Ziogos, E., Harb, T., Gerstenblith, G., & Leucker, T. M. (2024) · European Journal of Clinical Investigation · doi:10.1111/eci.14273 · Cited by 6
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Ding, S., Liu, W., Zhang, Z., Yang, X., Sun, D., Zhu, J., Zhu, X., Wang, S., Xie, M., Shi, H., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.188904 · Cited by 5
Que, N. L. S., Seidler, P. M., Aw, W. J., Chiosis, G., & Gewirth, D. T. (2024) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26756 · Cited by 5
Chandran, M., Rameshkumar, K. B., Jaleel, A., & Ayyappan, J. P. (2025) · Chemical Biology & Drug Design · doi:10.1111/cbdd.70055 · Cited by 4
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Malvandi, A. M., Canclini, L., Alliaj, A., Magni, P., Zambon, A., & Catapano, A. L. (2020) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2020.1801628 · Cited by 3
Azar, Y., Ludwig, T. E., Bon, H. L., Strøm, T. B., Bluteau, O., Filippo, M. D., Carrié, A., Chtioui, H., Béliard, S., Marmontel, O., et al. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.118596 · Cited by 2
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Gorza, L., & Vitadello, M. (2017) · Springer eBooks · doi:10.1007/978-3-319-67199-4_77 · Cited by 1
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Gorza, L., & Vitadello, M. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6438-9_77-1
Varghese, D. S., Oommen, D., John, A., & Ali, B. R. (2024) · Figshare · doi:10.6084/m9.figshare.26592611
Muzammil, K., Hooshiar, M. H., Varmazyar, S., Omar, T. M., Karim, M. M., Aadi, S., Kalavi, S., & Yasamineh, S. (2024) · Figshare · doi:10.6084/m9.figshare.26697524
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Schwarz, M. M. (2023) · D-Scholarship@Pitt (University of Pittsburgh)
Moreau, F. (2017) · theses.fr (ABES) · doi:10.70675/33f3cc01z0a95z4edeza336zb3020f9a5ac4
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Saitoski, K. (2021) · theses.fr (ABES) · doi:10.70675/58b8c006z57e2z47a2zbb66z1e469544d6a5
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Ramin‐Mangata, S. (2020) · theses.fr (ABES) · doi:10.70675/26622ba5zb0fcz4d30za6e6z5c95a0b5a33d
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Jaafar, A. K. (2023) · theses.fr (ABES) · doi:10.70675/052d27efz680bz4b84z971fz32bbbc915092
Identification et caractérisation de la fonction de MESD dans l'infection par le virus Oropouche
Fery, L. (2024) · theses.fr (ABES) · doi:10.70675/c976abc9z30d1z4366z8cf9z3ba728784a78
Dababneh, M. F., Alhasso, B., Shareef, A., Kyada, A., Malathi, H., Maharana, L., Puri, D., Gupta, H., Yarmukhamedova, N. A., Sameer, H. N., et al. (2026) · Journal of Pharmaceutical Innovation · doi:10.1007/s12247-026-10651-6
SAIMSARA (2026) · SAIMSARA Journal · doi:10.62487/saimsarac25dcb0d
Ly, K. (2016) · Knowledge UdeS (Institutional Deposit of the University of Sherbrooke)
BindingDB (2021) · UC San Diego · doi:10.7270/q2j38wzz
BindingDB (2024) · UC San Diego · doi:10.7270/q25x2f5v
Metadata
- Authors
- Poirier, S., Mamarbachi, M., Chen, W.-T., Lee, A. S., & Mayer, G.
- Affiliations
- Montreal Heart Institute (CA)
- University of Southern California (US)
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 13
- Issue
- 10
- Pages
- 2064-2071
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2174098513
- Cited by
- 86
- References
- 31
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 13 · 2023: 6 · 2022: 8 · 2021: 11 · 2020: 10 · 2019: 5 · 2018: 8 · 2017: 10 · 2016: 9
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- National Institutes of Health (CA-027607)
- Fondation Institut de Cardiologie de Montréal
- Canadian Institutes of Health Research (MOP133598)
- Fonds de Recherche du Québec - Santé
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- GRP94, PCSK9, LDL receptor, LDL cholesterol, LDL receptor degradation, endoplasmic reticulum, hepatocytes, secretory pathway, cholesterol homeostasis, protein-protein binding, LDL clearance
- MeSH terms
- Proprotein Convertase 9, Animals, Cholesterol, Chromatography, Gel, Male, Membrane Glycoproteins, Receptors, LDL, Serine Endopeptidases, Mass Spectrometry, Transfection, Blotting, Western, Mice, Knockout, Hepatocytes, Proprotein Convertases, Immunoprecipitation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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