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Cited by 16Cholesterol and Lipid MetabolismCellular transport and secretionLipid metabolism and disorders

The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index; none of the 100 sources its claims cite is checked for support yet.

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins

Open access
Vos, Dyonne Y., Wijers, Melinde, Smit, Marieke, Huijkman, Nicolette, Kloosterhuis, Niels J., Wolters, Justina C., Tissink, Joël J., Pronk, Amanda C.M., Kooijman, Sander, Rensen, Patrick C.N., Kuivenhoven, Jan Albert, van de Sluis, Bart·2023·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.122.318169
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Abstract

Background: The copper metabolism MURR1 domains/coiled-coil domain containing 22/coiled-coil domain containing 93 (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. Methods: Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. Results: Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma triglyceride levels by 26%. Conclusions: Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial triglyceride-rich lipoprotein remnants.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Hepatic VPS35L is required for CCC/retriever-linked endosomal recycling of LDLR and LRP1 and for plasma cholesterol homeostasis, while retriever subunit VPS26C selectively supports LRP1 recycling and postprandial triglyceride-rich lipoprotein clearance. VPS26C loss does not impair CCC integrity or raise plasma lipids under chow conditions, but on an LDLR-deficient background it increases plasma triglycerides and delays postprandial TG clearance.

Key findings

  • Hepatocyte VPS35L depletion reduced VPS35L by 84%, CCDC22 by 52%, CCDC93 by 48%, and VPS26C by 68%; it reduced COMMD1–VPS26C binding by 90%, impaired LDLR and LRP1 plasma membrane levels, and increased plasma cholesterol by 21%, mainly in LDL fractions with increased apoB100.
  • Hepatocyte VPS26C depletion reduced VPS26C protein by 75% without affecting CCC subunits CCDC93, COMMD1, or VPS35L; hepatic LDLR protein was almost doubled, but plasma cholesterol and TG levels were unaffected.
  • In Hepa1-6 cells, VPS26C ablation decreased total and cell-surface LRP1 and increased cell-surface LDLR; GST pulldown showed VPS26C interacted with the LRP1 intracellular domain but not the LDLR intracellular domain.
  • With LDLR blunted by AAV-PCSK9-D377Y, hepatic VPS26C deficiency increased plasma TG by 26%, mainly in chylomicron remnant/VLDL and IDL/LDL fractions, increased the apoB48/apoB100 ratio, and delayed postprandial TG clearance after an oral fat load, without affecting VLDL secretion or hepatic uptake of VLDL-like particles.

Methods

  • Male C57BL/6J littermate mice, 8–12 weeks old, with hepatocyte-specific Cas9 expression were used; Vps35l or Vps26c was targeted in hepatocytes by CRISPR/Cas9 via AAV sgRNAs, and in some experiments LDLR was blunted with AAV-PCSK9-D377Y.
  • Phenotyping included oral fat tolerance tests, VLDL-mimicking particle clearance and tissue uptake, VLDL-TG production with poloxamer 407, plasma/liver lipid measurements, FPLC, sucrose gradients, immunoblotting, qRT-PCR, targeted proteomics, immunoprecipitation, biotinylation, and GST pulldown in Hepa1-6, primary hepatocytes, and HEK293T cells.
  • Statistical analysis used GraphPad 9.1 with Shapiro-Wilk and F tests, Student/Welch t tests, Mann-Whitney U tests, Holm-Šídák correction, and repeated measures ANOVA with Geisser-Greenhouse correction and Šídák’s multiple comparison test; P<0.05 was considered significant.

Limitations

  • The paper states that only male mice were used, to compare with previous studies, and that this is a limitation; it also states that no randomization or blinding methods were used for animal studies.
  • The paper states that it cannot rule out other mechanisms explaining increased plasma TG after hepatic Vps26c ablation in an LDLR-deficient background, and that surface LRP1 levels could not be assessed in vivo, so other mechanisms for decreased TG clearance cannot be excluded.
  • The paper states that VPS29 was not investigated because it is shared by retriever and retromer, and that future studies are needed to understand cargo specificity, molecular organization, metabolic effects, and whether human VPS35L/VPS26C mutations affect plasma lipids; evident from the text, several experiments used small samples (e.g., n=4–9) and some FPLC analyses used pooled plasma.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/atvbaha.122.318169

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 100 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Hepatic ablation of VPS35L did not decrease protein levels of COMMD1 and COMMD3.

    “Hepatic ablation of VPS35L did not decrease the protein levels of COMMD1 and COMMD3 (Figure 1C and 1D), which was confirmed by targeted proteomics analysis (Figure S1A).”
    Quote in the paperSubstantial claim
  • Findingown data

    In mouse livers, VPS35L ablation reduces VPS26C protein levels by 68%.

    “reduced by 68% upon VPS35L ablation (Figure 1E).”
    Quote in the paperSubstantial claim
  • Findingnone given

    The same level of reduction in VPS26C was observed in mice lacking CCC subunit COMMD1 in their livers.

    “The same level of reduction in VPS26C was observed in mice lacking CCC subunit COMMD1 in their livers”
    Quote in the paperSubstantial claim
  • Findingown data

    Loss of hepatocytic VPS35L does not affect the cellular distribution of CCDC22 and CCDC93 despite reduced levels of these proteins.

    “Despite the reduced levels of CCDC22 and CCDC93 (Figure 1C and 1D), loss of hepatocytic VPS35L did not affect their distribution (Figure 1E).”
    Quote in the paperNot a substantial claim
  • Findingown data

    apoB100 levels are increased in the plasma of VPS35L-deficient mice.

    “which was supported by increased apoB100 levels in the plasma (Figure 2D).”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 56
  • Probably not a substantial claim. 48
  • The quote only partly states this claim. 1

  • It may state two separate claims as one.

    Findingown data

    Loss of hepatic VPS35L reduces CCC core components CCDC93 and CCDC22 by approximately 50% without a profound impact on COMMD proteins, but strongly decreases VPS26C levels.

    “Here, we found that loss of hepatic VPS35L reduces CCC core components CCDC93 and CCDC22 by only approximately 50% without a profound impact on COMMD proteins, but it strongly decreases VPS26C levels.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic VPS26C ablation in an LDLR-deficient background affects neither the hepatic uptake of [3H]TO and [14C]CO-derived activity nor the plasma decay.

    “Under these conditions, hepatic VPS26C ablation in an LDLR-deficient background affected neither the hepatic uptake of [ 3 H]TO and [ 14 C]CO-derived activity, nor the plasma decay (Figure S2B and S2C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The VLDL-like particles used are representative of endogenous VLDL particles for assessing hepatic uptake.

  • It may state two separate claims as one.

    Findingown data

    Plasma cholesterol and TG levels are not affected by Vps26c editing despite increased LDLR protein levels.

    “However, despite increased LDLR protein levels, plasma cholesterol and TG levels were not affected by Vps26c editing (Figure 4D through 4F).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS26C ablation in Hepa1-6 cells has no marked effects on the protein expression of CCC subunits, while it slightly increases the subunits of retriever and retromer.

    “Using CRISPR/ Cas9 technology, we ablated VPS26C (Figure 5A) and found that its loss had no marked effects on the protein expression of CCC subunits (Figure 5B; Figure S1B), while it slightly increased the subunits of retriever and retromer (Figure 5B; Figure S1C).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS26C ablation significantly decreases the total levels, as well as the cell surface levels, of LRP1.

    “VPS26C ablation significantly decreased the total levels, as well as the cell surface levels, of LRP1 (Figure 5C and 5D; Figure S1D)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In the absence of LDLR, loss of hepatic VPS26C does not affect plasma cholesterol levels or hepatic lipids but significantly increases plasma TG levels by 26%.

    “In the absence of LDLR, loss of hepatic VPS26C did not affect plasma cholesterol levels (Figure 6D and 6E) or hepatic lipids (Figure S2A) but significantly increased plasma TG levels by 26% (Figure 6D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS26C specifically interacts with the ICD of LRP1, but not with the ICD of LDLR.

    “Here, we observed a specific interaction between VPS26C and the ICD of LRP1, but not of LDLR (Figure 5E).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Protein levels of retromer subunits VPS35 and VPS26 were not affected by loss of VPS35L, nor was VPS29.

    “The protein levels of retromer subunits VPS35 and VPS26 were also not affected by the loss of VPS35L, nor was VPS29, a subunit of retromer and retriever 31 (Figure 1C and 1D).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Findingown data

    Hepatocyte VPS26C deletion does not affect the levels of CCC subunits CCDC93, COMMD1, and VPS35L, while CCDC22 tends to increase.

    “Although the protein level of the CCC subunit CCDC22 tend to increase upon hepatocyte VPS26C deletion, the level of the other CCC subunits CCDC93, COMMD1, and VPS35L were unaffected, as assessed by Western blot analysis (Figure 3C and 3D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In VPS26C-deficient cells, LRP1 levels are reduced both in the whole-cell lysate and at the plasma membrane, and its binding to LRP1, but not LDLR, is affected.

    “This is evident from our results in cells deficient for VPS26C, where LRP1 levels are reduced both in the whole-cell lysate and at the plasma membrane and its binding to LRP1, but not LDLR.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS35L deficiency had only a very mild impact on levels of most COMMD proteins, but COMMD10 levels were decreased by 42%.

    “Although VPS35L deficiency had only a very mild impact on the levels of most of the COMMD proteins, COMMD10 levels were decreased by 42% (Figure S1A).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS26C deletion reduces retromer subunit VPS35 by 39% but does not affect VPS26 and VPS29.

    “Retromer subunit VPS35 was significantly reduced by 39%, but the other retromer subunits, VPS26 and VPS29, were not affected by VPS26C deletion (Figure 3C and 3D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatocyte-specific expression of 3 sgRNAs targeting exon 1 of Vps26c results in efficient editing of the Vps26C locus and a 75% reduction of VPS26C protein levels.

    “Hepatocytespecific expression of 3 sgRNAs targeting exon 1 of Vps26c (Figure 3A) resulted in efficient editing of the Vps26C locus, as determined by RT-PCR analysis using primers annealing to the sequence edited by CRISPR/ Cas9 (Figure 3B); this resulted in a 75% reduction of VPS26C protein levels (Figure 3B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The sgRNAs targeting Vps26c do not have off-target effects that contribute to the observed phenotype.

  • It may state two separate claims as one.

    Findingown data

    VPS35L depletion resulted in a 52% reduction of CCDC22 and a 48% reduction of CCDC93 protein levels.

    “This resulted in a 52% and 48% reduction of the protein levels of the CCC core components CCDC22 and CCDC93, respectively (Figure 1C and 1D).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS26C ablation increases cell surface LDLR expression without affecting total LDLR levels.

    “whereas LDLR expression at the cell surface was increased without affecting total LDLR levels (Figure 5C and 5D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS35L ablation strongly reduces total LDLR and LRP1 levels, as well as their levels at the plasma membrane, in primary hepatocytes.

    “VPS35L ablation strongly reduced total LDLR and LRP1 levels, as well as levels at the plasma membrane (Figure 2A)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS35L deficiency reduces COMMD1-associated CCDC22 levels by 29% but does not affect levels of other CCC subunits associated with COMMD1.

    “We found that VPS35L deficiency reduced the levels of CCDC22 by 29% but did not affect the levels of other CCC subunits associated with COMMD1 (Figure 1H).”
    • Also stated in: § DISCUSSION · boosted
      “We also demonstrated that the composition of the CCC complex is minimally affected upon VPS35L ablation; only the association of CCDC22 with the CCC complex was reduced by 29%, while the other CCC core subunits were unaffected.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    sgRNAs targeting Vps26c strongly downregulate VPS26C protein levels, and hepatic expression of PCSK9-D377Y blunts hepatic LDLR expression.

    “Again, expressing the sgRNAs targeting Vps26c strongly downregulated VPS26C protein levels (Figure 6A), and hepatic expression of PCSK9-D377Y blunted hepatic LDLR expression (Figure 6B and 6C).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: AAV-mediated expression of PCSK9-D377Y blunts hepatic LDLR expression without other effects that could explain the phenotype.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    In several studies, only small changes for some subunits of retriever, retromer, and the CCC complex were observed in livers of NAFLD/NASH patients.

    “In several studies, only small changes for some of the subunits were observed (Figure S3)”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingcitation

    Hepatic VPS26C deficiency results only in an increase in plasma TG levels, with an effect size comparable to LDLR-deficient mice carrying a mutation in the distal NPxY motif of LRP1.

    “In contrast, hepatic VPS26C deficiency results only in an increase in plasma TG levels, with an effect size comparable to LDLR-deficient mice carrying a mutation in the distal NPxY motif of LRP1.56”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    Hepatic uptake of triglyceride-rich lipoproteins and their remnants highly depends on the LDL receptor (LDLR) and LRP1, both members of the LDLR family.

    “Hepatic uptake of these types of TRLs and remnants highly depends on the LDL receptor (LDLR) and LRP1 (LDLR-related protein 1), both members of the LDLR family.5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5]

      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.

    Premisecitation

    Genetic studies have identified a single nucleotide polymorphism in the LRP1 locus associated with triglyceride levels.

    “In addition, genetic studies have identified a single nucleotide polymorphism in the LRP1 locus associated with triglyceride (TG) levels.12,13”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    A recent study identified retriever as a novel protein complex composed of VPS26C, VPS35L, and VPS29.

    “Interestingly, a recent study identified a novel protein complex called retriever, which is composed of VPS26C, VPS35L, and VPS29 (Figure 1A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      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.

    Premisecitation

    The association of the CCDC93 variant with reduced LDL cholesterol and lower cardiovascular risk is explained by enhanced functioning of the CCC complex, resulting in improved LDLR recycling.

    “This was explained by enhanced functioning of the CCC complex, resulting in improved LDLR recycling.27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27]

      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

    A common genetic variant in CCC subunit CCDC93 is associated with reduced LDL cholesterol levels and lower risk of myocardial infarction and cardiovascular mortality.

    “Furthermore, a common genetic variant in CCC subunit CCDC93 is associated with reduced LDL cholesterol levels, and lower risk of myocardial infarction and cardiovascular mortality.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27]

      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.

    Premisecitation

    Several studies have demonstrated a role for hepatic LRP1 in hepatic uptake of chylomicron remnants.

    “Although the contribution of hepatic LRP1 to plasma lipid clearance is less clear, several studies have demonstrated a role in the hepatic uptake of chylomicron remnants.[8][9][10][11]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10]

      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

    Retriever shows structural similarities with retromer and both contain a VPS29 subunit.

    “It shows structural similarities with retromer and they both contain a VPS29 subunit.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Retriever likely facilitates receptor recycling through coupling of VPS26C to SNX17, whereas retromer recognizes receptors via SNX27.

    “Retriever likely facilitates receptor recycling through coupling of VPS26C to the adaptor protein sorting nexin (SNX) 17, whereas retromer recognizes receptors via the adaptor protein SNX27.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      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

    LDLR mediates clearance of LDL particles through binding to apoB, and of TRL remnants such as chylomicron remnants and VLDL remnants through binding of apoE.

    “LDLR mediates the clearance of LDL particles through binding to apoB (apolipoprotein B), and of TRL remnants, such as chylomicron remnants and VLDL (very-low-density lipoprotein) remnants through binding of apoE (apolipoprotein E). 6,7”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The endosomal sorting system plays a crucial role in the functioning of LDLR and LRP1 and in hepatic uptake of lipoproteins.

    “but in recent years, it has become clear that the endosomal sorting system also plays a crucial role in their functioning and, consequently, in the hepatic uptake of lipoproteins (reviewed by Wijers et al, 20 Van De Sluis et al, 21”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Wijers et al, 20

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Van De Sluis et al, 21

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Vos et al 22

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    Previous in vitro studies have demonstrated that SNX17 mediates endosomal sorting of cargos containing a NPxY/NxxY-motif in their cytoplasmic domain, including LDLR and LRP1.

    “Previous in vitro studies have demonstrated that SNX17 mediates endosomal sorting of cargos containing a NPxY/NxxY-motif in their cytoplasmic domain, including LDLR and LRP1.5,[32][33][34][35][36]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [33]

      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.

    Premisecitation

    Localization of WASH and CCC complexes to endosomes partially depends on the trimeric protein complex retromer.

    “In vitro studies have shown that the localization of the WASH and CCC complexes to endosomes partially depends on the trimeric protein complex retromer (vacuolar protein sorting [VPS] 35, VPS26, VPS29), a key regulator of endosomal cargo”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    Retriever physically associates with CCC and WASH complexes at endosomes to form a retromer-independent endosomal sorting pathway.

    “Retriever physically associates with CCC and WASH complexes at endosomes to form a retromer-independent endosomal sorting pathway.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    Upregulation of LDLR is explained as a mechanism to compensate for the loss of LRP1 function.

    “In these studies, the upregulation of LDLR was explained as a mechanism to compensate for the loss of LRP1 function.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8]

      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

    VPS35L is shared by retriever and CCC complex and is required for plasma cholesterol homeostasis by facilitating the transport of LDLR and LRP1 to the plasma membrane of hepatocytes.

    “VPS35L is shared by retriever and CCC complex and is required for plasma cholesterol homeostasis by facilitating the transport of LDLR (low-density lipoprotein receptor) and LRP1 (LDLR-related protein 1) to the plasma membrane of hepatocytes.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    CCC complex formation does not completely rely on VPS35L but needs VPS35L for its function to transport LDLR and LRP1 from the endosome to the cell surface.

    “We demonstrate that CCC complex formation does not completely rely on VPS35L but needs VPS35L for its function to transport LDLR and LRP1 from the endosome to the cell surface”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductcitation

    To minimize inaccuracies from pooling samples for FPLC, no selection criteria were used to select specific samples, and equal volumes of all individual samples were pooled for each experimental group.

    “To minimize inaccuracies as a consequence of pooling samples for FPLC as described in the AHA statement, 44 no selection criteria were used to select specific samples, thus we have pooled equal volumes of all individual samples for each experimental group of mice”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites AHA statement, 44

      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

    CCC promotes surface expression of both LRP1 and LDLR.

    “Whereas CCC promotes surface expression of both LRP1 and LDLR, 24,25”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      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.

    Premisecitation

    Systems biology studies have suggested that CCC and retriever likely form a large evolutionary conserved multiprotein complex, named COMMander.

    “In line with this, systems biology studies have suggested that CCC and retriever likely form a large evolutionary conserved multiprotein complex, named COMMander.39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39]

      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

    VPS35L participates in CCC complex formation and does not form a distinct protein complex.

    “suggesting that VPS35L participates in CCC complex formation, and does not form a distinct protein complex.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    VPS35L is not a core subunit of the CCC complex, but is a shared component of CCC and retriever.

    “Our data therefore favor the model that VPS35L is not a core subunit of the CCC complex, but is a shared component of CCC and retriever.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The differential effect on TRL remnants versus VLDL-like particles may be explained by the different composition of these particles, such as the absence of apoB.

    “which may be explained by the different composition of these particles, such as the absence of apoB.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    VPS29 is a subunit of retriever and retromer.

    “Since VPS29 is a subunit of retriever and retromer, 31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    LDLR can compensate for the loss of LRP1 in the liver.

    “As mentioned previously, LDLR can compensate for the loss of LRP1 in the liver.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8]

      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

    VPS35L is needed for the physical association between retriever and the CCC complex without having a strong adverse effect on CCC complex composition.

    “these data indicate that VPS35L is needed for the physical association between retriever and the CCC complex without having a strong adverse effect on CCC complex composition.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Hepatocytes in vivo are polarized and contain an apical and basolateral surface with distinct sorting pathways.

    “Hepatocytes in vivo are polarized and contain an apical and basolateral surface with distinct sorting pathways 52”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52]

      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.

    Study design and conductnone given

    To correct for multiple testing, the Holm-Šídák multiple comparison test was performed in several cases.

    “To correct for multiple testing, the Holm-Šídák multiple comparison test was in several cases also performed, as indicated in the figure legends (Figures 1D and 3D; Figure S1A).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    CCC deficiency reduces levels of both LDLR and LRP1 in the whole-cell lysate and plasma membrane of MEFs and primary hepatocytes, but not in total liver lysates.

    “However, this observation is in line with our previous studies, where we observed that CCC deficiency reduces levels of both LDLR and LRP1 in the whole-cell lysate and plasma membrane of MEFs and primary hepatocytes, but not in total liver lysates.24,25”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      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.

    Study design and conductnone given

    Data were checked for normality by Shapiro-Wilk test and for equal variance by the F test.

    “Data were checked for normality by Shapiro-Wilk test and for equal variance by the F test.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    Multiple comparison testing was performed in some cases after a parametric t test because the non-parametric test has a minimum P of 0.0286 when n=4/group.

    “Since a property of the non-parametric test is that P=0.0286 is the minimum P possible when n=4/group, multiple comparison testing was in some cases also performed after a parametric t test (Figure 1D; Figure S1A).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Retriever subunit VPS26C has a specific role in transport of lipoprotein receptors, as it regulates LRP1 functioning, but not LDLR, to facilitate hepatic uptake of postprandial TRL remnants.

    “Conversely, retriever subunit VPS26C has a specific role in transport of lipoprotein receptors, as it regulates LRP1 functioning, but not LDLR, to facilitate hepatic uptake of postprandial TRL remnants.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    No randomization or blinding methods were used for the animal studies.

    “Sample size of each experiment is described in the figure legends, no randomization or blinding methods were used for the animal studies.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Hepatic loss of VPS35L slightly affects CCC complex formation without having an impact on retromer, but strongly reduces the protein level of retriever component VPS26C and the association between VPS29 and CCC.

    “Overall, these findings show that hepatic loss of VPS35L slightly affects CCC complex formation without having an impact on retromer, but strongly reduces the protein level of retriever component VPS26C and the association between of VPS29 and CCC”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    VPS26C deficiency does not adversely affect the integrity of the CCC complex and retromer, nor the protein levels of VPS35L.

    “These data suggest that VPS26C deficiency neither adversely affects the integrity of the CCC complex and retromer, nor the protein levels of VPS35L.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    The decreased LRP1 surface levels can probably be explained by reduced endosomal receptor recycling, resulting in impaired retrieval of the receptor from lysosomal degradation.

    “The decreased LRP1 surface levels can probably be explained by reduced endosomal receptor recycling, resulting in impaired retrieval of the receptor from lysosomal degradation.24,25”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      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

    Hepatic deletion of VPS26C specifically delays the uptake of postprandial TRL remnants, rather than VLDL-like particles.

    “These results suggest that hepatic deletion of VPS26C specifically delays the uptake of postprandial TRL remnants, rather than VLDL-like particles”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductreasoning

    Only male mice were used, which is a limitation of the current study.

    “Only male mice were used to compare our results with previous studies in which we investigated the role of the endosomal sorting machinery in cholesterol homeostasis [24][25][26] ; using only male mice is a limitation of the current study.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [26]

      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.

    Interpretationreasoning

    Taken together, contradictory findings show that neither the molecular organization nor the physiological role of retriever in endosomal sorting are as yet fully understood.

    “Taken together, these contradictory findings show that neither the molecular organization nor the physiological role of retriever in endosomal sorting are as yet fully understood.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: There is no evidence whether retriever is required for the endosomal transport of hepatocytic LDLR and LRP1.
    • Rests on an assumption: There is no consensus whether VPS35L is a shared subunit between the 2 complexes or participates in only one of the 2 complexes.

  • It may state two separate claims as one.

    Interpretationown data

    Retriever subunit VPS26C selectively controls the recycling of LRP1, but not LDLR, and regulates clearance of postprandial remnant lipoproteins.

    “Retriever subunit VPS26C selectively controls the recycling of LRP1, but not low-density lipoprotein receptor, and regulates clearance of postprandial remnant lipoproteins.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    It has recently been reported that VPS35L is a subunit shared by the CCC complex and retriever.

    “It has recently been reported that VPS35L is a subunit shared by the CCC complex and retriever 37 (Figure 1A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37]

      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.

    Premisecitation

    VPS35L was recognized as forming the CCC complex, together with CCDC22, CCDC93, and the 10 COMMD proteins.

    “Initially, VPS35L was recognized as forming the CCC complex, together with CCDC22, CCDC93, and the 10 COMMD proteins.28”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28]

      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

    VPS26C is required for the transport of LRP1, but not LDLR, from the endosome to the plasma membrane.

    “Taken together, these findings suggest that VPS26C is required for the transport of LRP1-but not LDLR-from the endosome to the plasma membrane.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductcitation

    The role of VPS29 was not investigated because loss of VPS29 would negatively affect both retriever and retromer.

    “The role of VPS29 was not investigated in the current study, since this subunit is a subunit of retriever and retromer, and loss of VPS29 would therefore negatively affect retriever as well retromer.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      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

    Hepatic ablation of VPS35L impairs the endosomal transport of LDLR and LRP1 and mimics the hypercholesterolemic phenotype of hepatocyte-specific CCC-deficient mice.

    “These data show that hepatic ablation of VPS35L impairs the endosomal transport of LDLR and LRP1 and mimics the hypercholesterolemic phenotype of hepatocyte-specific CCC-deficient mice, 24,25”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      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

    VPS26C is required for hepatic uptake of postprandial TRL by promoting surface expression of LRP1 but not LDLR.

    “our data show that retriever subunit VPS26C is required for hepatic uptake of postprandial TRL, by promoting surface expression of LRP1 but not LDLR”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    Previous studies have shown that the integrity of the CCC complex is dependent on all its core subunits.

    “As previous studies have shown that the integrity of the CCC complex is dependent on all its core subunits, 25,28 we examined”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28]

      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

    VPS26C specifically facilitates the surface levels of LRP1, but not LDLR.

    “VPS26C specifically facilitates the surface levels of LRP1, but not LDLR.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Retriever has recently been identified as a trimeric protein complex consisting of VPS26C, VPS29, and VPS35L, which is physically associated with the CCC complex.

    “Retriever has recently been identified as a trimeric protein complex consisting of VPS26C, VPS29, and VPS35L (Figure 1A), which is physically associated with the CCC complex.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31]

      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.

    Interpretationnone given

    It cannot be ruled out that other mechanisms explain the increased plasma TG levels upon hepatic ablation of Vps26c in an LDLR-deficient background.

    “However, we cannot rule out other mechanisms explaining the increased plasma TG levels upon hepatic ablation of Vps26c in a LDLR-deficient background.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.

    Premisecitation

    Endosomal recycling of LDLR and LRP1 is orchestrated by a direct interaction between VPS26C and the adaptor protein SNX17.

    “Interestingly, it has been postulated that endosomal recycling of LDLR and LRP1 is orchestrated by a direct interaction between VPS26C and the adaptor protein SNX17.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31]

      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.

    Premisecitation

    Hepatic LPL plays an important role in TG clearance.

    “For example, it has been shown that hepatic LPL (lipoprotein lipase) plays also an important role in TG clearance.53,54”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [54]

      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

    Loss of hepatic PID1 increases LDLR levels, and hepatic PID1 inactivation in LDLR knockout mice results in decreased postprandial TRL clearance, with subsequent plasma TG accumulation.

    “Loss of hepatic PID1 increases LDLR levels, and hepatic PID1 inactivation in LDLR knockout mice results in decreased postprandial TRL clearance, with subsequent plasma TG accumulation.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11]

      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

    VPS26C specifically facilitates the transport of LRP1, but not LDLR, from the endosomes to the plasma membrane, and hereby controls postprandial TG levels in plasma.

    “VPS26C specifically facilitates the transport of LRP1, but not of LDLR, from the endosomes to the plasma membrane, and hereby controls postprandial TG levels in plasma.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    VPS26C does not act together with SNX17 to facilitate endosomal recycling of both members of the LDLR family, but likely only of LRP1.

    “our data may implicate that VPS26C does not act together with SNX17 to facilitate endosomal recycling of both members of the LDLR family, but likely only of LRP1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Hepatic LPL deficiency increases plasma TG due to a decrease in postprandial TG clearance.

    “Hepatic LPL deficiency increases plasma TG due to a decrease in postprandial TG clearance.55”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Mice carrying a mutation in the distal NPxY motif of LRP1 show hepatic upregulation of LDLR, and on an LDLR-deficient background these LRP1 mutant mice show elevated plasma TG levels due to delayed postprandial TRL clearance.

    “Like hepatic VPS26C-deficient mice, mice carrying a mutation in the distal NPxY motif of LRP1 show hepatic upregulation of LDLR, and on an LDLRdeficient background these LRP1 mutant mice show elevated plasma TG levels due to delayed postprandial TRL clearance.56”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    The distal NPxY motif of LRP1 is essential for postprandial TRL clearance.

    “The distal NPxY motif of LRP1 is essential for postprandial TRL clearance.56”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    LRP1 contains a proximal NPTY motif recognized by SNX17, as well as a distal NPVY motif; LDLR has only one NPVY motif, which can also be recognized by SNX17.

    “LRP1 contains a proximal NPTY motif, which is recognized by SNX17, as well as a distal NPVY motif; LDLR has only one NPVY motif, which can also be recognized by SNX17.32,[34][35][36]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 32,[34][35][36]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    The translocation of LRP1 is likely mediated by insulin, as insulin can phosphorylate the tyrosine residue within the distal NPxY motif, resulting in dissociation of LRP1-adaptor protein PID1.

    “This translocation is likely mediated by insulin, as insulin can phosphorylate the tyrosine residue within the distal NPxY motif, resulting in dissociation of LRP1-adaptor protein PID1.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationnone given

    VPS35L participates in retriever and the CCC complex, while VPS26C is only a component of retriever.

    “VPS35L participates in retriever and the CCC complex, while VPS26C is only a component of retriever.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.

    Study design and conductown data

    The immunoblot data in Figure 5C and 5E represent 2 independent experiments.

    “Data represent 2 independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Mutations in CCDC22 and WASHC5 cause hypercholesterolemia.

    “We previously demonstrated that mutations in CCDC22 and WASHC5 cause hypercholesterolemia, [24][25][26]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [26]

      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.

    Premisecitation

    Pathogenic variants in VPS35L have been reported in patients with a 3C/Ritscher-Schinzel (RSS)-like syndrome.

    “Recently, Kato et al 58 reported pathogenic variants in VPS35L in patients with a 3C/Ritscher-Schinzel (RSS)-like syndrome.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58]

      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.

    Interpretationreasoning

    It cannot be ruled out that the decreased TG clearance can be explained by other mechanisms.

    “we can therefore not rule out that the decreased TG clearance can be explained by other mechanisms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    PID1 sequesters LRP1 in endosomes under fasting conditions.

    “PID1 sequesters LRP1 in endosomes under fasting conditions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11]

      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

    Mutations in WASHC4 and WASHC5 have been identified in patients with non-syndromic autosomal recessive intellectual disability and 3C/RSS, respectively, and mutations in CCDC22 cause X-linked recessive intellectual disability with clinical features of 3C/RSS.

    “For example, mutations in WASHC4 and WASHC5 have been identified in patients with non-syndromic autosomal recessive intellectual disability 60 and 3C/RSS, 61 respectively, and mutations in CCDC22 cause X-linked recessive intellectual disability (XLID) with clinical features of 3C/RSS.62”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [60]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [61]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [62]

      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.

    Premisecitation

    LRP1 translocates in a postprandial state from the endosomes to the cell surface.

    “It has been demonstrated that LRP1 translocates in a postprandial state from the endosomes to the cell surface.57”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57]

      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.

    Premisecitation

    A homozygous nonsense variant in VPS26C has been described in individuals with a pleiotropic syndrome characterized by neurodevelopmental defects, growth failure, skeletal anomalies, and distinctive facial features.

    “Furthermore, a homozygous nonsense variant in VPS26C was described in individuals with a pleiotropic syndrome characterized by neurodevelopmental defects, growth failure, skeletal anomalies, and distinctive facial features.59”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    Hepatic loss of LPL results in elevated plasma cholesterol levels.

    “However, hepatic loss of LPL also results in elevated plasma cholesterol levels, 55”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    SNX17 regulates endosomal recycling by binding with its FERM-domain to NPxY motifs in intracellular domains of various proteins, including LDLR family members LDLR and LRP1.

    “SNX17 regulates endosomal recycling by binding with its FERM-domain to NPxY motifs in intracellular domains of various proteins, including LDLR family members LDLR and LRP1.[32][33][34][35][36]”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [34]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [35]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [36]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Hepatic CCC knockout on an LDLR-deficient background displays a marked increase in both plasma cholesterol and TG levels, similar to the phenotype of hepatic LRP1-deficient mice on an LDLR knockout background.

    “The latter model displays a marked increase in both plasma cholesterol and TG levels, 25 which is similar to the phenotype of hepatic LRP1-deficient mice on an LDLR knockout background, 8”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

91 of 91

  • The paper relies on this without support.

    There is no evidence whether retriever is required for the endosomal transport of hepatocytic LDLR and LRP1.

    “However, to date, there is no evidence whether retriever is required for the endosomal transport of hepatocytic LDLR and LRP1.”

  • The paper relies on this without support.

    There is no consensus whether VPS35L is a shared subunit between the 2 complexes or participates in only one of the 2 complexes.

    “To date, there is no consensus whether VPS35L is a shared subunit between the 2 complexes or participates in only one of the 2 complexes.”

  • The paper relies on this without support.

    The sgRNAs targeting Vps26c do not have off-target effects that contribute to the observed phenotype.

    “Hepatocytespecific expression of 3 sgRNAs targeting exon 1 of Vps26c (Figure 3A) resulted in efficient editing of the Vps26C locus, as determined by RT-PCR analysis using primers annealing to the sequence edited by CRISPR/ Cas9 (Figure 3B); this resulted in a 75% reduction of VPS26C protein levels (Figure 3B).”

  • The paper relies on this without support.

    AAV-mediated expression of PCSK9-D377Y blunts hepatic LDLR expression without other effects that could explain the phenotype.

    “hepatic expression of PCSK9-D377Y blunted hepatic LDLR expression (Figure 6B and 6C).”

  • The paper relies on this without support.

    The apoB48/apoB100 ratio is a valid marker for remnant lipoproteins.

    “the apoB48/apoB100 ratio, a marker for remnant lipoproteins, in plasma of hepatic VPS26C-deficient mice with blunted LDLR levels was increased compared with control mice (Inset Figure 6F).”

  • The paper relies on this without support.

    The VLDL-like particles used are representative of endogenous VLDL particles for assessing hepatic uptake.

    “we also assessed the hepatic uptake of VLDLlike particles.42”

  • The paper relies on this without support.

    The retriever protein complex consists of VPS26C, VPS35L, and VPS29.

    “The retriever protein complex, consisting of VPS26C, VPS35L, and VPS29, was recently described as a novel endosomal sorting complex in the CCC-WASH axis to promote recycling of receptors back to the cell surface.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mutations in WASHC5, CCDC22 and VPS35L all result in hypercholesterolemia in humans, thought to be due to abnormal LDL clearance secondary to defects in LDL receptor recycling.

    “It is worth noting that mutations in WASHC5, CCDC22 and VPS35L all result in hypercholesterolemia in humans thought to be due to abnormal LDL clearance secondary to defects in LDL receptor recycling, a phenotype also seen in mouse models of liver deficiency of Ccdc22, Vps35l and Commd1 [5, 7, 30–32].”

    From CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome (2025) · cites this paper as [32]

    The Discussion says mutations in CCDC22 and WASHC5 cause hypercholesterolemia, but explicitly says whether VPS35L mutations are associated with increased plasma lipid levels remains to be evaluated. The section on hepatic VPS35L loss links impaired LDL receptor recycling and increased cholesterol to mice, not to humans with VPS35L mutations. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Sucrose-gradient result points to the wrong figure panel

    Minor

    The text cites Figure 1E for the distribution of CCC subunits after sucrose-gradient fractionation, but the figure description assigns the fractionation experiment to Figure 1G. Figure 1E instead reports VPS26C protein levels.

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. 10.1161/atvbaha.113.301637.hepatic · DOI
  2. RStudio Team. RStudio: Integrated Development for R. RStudio, PBC, Boston, MA; 2020. http://www.rstudio.com/

Cited by

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Related

Metadata

Authors
Vos, D. Y., Wijers, M., Smit, M., Huijkman, N., Kloosterhuis, N. J., Wolters, J. C., Tissink, J. J., Pronk, A. C. M., Kooijman, S., Rensen, P. C. N., Kuivenhoven, J. A., & van de Sluis, B.
Affiliations
  • University Medical Center Groningen (NL)
  • University Hospital Heidelberg (DE)
  • Leiden University Medical Center (NL)
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-01
Volume
43
Issue
1
Pages
e29-e45
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.122.318169
OpenAlex
W4308679124
Cited by
16
References
62
Citations by year
2026: 4 · 2025: 7 · 2024: 3 · 2023: 2
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Site cant be reached (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
  • Stichting De Cock-Hadders
  • European Commission (953489)
  • H2020 Marie Skłodowska-Curie Actions (953489)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
VPS29, LDL receptor, LRP1, endosomal transport, hepatic lipoprotein metabolism, serum cholesterol, PCSK9, liver-specific knockout mice
MeSH terms
Proprotein Convertase 9, Animals, Humans, Lipoproteins, Receptors, LDL, Triglycerides, Mice, Knockout, Hepatocytes, Low Density Lipoprotein Receptor-Related Protein-1, Vesicular Transport Proteins, 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 2026-11-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

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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