CoChat
Sign Up
Cited by 127Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

The DOI matches its Crossref record; 40 of the 41 references it cites were found in a registry or an index; none of the 43 sources its claims cite is checked for support yet.

The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking

Open access
Fedoseienko, Alina, Wijers, Melinde, Wolters, Justina C., Dekker, Daphne, Smit, Marieke, Huijkman, Nicolette, Kloosterhuis, Niels, Klug, Helene, Schepers, Aloys, Willems van Dijk, Ko, Levels, Johannes H.M., Billadeau, Daniel D., Hofker, Marten H., van Deursen, Jan, Westerterp, Marit, Burstein, Ezra, Kuivenhoven, Jan Albert, van de Sluis, Bart·2018·Circulation Research
DOI 10.1161/circresaha.117.312004
Open this paper in CoChat — free accountOpen PDF

Abstract

Rationale: COMMD (copper metabolism MURR1 domain)-containing proteins are a part of the CCC (COMMD–CCDC22 [coiled-coil domain containing 22]–CCDC93 [coiled-coil domain containing 93]) complex facilitating endosomal trafficking of cell surface receptors. Hepatic COMMD1 inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the LDLR (low-density lipoprotein receptor), and increases plasma low-density lipoprotein cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1 and whether perturbation in the CCC complex promotes atherogenesis remain unclear. Objective: The main aim of this study is to unravel the contribution of evolutionarily conserved COMMD proteins to plasma lipoprotein levels and atherogenesis. Methods and Results: Using liver-specific Commd1 , Commd6 , or Commd9 knockout mice, we investigated the relation between the COMMD proteins in the regulation of plasma cholesterol levels. Combining biochemical and quantitative targeted proteomic approaches, we found that hepatic COMMD1, COMMD6, or COMMD9 deficiency resulted in massive reduction in the protein levels of all 10 COMMDs. This decrease in COMMD protein levels coincided with destabilizing of the core (CCDC22, CCDC93, and chromosome 16 open reading frame 62 [C16orf62]) of the CCC complex, reduced cell surface levels of LDLR and LRP1 (LDLR-related protein 1), followed by increased plasma low-density lipoprotein cholesterol levels. To assess the direct contribution of the CCC core in the regulation of plasma cholesterol levels, Ccdc22 was deleted in mouse livers via CRISPR/Cas9-mediated somatic gene editing. CCDC22 deficiency also destabilized the complete CCC complex and resulted in elevated plasma low-density lipoprotein cholesterol levels. Finally, we found that hepatic disruption of the CCC complex exacerbates dyslipidemia and atherosclerosis in ApoE3*Leiden mice. Conclusions: Collectively, these findings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR trafficking. Hepatic disruption of either of these CCC components causes hypercholesterolemia and exacerbates atherosclerosis. Our results indicate that not only COMMD1 but all other COMMDs and CCC components may be potential targets for modulating plasma lipid levels in humans.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

The COMMD family stabilizes the CCC complex in hepatocytes, and loss of Commd1, Commd6, Commd9, or Ccdc22 reduces cell-surface LDLR/LRP1 and raises plasma LDL cholesterol. In ApoE3*Leiden mice, hepatic CCC inactivation exacerbates hyperlipidemia and accelerates aortic-root atherosclerosis.

Key findings

  • Hepatic Commd6 knockout increased plasma total cholesterol by ≈37% on chow (P<0.01) and ≈40% on high-fat high-cholesterol diet (P<0.001), with increased LDL cholesterol and ApoB100; hepatic Commd9 ablation similarly increased plasma total cholesterol and ApoB100 (P<0.001).
  • COMMD6 colocalized with WASH1, FAM21, COMMD1, and VPS35; COMMD6 deficiency reduced total and plasma-membrane LDLR and LRP1 in primary hepatocytes.
  • COMMD6 silencing reduced COMMD1 protein without affecting COMMD1 mRNA; MG132 partially restored COMMD1. Hepatic Commd1 or Commd6 deletion reduced all COMMD proteins and CCC core subunits by ≈70% (P<0.05), increased WASH1 by ≈50% (P<0.05), while retromer, LDLR, and LRP1 were unaffected; Commd9 loss reduced CCC core similarly but COMMD1/2/3/6/8 only by 40%–50%.
  • Liver CRISPR/Cas9 Ccdc22 editing reduced CCDC22 by ≈70%, lowered CCDC93/C16orf62/COMMD1, and raised plasma total cholesterol by ≈35% (P<0.01) via LDL cholesterol and ApoB100. In ApoE3*L;Commd1ΔHep mice fed HFC for 12 weeks, plasma total cholesterol and triglyceride rose ≈100% (P<0.001) and aortic-root lesion area was ≈50% larger (P<0.01); no aortic arch lesions were observed.

Methods

  • Mouse models included liver-specific Commd1, Commd6, and Commd9 knockouts; adenoviral CRISPR/Cas9 Ccdc22 editing; ApoE3*Leiden mice; AAV-PCSK9-D377Y; and WT/Cas9 controls. Cell work used HEK293T, HepG2, Huh7, RAW264.7, and primary hepatocytes.
  • Assays included plasma/liver cholesterol and triglyceride measurements, FPLC lipoprotein fractionation, Western blot, qRT-PCR, immunoprecipitation, sucrose gradients, targeted proteomics (QconCAT LC-MS), and atherosclerosis lesion histology/en face Oil Red O.
  • Statistics used Student t test with P<0.05 considered significant; in vitro data were from 3 independent experiments, and mouse data show averages ± SEM with n=7–12 (some analyses n=4–11).

Limitations

  • Stated in the paper: whether human genetic variants in COMMDs, CCDC93, and C16orf62 are associated with plasma lipid levels and cardiovascular events needs validation; the stoichiometry of heterogeneous CCC complexes and the relation between PCSK9-mediated LDLR degradation and CCC-dependent recycling require further study; a possible role for the CCC complex in SR-B1-mediated HDL cholesteryl ester uptake warrants further studies.
  • Evident from the text: the findings rely on mouse liver-specific models and cultured cells rather than human cohorts, and some cited heterozygous-loss data are unpublished (B. van de Sluis, unpublished data, 2017).

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

Integrity signals

Registry

Crossref · 10.1161/circresaha.117.312004

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 43 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The integrity of the CCC complex is not exclusively controlled by COMMD1 but by numerous members of the COMMD family.

    “We found that the integrity of the CCC complex is not exclusively controlled by COMMD1 but by numerous members of the COMMD family.”
    Quote in the paperSubstantial claim
  • Findingown data

    Plasma levels of ApoB100 were significantly elevated (P<0.01) in Commd6ΔHep mice, both on chow and HFC diet feeding.

    “the plasma levels of ApoB100 were significantly elevated (P<0.01) in Commd6Δ Hep mice, both on chow and HFC diet feeding”
    Quote in the paperSubstantial claim
  • Findingreasoning

    The specific decrease in the CCC core components in all 3 models of hepatic COMMD deficiency coincides with elevated plasma cholesterol levels.

    “This specific decrease in the CCC core components in all 3 models of hepatic COMMD deficiency coincides with elevated plasma cholesterol levels.”
    Quote in the paperSubstantial claim
  • Findingown data

    Ablation of COMMD6 impaired the total and plasma membrane expression of LRP1.

    “Similar effect on the total and plasma membrane expression of LRP1 was seen”
    Quote in the paperNot a substantial claim
  • Findingown data

    The stability of the COMMDs in hepatocytes relies on the CCC core component CCDC22.

    “we showed that the stability of the COMMDs in hepatocytes relies on the CCC core component CCDC22”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 34
  • The quote only partly states this claim. 1
  • Probably not a substantial claim. 10

  • It may state two separate claims as one.

    Findingown data

    Plasma triglyceride, hepatic cholesterol, and triglyceride concentrations were unaltered by hepatic Commd6 ablation.

    “Plasma triglyceride, hepatic cholesterol, and triglyceride concentrations were unaltered by hepatic Commd6 ablation”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Depletion of Commd6 in mouse hepatocytes blunted COMMD1 protein levels, accompanied by reduced protein levels of the CCC core components CCDC22 and CCDC93.

    “depletion of Commd6 in mouse hepatocytes blunted COMMD1 protein levels, accompanied by reduced protein levels of the CCC core components CCDC22 and CCDC93”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In WT livers, COMMD1 and COMMD3 had a similar distribution and partially cosedimented with vesicles containing the CCC and WASH complexes; a percentage of COMMD1 and COMMD3 were present in the same fractions as LDLR.

    “In WT livers, COMMD1 and COMMD3 had a similar distribution and partially cosedimented with vesicles containing the CCC (CCDC22 and CCDC93) and WASH (WASH1 and FAM21) complexes.Furthermore, a percentage of COMMD1 and COMMD3 were present in the same fractions as LDLR”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Ablation of COMMD6 impaired the total expression and the expression of LDLR at the plasma membrane.

    “Ablation of COMMD6 impaired the total expression and the expression of LDLR at the plasma membrane”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    CCDC22 inactivation did not alter body weight, liver weight, or cause overt liver pathology.

    “CCDC22 inactivation did not alter the body weight, liver weight, or cause overt liver pathology”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Silencing of COMMD6 significantly decreased COMMD1 protein levels without affecting COMMD1 mRNA.

    “silencing of COMMD6 significantly decreased COMMD1 protein levels (Figure 2A) without affecting COMMD1 mRNA”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic expression of the 3 gRNAs reduced CCDC22 expression by ≈70% and diminished the levels of CCDC93, C16orf62, and COMMD1.

    “Hepatic expression of the 3 gRNAs reduced CCDC22 expression by ≈70% and diminished the levels of CCDC93, C16orf62, and COMMD1”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Inactivation of the CCC complex notably increases very-low-density lipoprotein cholesterol and LDL cholesterol levels, supported by increased plasma ApoB100 levels.

    “Very-lowdensity lipoprotein cholesterol and LDL cholesterol levels were notably increased by inactivation of the CCC complex (Figure 7B), supported by the increased plasma ApoB100 levels.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Using liver-specific knockout mice for Commd1, Commd6, Commd9, and Ccdc22, the integrity of the CCC complex and the protein stability of all members of the COMMD family are dependent on each other.

    “Using liver-specific knockout mice for Commd1, Commd6, Commd9, and Ccdc22, we show that the integrity of the CCC complex and the protein stability of all members of the COMMD family are dependent on each other”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Plasma ApoA1 levels were increased (P<0.01) in Commd6ΔHep mice after feeding chow diet but not on HFC diet feeding.

    “Plasma ApoA1 levels were also increased (P<0.01) in Commd6Δ Hep mice but only after feeding chow diet and not on HFC diet feeding”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Not only the surface levels of LDLR are affected by CCC inactivation but also the surface levels of LRP1.

    “we found that not only the surface levels of LDLR are affected by CCC inactivation but also the surface levels of LRP1”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Atherosclerotic lesions in the aortic root were small and foam-cell rich.

    “Atherosclerotic lesions in the aortic root were small and foam-cell rich (Figure 7C and 7D).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Deletion of hepatic Commd6 markedly decreased all detectable COMMD proteins, but not all to the same degree; COMMD3 levels were only moderately decreased compared with other COMMD proteins.

    “Deletion of hepatic Commd6 markedly decreased all detectable COMMD proteins (Figure 3A), however, not all to the same degree (Figure 3A), as COMMD3 levels were only moderately decreased compared with other COMMD proteins”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The protein and mRNA levels of COMMD6 were both markedly reduced in HEK293T and RAW264.7 cells expressing short hairpin RNA targeting COMMD6.

    “The protein and mRNA levels of COMMD6 were both markedly reduced in HEK293T and RAW264.7 cells expressing short hairpin RNA targeting COMMD6”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Increased plasma cholesterol levels after CCDC22 inactivation were because of increased plasma LDL cholesterol, supported by increased plasma ApoB100 levels.

    “Lipoprotein fractionation by fast-performance liquid chromatography revealed that increased plasma cholesterol levels were because of increased plasma LDL cholesterol (Figure 5D), supported by the increased plasma ApoB100 levels”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic COMMD1 inactivation blunted the expression of CCDC22 and CCDC93 and markedly abolished COMMD3 associated with the CCC and WASH complexes and LDLR, without affecting COMMD3 present in other fractions.

    “Hepatic COMMD1 inactivation not only blunted the expression of CCDC22 and CCDC93 (Figure 4A) but also markedly abolished COMMD3 associated with the CCC and WASH complexes and LDLR, without affecting COMMD3 present in other fractions”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Hepatic COMMD6 deficiency resulted in a ≈37% increase (P<0.01) in plasma TC levels on a chow diet and a ≈40% increase (P<0.001) in plasma TC levels on a high-fat high-cholesterol diet compared with WT animals.

    “hepatic COMMD6 deficiency resulted in a ≈37% increase (P<0.01) in plasma TC levels on a chow diet and a ≈40% increase (P<0.001) in plasma TC levels on a high-fat high-cholesterol (HFC) diet compared with WT animals”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    CRISPR/Cas9-mediated somatic gene targeting achieved extensive reduction in hepatocyte CCDC22 levels and provided evidence for a direct role for the core of the CCC complex in regulating plasma cholesterol levels in mice.

    “Indeed, using CRISPR/Cas9-mediated somatic gene targeting, we achieved extensive reduction in hepatocyte CCDC22 levels and provided evidence for a direct role for the core of the CCC complex in the regulating of plasma cholesterol levels in mice.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The stability of the core of the CCC complex depends on numerous COMMDs, as CCDC22, CCDC93, and C16orf62 levels are massively reduced on hepatic deletion of Commd1, Commd6, or Commd9.

    “we identified for the first time that the stability of the core of the CCC complex depends on numerous COMMDs, as CCDC22, CCDC93, and C16orf62 levels were massively reduced on hepatic deletion of Commd1,”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Destabilization of the CCC complex exacerbates dyslipidemia and atherosclerosis.

    “Destabilization of the CCC (COMMD-CCDC22-CCDC93) complex exacerbates dyslipidemia and atherosclerosis.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    This study provides novel insights into the molecular organization of the endosomal sorting machinery in the coordination of intracellular trafficking of members of the LDLR family, such as LDLR and LRP1, and implies that all 10 COMMD proteins and the CCC core components may be potential targets modulating plasma lipid levels in humans.

    “This study provides novel insights into the molecular organization of the endosomal sorting machinery in the coordination of intracellular trafficking of members of the LDLR family, such as LDLR and LRP1 (LDLR-related protein 1) and imply that all 10 COMMD proteins and the CCC core components may be potential targets modulating plasma lipid levels in humans.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mechanism preventing the lysosomal fate and directing LDLR back to the cell surface is not fully elucidated.
    • Rests on an assumption: The role of COMMD proteins in the regulation of plasma cholesterol levels and atherogenesis has yet to be determined.
    • Rests on an assumption: The mechanisms by which intracellular LDLR trafficking is orchestrated remain unclear.

  • It may state two separate claims as one.

    Premisecitation

    ApoE3*Leiden transgenic mice are hyperlipidemic, develop atherosclerosis, and express LDLR in their livers.

    “We used ApoE3*Leiden (ApoE3*L) transgenic mice as a model for atherosclerosis 30 because these mice are hyperlipidemic, develop atherosclerosis, and express LDLR in their livers, 31”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30]

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

    COMMD1 facilitates endosomal trafficking of other receptors, such as ATP7A and ATP7B, to maintain copper homeostasis.

    “In addition to LDLR, COMMD1 also facilitates the endosomal trafficking of other receptors, such as the copper transporting protein ATP7A (ATPase copper transporting α) and ATP7B (ATPase copper transporting β), to maintain copper homeostasis.[9][10][11]”
    Quote in the paperNot a substantial claim0 of 3 sources 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.

    • 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

    Commd1, Commd6, Commd9, or Commd10 knockout mice are embryonically lethal and die at different stages of embryogenesis, suggesting nonredundant functions of COMMD proteins during development.

    “Commd1, Commd6, Commd9, or Commd10 knockout mice are embryonically lethal [17][18][19][20] and die at different stages of embryogenesis, suggesting nonredundant functions of COMMD proteins during development.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [17]

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

    • cites [18]

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

    • cites [19]

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

    • cites [20]

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

  • It may state two separate claims as one.

    Interpretationreasoning

    Reduced surface levels of LDLR and LRP1 eventually resulted in increased plasma ApoB-containing particles and accelerated atherosclerosis in mice.

    “These reduced surface levels of LDLR and LRP1 eventually resulted in increased plasma ApoB-containing particles and accelerated atherosclerosis in mice.”
    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

    COMMD1 belongs to the COMMD family, which consists of 10 members, each characterized by a carboxyl-terminal COMM domain that mediates physical interaction with other COMMD proteins.

    “COMMD1 belongs to the COMMD family, which consists of 10 members, each characterized by a carboxyl-terminal COMM (copper metabolism MURR1) domain, which mediates physical interaction with other COMMD proteins.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15]

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

  • It may state two separate claims as one.

    Premisecitation

    Loss of hepatic COMMD1 impairs endocytic LDLR recycling, which subsequently results in increased plasma LDL cholesterol in dogs and mice.

    “Loss of hepatic COMMD1 impairs the endocytic LDLR recycling, which subsequently results in increased levels of plasma LDL cholesterol in dogs and mice.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.

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

    Premisecitation

    COMMD proteins are ubiquitously expressed and conserved throughout evolution from lower organisms to higher vertebrates.

    “COMMD proteins are ubiquitously expressed and are conserved throughout evolution from lower organisms to higher vertebrates.15,16”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15]

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

    • cites [16]

      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

    Both COMMD6 and COMMD1 are localized in a WASH and retromer-enriched subcompartment of the endosome.

    “These observations indicate that both COMMD6 and COMMD1 are localized in a WASH and retromer-enriched subcompartment of the endosome”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Several proteins, such as PCSK9 and IDOL, avert the reuse of LDLR by directing LDLR to lysosomes.

    “several proteins, such as PCSK9 (proprotein convertase subtilisin/kexin type 9) and IDOL (inducible degrader of the LDLR), [5][6][7] have been identified that avert the reuse of LDLR through directing LDLR to the lysosomes”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [5]

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

    Heterozygous loss of Commd1 or Commd6 does not alter plasma cholesterol levels.

    “Heterozygous loss of Commd1 or Commd6 does not alter plasma cholesterol levels (B.van de Sluis, unpublished data, 2017), 8,10”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8]

      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.

  • It may state two separate claims as one.

    Interpretationown data

    The integrity of CCC core complex (CCDC22, CCDC93, and C16orf62) and the protein expression of all COMMDs depend on the expression of COMMD1 and COMMD6.

    “these results suggest that the integrity of CCC core complex (CCDC22, CCDC93, and C16orf62) and the protein expression of all COMMDs depend on the expression of COMMD1 and COMMD6.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    The 10 COMMD proteins exist in large macromolecular complexes containing the CCC core components CCDC22, CCDC93, and C16orf62.

    “Although several studies have shown that the 10 COMMD proteins exist in large macromolecular complexes containing the CCC core components CCDC22, CCDC93, and C16orf62, 9,18,21,22”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [9]

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

    • cites [18]

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

    • cites [21]

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

    • cites [22]

      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

    WASH activates the Arp2/3 complex to deposit branched actin filaments on endosomes, which is essential for the architecture of the endosomal and lysosomal network and endosomal receptor trafficking.

    “WASH activates the Arp2/3 (actin-related protein 2/3) complex to deposit branched actin filaments on endosomes, which is essential for the architecture of the endosomal and lysosomal network and endosomal receptor trafficking.[12][13][14]”
    Quote in the paperNot a substantial claim0 of 3 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.

    • cites [14]

      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

    The protein expression of COMMDs relies on each other through forming multiprotein complexes, and the degree of dependency differs between COMMD proteins.

    “Taken together, these results indicate that the protein expression of COMMDs relies on each other through forming multiprotein complexes, and the degree of dependency differs between COMMD proteins.”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    The CCC complex may have a role in SR-B1-mediated high-density lipoprotein cholesteryl esters uptake.

    “Because different studies have shown that SR-B1 can be endocytosed, 40 this may indicate that the CCC complex has also a role in SR-B1-mediated high-density lipoprotein cholesteryl esters uptake, but further studies are warranted.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

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

  • It may state two separate claims as one.

    Interpretationreasoning

    The fraction of a COMMD protein not affected by loss of another COMMD protein is likely present in other cellular compartments, where they likely mediate other biological activities.

    “The fraction of a COMMD protein that is not affected by the loss of another COMMD protein is likely present in other cellular compartments, where they likely mediate other biological activities of these factors, similarly to what has been reported for COMMD1, which can also regulate NF-κB (nuclear factor kappa B) and HIF-1 (hypoxia inducible factor 1) signaling.17,19,32”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17]

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

    • cites [19]

      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.

  • It may state two separate claims as one.

    Interpretationown data

    The COMMD proteins maintain the integrity and function of the hepatocyte CCC complex during endosomal LDLR and LRP1 trafficking.

    “Collectively, our study has uncovered a previously unknown role for the evolutionarily conserved COMMD proteins in maintaining the integrity and function of the hepatocyte CCC complex during endosomal LDLR and LRP1 trafficking.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Hepatic CCC deficiency leads to increased plasma LDL cholesterol levels and accelerated atherosclerosis.

    “Although the total protein levels of hepatic LDLR and LRP1 in WT and ApoE3*L mice are not affected on CCC inactivation, this study and our previous work 8 showed that hepatic CCC deficiency reduces surface levels of LDLR and LRP1-likely because of impaired endosomal receptor trafficking 8 -leading to increased plasma LDL cholesterol levels and accelerated atherosclerosis (Online Figure IX).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Premisecitation

    The CCC complex is a novel factor of endosomal LDLR trafficking.

    “Recently, the CCC complexa multiprotein complex associated with vital elements of the endocytic sorting machinery 9 -was identified as a novel factor of endosomal LDLR trafficking (Online Figure IX).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.

40 of 40

  • The paper relies on this without support.

    The mechanism preventing the lysosomal fate and directing LDLR back to the cell surface is not fully elucidated.

    “but the mechanism preventing the lysosomal fate and directing LDLR back to the cell surface is still not fully elucidated.”

  • The paper relies on this without support.

    The role of COMMD proteins in the regulation of plasma cholesterol levels and atherogenesis has yet to be determined.

    “their role in the regulation of plasma cholesterol levels and atherogenesis has yet to be determined.”

  • The paper relies on this without support.

    The mechanisms by which intracellular LDLR trafficking is orchestrated remain unclear.

    “but the mechanisms by which intracellular LDLR trafficking is orchestrated remain unclear.”

  • The paper relies on this without support.

    Evaluating the contribution of the CCC complex to dyslipidemia and atherogenesis requires hepatic LDLR expression.

    “which we thought to be essential in evaluating the contribution of the CCC complex to dyslipidemia and atherogenesis.”
4 of 4

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?

  • The CCDC22-CCDC93 heterodimer is destabilized whenever any given COMMD protein is knocked out in cells or tissues.

    “This could explain why the CCDC22-CCDC93 heterodimer is destabilized whenever any given COMMD protein is knocked out in cells or in tissues14,25,46.”

    From Structural organization of the retriever–CCC endosomal recycling complex (2024) · cites this paper as [46]

    The ‘Stability of COMMD Proteins Associated With the CCC Complex’ section reports reduced CCDC22 and CCDC93 in livers deficient in COMMD1, COMMD6, or COMMD9; the COMMD6 section also reports reduced levels after COMMD6 depletion in cells. The Discussion limits its conclusion to ‘any COMMD studied,’ so the paper does not establish that this happens whenever any member of the COMMD family is knocked out. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • CCC is required for retromer- and retriever-dependent protein trafficking.

    “the CCC protein complex, which consists of CCDC22, CCDC93, and any of the 10 COMMD proteins, is required for retromer- and retriever-dependent protein trafficking27–32”

    From Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling (2019) · cites this paper as [32]

    The Abstract describes CCC as containing COMMD proteins, CCDC22, and CCDC93, and says its recruitment to endosomes depends on the retromer subunit VPS35. The Discussion says retriever recruitment relies on CCC and WASH and reports that inactivating CCC affects LDLR and LRP1 trafficking. These passages support a role in both pathways, but do not establish that CCC is required for retromer- and retriever-dependent protein trafficking generally; the paper also treats the precise organization of the retriever–CCC pathway as unresolved. Page numbers are unavailable in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • CCC deficiency in human and mouse cells causes defective recycling of SNX17-retriever cargoes such as β1 integrin, LDLR, and LRP1.

    “CCC deficiency in human and mouse cells causes defective recycling of SNX17-retriever cargoes such as β1 integrin, LDLR, and LRP120,31,32”

    From Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling (2019) · cites this paper as [32]

    The Discussion (page unavailable) reports that CCC inactivation affects LDLR and LRP1 function and reduces their surface levels in mouse liver, likely through impaired endosomal trafficking. It describes their recycling through the SNX17–CCC–WASH pathway as a speculation, not an established retriever-cargo result. The passages do not establish defective β1-integrin recycling or the claimed recycling defect in human cells. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The CCC protein complex consists of CCDC22, CCDC93, and any of the 10 COMMD proteins.

    “the CCC protein complex, which consists of CCDC22, CCDC93, and any of the 10 COMMD proteins”

    From Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling (2019) · cites this paper as [32]

    The section on COMMD protein stability identifies CCDC22 and CCDC93 as CCC core components and describes their association with COMMD proteins. But it repeatedly identifies C16orf62 as a third CCC core component, which the claimed description of what the complex consists of omits. Our copy also describes all 10 COMMD proteins as assembled into CCC complexes, rather than specifying that a complex contains any one of them. Page numbers are not provided for these passages. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • The fact that the endosomal recycling process is primarily regulated at the post-translational (protein) level supports the hypothesis that the CCDC93 variant (rs17512204) encodes a protein with improved function.

    “This can be explained by the fact that this process is primarily regulated at the post-translational (protein) level, 12,13,40 which, in turn, supports our hypothesis that the CCDC93 variant (rs17512204) encodes a protein with improved function.”

    From A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor (2020) · cites this paper as [12]

    In “COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression” (page unavailable), the paper reports reduced CCC-component protein levels without aberrant gene expression and links protein stability to endosomal receptor recycling. This supports protein-level regulation of the CCC complex, but not the broader assertion that endosomal recycling is primarily regulated post-translationally. The CCDC93-variant hypothesis is the citing authors’ own inference, not a finding attributed to this source. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

Citations

Cites

Flagged first, then by citations

1 of the 41 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Metadata

Authors
Fedoseienko, A., Wijers, M., Wolters, J. C., Dekker, D., Smit, M., Huijkman, N., Kloosterhuis, N., Klug, H., Schepers, A., Willems van Dijk, K., Levels, J. H. M., Billadeau, D. D., Hofker, M. H., van Deursen, J., Westerterp, M., Burstein, E., Kuivenhoven, J. A., & van de Sluis, B.
Affiliations
  • From the Molecular Genetics Section, Department of Pediatrics (A.F., M. Wijers, J.C.W., D.D., M.S., N.H., N.K., M.H.H., M. Westerterp, J.A.K., B.v.d.S)
  • University Medical Center Groningen (NL)
  • Helmholtz Munich (DE)
  • Department of Human Genetics (K.W.v.D.) and Department of Medicine (K.W.v.D.)
  • Leiden University Medical Center (NL)
  • Division of Oncology Research, Department of Immunology and Biochemistry (D.D.B.)
  • Mayo Clinic (US)
Corresponding author
  • Fedoseienko, Alina
  • Wijers, Melinde
  • Hofker, Marten H.
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-06-08
Volume
122
Issue
12
Pages
1648-1660
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.117.312004
OpenAlex
W2789459269
Semantic Scholar
a85c0318e11c0e80da25385a3262f6b70ce81412
Cited by
126
References
41
Citations by year
2026: 10 · 2025: 16 · 2024: 20 · 2023: 18 · 2022: 11 · 2021: 21 · 2020: 9 · 2019: 16 · 2018: 5
FWCI
5.56
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • Jan Kornelis de Cock Stichting
  • Rijksuniversiteit Groningen
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
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
COMMD1, LDL receptor, LRP1, plasma LDL cholesterol, hypercholesterolemia, atherosclerosis, dyslipidemia, hepatic lipid metabolism
MeSH terms
Animals, Carrier Proteins, Cell Line, Cholesterol, Chromatography, High Pressure Liquid, Cytoskeletal Proteins, Humans, Cholesterol, LDL, Liver, Male, Receptors, LDL, Endosomes, Triglycerides, Gene Expression, Gene Deletion, Mice, Knockout, Protein Transport, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Adaptor Proteins, Signal Transducing, Atherosclerosis, Mice, Hep G2 Cells, HEK293 Cells

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 ›

Are you an author, or do you see a problem with this page? Request a review