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The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking
Open accessAbstract
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.
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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).
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72 Own result · 29 Own interpretation · 22 Sources not found · 3 No basis given · 1 Own method
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In the paper
“We found that the integrity of the CCC complex is not exclusively controlled by COMMD1 but by numerous members of the COMMD family.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
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“the plasma levels of ApoB100 were significantly elevated (P<0.01) in Commd6Δ Hep mice, both on chow and HFC diet feeding”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Commd6 Ablation Results in Increased Plasma LDL Cholesterol Levels
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“This specific decrease in the CCC core components in all 3 models of hepatic COMMD deficiency coincides with elevated plasma cholesterol levels.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
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“Similar effect on the total and plasma membrane expression of LRP1 was seen”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Colocalizes With the WASH Complex and Retromer
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“we showed that the stability of the COMMDs in hepatocytes relies on the CCC core component CCDC22”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
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“This further rise in both plasma TC and ApoB48 levels was also reflected by the marked change in their plasma lipoprotein profile”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“we observed that COMMD1 and COMMD6 are physically associated with each other, as determined by coimmunoprecipitation assay”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
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In the paper
“it increased plasma TC levels by ≈35% (P<0.01)compared with WT mice injected with Ad-gRNA_Ccdc22”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Ablation of the CCC Component CCDC22 Increases Circulating Cholesterol Levels
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“hepatic ablation of both LDLR and COMMD1 further increased ApoB48 levels compared with control animals”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“COMMD3 protein levels were only decreased by ≈50% (P<0.05).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
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In the paper
“inactivation of the CCC complex in mouse livers leads to reduced cell surface levels of LDLR and LRP1 (LDLR-related protein 1)”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
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“Targeted proteomics analysis showed that the expression of all COMMD proteins was significantly reduced by targeting Ccdc22, with the exception of COMMD6”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Ablation of the CCC Component CCDC22 Increases Circulating Cholesterol Levels
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“LDLR deficiency led to a significant increase in plasma TC and triglyceride (Figure 6B) in WT mice.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“The effect of hepatic Commd1 deletion on COMMD protein amounts was similar to Commd6 depletion”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
plaincorrelational- Asserted: passes — The authors put it forward as true.
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“the CCC core subunits were reduced by ≈70% (P<0.05) in COMMD1-and COMMD6-deficient livers”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
plaindirect- Asserted: passes — The authors put it forward as true.
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“This dramatic increase in ApoB48 in mice deficient for both COMMD1 and LDLR is supported by targeted proteomics analysis”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“the expression of the WASH component WASH1 was increased by ≈50% (P<0.05) after loss of COMMD1 or COMMD6.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
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“but resulted in a dramatical rise in plasma TC and triglyceride levels (≈100% increase; P<0.001; Figure 7A).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“accompanied by increased plasma low-density lipoprotein cholesterol levels.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
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“This partial reduction in COMMD1 and COMMD6 levels was confirmed by Western blot analysis”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
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“the lipoprotein profile of WT and Commd6Δ Hep animals fed a chow or HFC diet (Figure 1C and 1D; Online Figure IID and IIE) showed an increase in plasma LDL cholesterol in Commd6 knockout animals.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Commd6 Ablation Results in Increased Plasma LDL Cholesterol Levels
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In the paper
“hepatic Commd1 and Commd6 depletion in mice significantly reduced the expression of all COMMD proteins”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
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“PCSK9-D377Y expression blunted the protein expression of LDLR, but not LRP1, in the liver of WT and Commd1Δ Hep mice”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“Hepatic COMMD1 deficiency did not affect the total protein expression of LDLR and LRP1 in the liver of ApoE3*L (Online Figure VIIIA) mice fed a HFC diet for 12 weeks”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“Immunofluorescence staining showed that COMMD6 strongly colocalizes with WASH1, FAM21, and COMMD1, almost to a similar degree as seen between COMMD1 and WASH1 and FAM21”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Colocalizes With the WASH Complex and Retromer
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“However, silencing of COMMD1 did not reduce COMMD6 protein levels”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
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“Blocking proteasome activity partially restored COMMD1 protein levels in COMMD6 knockdown cell lines”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
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“Animals that lack the protein expression of both COMMD1 and LDLR showed higher increase in plasma TC and triglyceride levels compared with mice only deficient for LDLR in the liver”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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In the paper
“COMMD6 overlapped with VPS35 almost to the same extent as COMMD1 and VPS35”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Colocalizes With the WASH Complex and Retromer
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In the paper
“LDLR deficiency resulted in a marked increase in both apolipoproteins”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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In the paper
“Ablation of Commd9 reduced the expression of the CCC complex subunits CCDC22, CCDC93, and C16orf62 (P<0.05) to a similar extent as COMMD1 or COMMD6 inactivation”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
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“whereas the expression of the retromer subunits, LDLR and LRP1, were unaffected”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
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“Hepatic deficiency of both COMMD1 and LDLR led to a large increase of plasma lipoproteins in the chylomicron remnant/very-low-density lipoprotein and LDL size range.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
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“Hepatic inactivation of the CCC complex accelerates atherosclerosis in a mouse model with a human-like lipoprotein profile.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
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“we also silenced COMMD6 in the hepatocellular carcinoma cell lines HepG2 and Huh7 and found similar effects as described above”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
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“COMMD9 seems to be less essential for COMMD stability, because COMMD1, 2, 3, 6, and 8 expression were only reduced by 40% to 50% (P<0.05)after Commd9 depletion”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“This rise in plasma cholesterol levels coincided with ≈50% larger atherosclerotic lesion area (P<0.01) in the aortic root of these animals (Figure 7C and 7D).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that all COMMD and CCC core proteins interact with COMMD1 (Figure 4B).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The decreased COMMD1, CCDC22, and CCDC93 levels were not caused by aberrant gene expression”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“For example, COMMD5 and COMMD10 are reduced by ≈70%, whereas COMMD3 is only diminished by 50% on Commd1, Commd6, or Commd9 depletion.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hepatic CRISPR/Cas9-mediated Ccdc22 editing increases plasma cholesterol levels.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirectn = 5- Asserted: passes — The authors put it forward as true.
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In the paper
“We observed no atherosclerotic lesions in the aortic arch of both genotypes (Online Figure VIIIB),”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“our cell fractionation experiments showed that only the fraction of COMMD3 proteins associated with the CCC and WASH complexes are adversely affected after Commd1 deletion.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hepatic Commd deletion perturbs the protein stability of the complete COMMD (copper metabolism MURR1 domain) family.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirectn = 4- Asserted: passes — The authors put it forward as true.
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In the paper
“This study shows also for the first time that the expression of the COMMD proteins in hepatocytes relies on each other, but intriguingly, the degree of dependency differs between COMMD proteins.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
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In the paper
“In addition, we found that perturbation in the CCC complex contributes in the progression of atherosclerosis in ApoE3*L mice, a mouse model with a human-like lipoprotein profile.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This loss of the CCC core subunits was correlated with elevated plasma LDL cholesterol levels in all our models, 8 indicating that specific disruption of the CCC core leads to the hypercholesterolemic phenotype.8,11”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“In this study, we revealed that the integrity of the CCC core components, namely, CCDC22, CCDC93 and C16orf62, is not exclusively controlled by COMMD1, 8 but by numerous members of the COMMD family (Online Figure IX).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, our data also suggest that the stability of the COMMDs in hepatocytes relies on the CCC core component CCDC22, indicating a strong interrelation between the COMMD family and the core of the CCC complex in endosomal trafficking of cell surface receptors, including LDLR and LRP1.8”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“COMMD6 (copper metabolism MURR1 domain 6) inactivation downregulates COMMD1 in different cell lines.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirectn = 3- Asserted: passes — The authors put it forward as true.
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In the paper
“We now show that in addition to COMMD1, also COMMD3 and COMMD6 are associated with the WASH complex.9”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Depletion of either COMMD1 (copper metabolism MURR1 domain 1) or COMMD9 perturbs the formation of the CCC (COMMD-CCDC22-CCDC93) complex.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirectn = 5- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, our data show that hepatic ablation of Commd1 8 and Commd6 in mice fed a chow diet also lead to elevated plasma high-density lipoprotein cholesterol levels.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CCC (COMMD-CCDC22-CCDC93) complex inactivation further increases dyslipidemia in hepatic LDLR (low-density lipoprotein receptor)-deficient mice.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirectn = 9- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hepatic COMMD6 (copper metabolism MURR1 domain 6) deficiency increases plasma cholesterol levels.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirectn = 7- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“These proteins were not detected in IgG negative control immunoprecipitates.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggest that COMMD6 may also participate in the CCC-WASH axis in endosomal sorting of receptors, including LDLR and LRP1.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Colocalizes With the WASH Complex and Retromer
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and that the integrity of the CCC complex relies on the expression of all members of the COMMD family.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that COMMD1 instability is partially ubiquitin dependent.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The reduced total LDLR and LRP1 levels can likely be explained by increased lysosomal degradation because of impaired receptor recycling, similar as seen in WASH1-deficient mouse fibroblast cells.8,26”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Colocalizes With the WASH Complex and Retromer
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Not matched
In the paper
“A similar increase in plasma ApoB48 levels and change in lipoprotein profile has been seen on hepatic depletion of both Ldlr and Lrp1, 28 suggesting that the CCC complex also facilitates the functioning of LRP1.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
What the sources say
- Not matchedcites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data indicate that COMMD6 form a protein complex with COMMD1 that is indispensable for the protein stability of CCC complex in endosomal receptor recycling.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This study assigns a large number of candidate genes controlling plasma low-density lipoprotein cholesterol levels”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“implying that the CCC complex facilitates the endosomal trafficking of several members of the LDLR family.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the stability of the CCC core components (CCDC22, CCDC93, and C16orf62) seems to be entirely dependent on the COMMD proteins.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, these results indicate that proper formation of the core of the CCC complex in hepatocytes is required to control plasma LDL cholesterol levels.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Ablation of the CCC Component CCDC22 Increases Circulating Cholesterol Levels
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The reduced surface levels of both LDLR and LRP1 on inactivation of the CCC complex (Online Figure VB) suggest that the CCC complex orchestrate the trafficking of both receptors.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic CCC Complex Ablation Exacerbates Hyperlipidemia and Accelerates Atherosclerosis
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The CCC complex localizes to endosomes through physical association with the WASH (Wiskott-Aldrich syndrome protein and SCAR homologue) complex.9”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
In the paper
“COMMD1 is assembled into the CCC (COMMD-CCDC22 [coiled-coil domain containing 22]-CCDC93 [coiled-coil domain containing 93]) complex together with chromosome 16 open reading frame 62 (C16orf62) and the coiled-coil proteins CCDC22 and CCDC93.9”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
In the paper
“these data demonstrate that, similar to Commd1 8 , hepatic Commd6 ablation causes hypercholesterolemia.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Commd6 Ablation Results in Increased Plasma LDL Cholesterol Levels
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, our studies suggest that the endosomal trafficking of LDLR and LRP1 in clearing ApoB-containing particles are dependent on the CCC complex”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Because LDLR can compensate for the loss of LRP1, studying LRP1 functioning in the clearance of plasma ApoEand ApoB-containing particles in mice is only possible in a hepatic LDLR-deficient background.28”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic CCC Complex Ablation Exacerbates Hyperlipidemia and Accelerates Atherosclerosis
What the sources say
- Not matchedcites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that the main disturbance of COMMD3 levels on COMMD1 deficiency is on the fraction of COMMD3 that is associated with the CCC and WASH complexes and LDLR.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
hedgeddirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The recruitment of the CCC and WASH complexes to the endosomes is dependent on the retromer subunit VPS35.8,9,12”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“C learing circulating atherogenic low-density lipoprotein (LDL) cholesterol is highly dependent on the LDLR (LDL receptor) in hepatocytes.1,2”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [1]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CCC complex facilitates endosomal trafficking of LDLR and LRP1.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, hepatic perturbations in the CCC complex exacerbates hyperlipidemia-likely because of a defect in LDLR and LRP1-mediated lipoprotein clearanceand accelerates atherosclerosis in ApoE3*L mice.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, hepatic perturbations in the CCC complex exacerbates hyperlipidemia-likely because of a defect in LDLR and LRP1-mediated lipoprotein clearanceand accelerates atherosclerosis in ApoE3*L mice.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is an interesting observation, as our study implies that C16orf62 does participate in the CCC complex because ablation of either Ccdc22 or a Commd gene leads to a dramatic reduction in C16orf62 levels.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that atherogenesis did not yet develop in this part of the aorta.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Now, we provide genetic evidence that CCDC22 insufficiency directly cause high plasma LDL cholesterol levels in X-linked intellectual disability patients and establish that CCC complex-mediated LDLR trafficking is conserved between mice and humans.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that the portion of the COMMDs assembled into the CCC complexes is particularly disturbed by removal of another COMMD protein.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Now, we provide genetic evidence that CCDC22 insufficiency directly cause high plasma LDL cholesterol levels in X-linked intellectual disability patients and establish that CCC complex-mediated LDLR trafficking is conserved between mice and humans.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This loss of the CCC core subunits was correlated with elevated plasma LDL cholesterol levels in all our models, 8 indicating that specific disruption of the CCC core leads to the hypercholesterolemic phenotype.8,11”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, hepatic perturbations in the CCC complex exacerbates hyperlipidemia-likely because of a defect in LDLR and LRP1-mediated lipoprotein clearanceand accelerates atherosclerosis in ApoE3*L mice.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 34
- The quote only partly states this claim. 1
- Probably not a substantial claim. 10
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Plasma triglyceride, hepatic cholesterol, and triglyceride concentrations were unaltered by hepatic Commd6 ablation”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Commd6 Ablation Results in Increased Plasma LDL Cholesterol Levels
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“depletion of Commd6 in mouse hepatocytes blunted COMMD1 protein levels, accompanied by reduced protein levels of the CCC core components CCDC22 and CCDC93”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ablation of COMMD6 impaired the total expression and the expression of LDLR at the plasma membrane”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Colocalizes With the WASH Complex and Retromer
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CCDC22 inactivation did not alter the body weight, liver weight, or cause overt liver pathology”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Ablation of the CCC Component CCDC22 Increases Circulating Cholesterol Levels
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“silencing of COMMD6 significantly decreased COMMD1 protein levels (Figure 2A) without affecting COMMD1 mRNA”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hepatic expression of the 3 gRNAs reduced CCDC22 expression by ≈70% and diminished the levels of CCDC93, C16orf62, and COMMD1”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Ablation of the CCC Component CCDC22 Increases Circulating Cholesterol Levels
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Commd6 Ablation Results in Increased Plasma LDL Cholesterol Levels
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we found that not only the surface levels of LDLR are affected by CCC inactivation but also the surface levels of LRP1”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Atherosclerotic lesions in the aortic root were small and foam-cell rich (Figure 7C and 7D).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The protein and mRNA levels of COMMD6 were both markedly reduced in HEK293T and RAW264.7 cells expressing short hairpin RNA targeting COMMD6”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Is Indispensable for COMMD1, CCDC22, and CCDC93 Protein Expression
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Ablation of the CCC Component CCDC22 Increases Circulating Cholesterol Levels
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Hepatic Commd6 Ablation Results in Increased Plasma LDL Cholesterol Levels
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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,”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Destabilization of the CCC (COMMD-CCDC22-CCDC93) complex exacerbates dyslipidemia and atherosclerosis.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirectn = 8- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Editorial, see p 1629
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- 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.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Commd1Δ
What the sources say
- Not matchedcites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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]”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Editorial, see p 1629
What the sources say
- Not matchedcites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [20]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These reduced surface levels of LDLR and LRP1 eventually resulted in increased plasma ApoB-containing particles and accelerated atherosclerosis in mice.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > What New Information Does This Article Contribute?
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Editorial, see p 1629
What the sources say
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
In the paper
“Loss of hepatic COMMD1 impairs the endocytic LDLR recycling, which subsequently results in increased levels of plasma LDL cholesterol in dogs and mice.8”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“COMMD proteins are ubiquitously expressed and are conserved throughout evolution from lower organisms to higher vertebrates.15,16”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Editorial, see p 1629
What the sources say
- Not matchedcites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations indicate that both COMMD6 and COMMD1 are localized in a WASH and retromer-enriched subcompartment of the endosome”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > COMMD6 Colocalizes With the WASH Complex and Retromer
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“Heterozygous loss of Commd1 or Commd6 does not alter plasma cholesterol levels (B.van de Sluis, unpublished data, 2017), 8,10”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Editorial, see p 1629
What the sources say
- Not matchedcites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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]”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Abstract
What the sources say
- Not matchedcites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Stability of COMMD Proteins Associated With the CCC Complex Depends on Other COMMD Proteins
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
What the sources say
- Not matchedcites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
What the sources say
- Not matchedcites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking > Discussion
What the sources say
- Not matchedcites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Not matched
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.”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This combined with the notion that a complete loss of components of the endosomal recycling machinery is lethal in mice 12,13,37 indicated that impairment of this pathway is very harmful.”
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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Most transmembrane proteins sorted by Commander, including α5β1 integrin, the amyloid precursor protein (APP), and lipoprotein receptors contain ΦxNxx[YF] sequence motifs (where Φ is a hydrophobic amino acid) that are recruited to Commander via the sorting nexin 17 (SNX17) cargo adaptor.6,20,23,24,25,26,27,28,29”
From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [28]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the structure provides an atomic level description of its organization that explains previous results including the co-dependence of each of the COMMD, CCDC, and VPS35L proteins for complex stability.13,28”
From Structure of the endosomal Commander complex linked to Ritscher-Schinzel syndrome (2023) · cites this paper as [28]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“although PCSK9 does not have an effect on hepatic LRP1 degradation in WT mice (17,37,38)”
From The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance (2019) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“we have shown that loss of the CCC complex leads to increased expression of several WASH subunits, including WASHC1 (17).”
From The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance (2019) · cites this paper as [17]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [31]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The CCC complex is a molecular assembly that has been recognized for its role in regulating endosomal recycling of various cargos20,27,30–32,34”
From Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling (2019) · cites this paper as [32]
The cited source says what the claim attributes to it.
In the citing paper
“Loss of proteins of the CCC complex studied thus far causes hypercholesterolaemia in mammals including man.”
The cited source says what the claim attributes to it.
In the citing paper
“This because we have recently shown that CCDC93 participates in an evolutionary conserved multiprotein complex, annotated as the CCC complex (COMMD/CCDC22/CCDC93; see Supple- mentary material online for additional information), that orchestrates the endosomal recycling of the LDL-receptor (LDLR).12,13”
The cited source says what the claim attributes to it.
In the citing paper
“These experimental studies in mice have shown that a loss of proteins of the endosomal sorting machinery causes hypercholesterolaemia and increased atherosclerosis.12,13”
The cited source says what the claim attributes to it.
In the citing paper
“However, we and others could not confirm a role for PCSK9 in hepatic LRP1 degradation in WT mice, nor in hepatic COMMD1-deficient mice (17,37,38).”
From The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance (2019) · cites this paper as [17]
The cited source says what the claim attributes to it.
In the citing paper
“Hepatic loss of proteins in the CCC has been shown to result in increased plasma lipid levels due to reductions in LDLR99.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [99]
The cited source says what the claim attributes to it.
In the citing paper
“Previous reports found the CCC and WASH complexes act together to facilitate endosomal trafficking of LDLR.17 30 31”
From Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome (2023) · cites this paper as [30]
The cited source says what the claim attributes to it.
In the citing paper
“Both CCDC93 and the CCC complex mediate endosomal sorting of the low-density lipoprotein receptor (LDLR) [43,48,49].”
From Genetic variation in CCDC93 is associated with elevated central systolic blood pressure, impaired arterial relaxation, and mitochondrial dysfunction (2024) · cites this paper as [48]
Citations
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The metabolic and molecular bases of inherited disease
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LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor
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Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and inlivers of parabiotic mice
Lagace, T. A., Curtis, D. E., Garuti, R., McNutt, M. C., Park, S. W., Prather, H. B., Anderson, N. N., Ho, Y. K., Hammer, R. E., & Horton, J. D. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29383 · Cited by 681
NARC-1/PCSK9 and Its Natural Mutants
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Panorama of ancient metazoan macromolecular complexes
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A FAM21-Containing WASH Complex Regulates Retromer-Dependent Sorting
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“As LDLR can compensate for the loss of LRP1, studying LRP1 functioning in the clearance of plasma ApoE and ApoB-containing particles in mice is only possible in a hepatic LDLR-deficient background (27).”
BackgroundInfluentialPratt, J. M., Simpson, D. M., Doherty, M. K., Rivers, J., Gaskell, S. J., & Beynon, R. J. (2006) · Nature Protocols · doi:10.1038/nprot.2006.129 · Cited by 375
Cited by
Sorted by citations
Mechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980
Regulation of glucose and lipid metabolism in health and disease
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A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry
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The cell biology of the hepatocyte: A membrane trafficking machine
Schulze, R. J., Schott, M. B., Casey, C. A., Tuma, P. L., & McNiven, M. A. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201903090 · Cited by 281
Hepatic cholesterol transport and its role in non-alcoholic fatty liver disease and atherosclerosis
Li, H., Yu, X.-H., Ou, X., Ouyang, X.-P., & Tang, C. (2021) · Progress in Lipid Research · doi:10.1016/j.plipres.2021.101109 · Cited by 237
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
- Published
- 2018-06-08
- Volume
- 122
- Issue
- 12
- Pages
- 1648-1660
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- 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
- green
- pure.amsterdamumc.nl
- 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 ›
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