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Circ Res. 2018 Jun 8;122(12):1648-1660. doi: 10.1161/CIRCRESAHA.117.312004. Epub 2018 Mar 15.

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

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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, University of Groningen, The Netherlands; PolyQuant GmbH, Bad Abbach, Germany (H.K.).
Monoclonal Antibody Core Facility and Research Group, Institute for Diabetes and Obesity, Helmholtz Zentrum, München, Germany (A.S.).
Department of Human Genetics (K.W.v.D.) and Department of Medicine (K.W.v.D.).
Division of Endocrinology, Leiden University Medical Center, The Netherlands; Department of Vascular and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands (J.H.M.L.).
Division of Oncology Research, Department of Immunology and Biochemistry (D.D.B.).
Department of Pediatrics and Adolescent Medicine, Mayo Clinic College of Medicine (J.v.D.).
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine (J.v.D.).
Mayo Clinic, Rochester, MN; and University of Texas Southwestern Medical Center, Dallas (E.B.).
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)
iPSC/CRISPR Center Groningen (B.v.d.S.).



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.


The main aim of this study is to unravel the contribution of evolutionarily conserved COMMD proteins to plasma lipoprotein levels and atherogenesis.


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.


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.


atherosclerosis; endosome; hypercholesterolemia; liver; mice, transgenic

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