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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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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- It may state two separate claims as one. 34
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“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.
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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
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“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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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
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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.
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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.
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“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
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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
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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?
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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
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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?
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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]
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- Not matchedcites [31]
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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
“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.
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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.
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.
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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.
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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COMMD Proteins, a Novel Family of Structural and Functional Homologs of MURR1
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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
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