The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR traffcking

Alina Fedoseienko, Melinde Wijers, Justina C. Wolters, Daphne Dekker, Marieke Smit, Nicolette Huijkman, Niels Kloosterhuis, Helene Klug, Aloys Schepers, Ko Willems Van Dijk, Johannes H.M. Levels, Daniel D Billadeau, Marten H. Hofker, Jan Van Deursen, Marit Westerterp, Ezra Burstein, Jan Albert Kuivenhoven, Bart Van De Sluis

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Rationale: COMMD (copper metabolism MURR1 domain)-containing proteins are a part of the CCC (COMMD-CCDC22 [coiled-coil domain containing 22]-CCDC93 [coiled-coil domain containing 93]) complex facilitating endosomal traffcking 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 lowdensity 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-specifc 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 defciency 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 defciency 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 fndings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR traffcking. 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.

Original languageEnglish (US)
Pages (from-to)1648-1660
Number of pages13
JournalCirculation Research
Volume122
Issue number12
DOIs
StatePublished - Jan 1 2018

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LDL Receptors
Copper
Atherosclerosis
Liver
LDL Cholesterol
Clustered Regularly Interspaced Short Palindromic Repeats
Cholesterol
Low Density Lipoprotein Receptor-Related Protein-1
Chromosomes, Human, Pair 16
Recycling
Cell Surface Receptors
Dyslipidemias
oxidized low density lipoprotein
Hypercholesterolemia
Knockout Mice
Proteomics
Open Reading Frames
Lipoproteins
Blood Proteins
Proteins

Keywords

  • Atherosclerosis
  • Endosome
  • Hypercholesterolemia
  • Liver
  • Mice transgenic

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR traffcking. / Fedoseienko, Alina; Wijers, Melinde; Wolters, Justina C.; Dekker, Daphne; Smit, Marieke; Huijkman, Nicolette; Kloosterhuis, Niels; Klug, Helene; Schepers, Aloys; Van Dijk, Ko Willems; Levels, Johannes H.M.; Billadeau, Daniel D; Hofker, Marten H.; Van Deursen, Jan; Westerterp, Marit; Burstein, Ezra; Kuivenhoven, Jan Albert; Van De Sluis, Bart.

In: Circulation Research, Vol. 122, No. 12, 01.01.2018, p. 1648-1660.

Research output: Contribution to journalArticle

Fedoseienko, A, Wijers, M, Wolters, JC, Dekker, D, Smit, M, Huijkman, N, Kloosterhuis, N, Klug, H, Schepers, A, Van Dijk, KW, Levels, JHM, Billadeau, DD, Hofker, MH, Van Deursen, J, Westerterp, M, Burstein, E, Kuivenhoven, JA & Van De Sluis, B 2018, 'The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR traffcking', Circulation Research, vol. 122, no. 12, pp. 1648-1660. https://doi.org/10.1161/CIRCRESAHA.117.312004
Fedoseienko, Alina ; Wijers, Melinde ; Wolters, Justina C. ; Dekker, Daphne ; Smit, Marieke ; Huijkman, Nicolette ; Kloosterhuis, Niels ; Klug, Helene ; Schepers, Aloys ; Van Dijk, Ko Willems ; Levels, Johannes H.M. ; Billadeau, Daniel D ; Hofker, Marten H. ; Van Deursen, Jan ; Westerterp, Marit ; Burstein, Ezra ; Kuivenhoven, Jan Albert ; Van De Sluis, Bart. / The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR traffcking. In: Circulation Research. 2018 ; Vol. 122, No. 12. pp. 1648-1660.
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T1 - The COMMD family regulates plasma LDL levels and attenuates atherosclerosis through stabilizing the CCC complex in endosomal LDLR traffcking

AU - Fedoseienko, Alina

AU - Wijers, Melinde

AU - Wolters, Justina C.

AU - Dekker, Daphne

AU - Smit, Marieke

AU - Huijkman, Nicolette

AU - Kloosterhuis, Niels

AU - Klug, Helene

AU - Schepers, Aloys

AU - Van Dijk, Ko Willems

AU - Levels, Johannes H.M.

AU - Billadeau, Daniel D

AU - Hofker, Marten H.

AU - Van Deursen, Jan

AU - Westerterp, Marit

AU - Burstein, Ezra

AU - Kuivenhoven, Jan Albert

AU - Van De Sluis, Bart

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 traffcking 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 lowdensity 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-specifc 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 defciency 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 defciency 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 fndings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR traffcking. 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.

AB - 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 traffcking 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 lowdensity 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-specifc 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 defciency 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 defciency 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 fndings demonstrate a strong interrelationship between COMMD proteins and the core of the CCC complex in endosomal LDLR traffcking. 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.

KW - Atherosclerosis

KW - Endosome

KW - Hypercholesterolemia

KW - Liver

KW - Mice transgenic

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