The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking
| Autor: | Marten H. Hofker, Johannes H.M. Levels, Marieke Smit, Ko Willems van Dijk, Ezra Burstein, Melinde Wijers, Helene Klug, Jan Albert Kuivenhoven, Alina Fedoseienko, Daphne Dekker, Daniel D. Billadeau, Nicolette C. A. Huijkman, Jan M. van Deursen, Justina C. Wolters, Marit Westerterp, Bart van de Sluis, Niels J. Kloosterhuis, Aloys Schepers |
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| Přispěvatelé: | Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), AGEM - Digestive immunity, ACS - Diabetes & metabolism, Experimental Vascular Medicine, AGEM - Endocrinology, metabolism and nutrition |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine HYPERLIPOPROTEINEMIA CLEARANCE Physiology Gene Expression chemistry.chemical_compound 0302 clinical medicine DOMAIN Receptor Chromatography High Pressure Liquid Mice Knockout TRANSGENIC MICE hypercholesterolemia CHOLESTEROL Hep G2 Cells LRP1 Cell biology DENSITY-LIPOPROTEIN RECEPTOR Protein Transport Knockout mouse lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine Low Density Lipoprotein Receptor-Related Protein-1 MULTIPROTEIN COMPLEX Atherosclerosis Endosome Hypercholesterolemia Liver Mice Transgenic mice PROTEINS ENDOCYTOSIS Endosomes liver Cell Line 03 medical and health sciences Cell surface receptor Animals Humans endosome Triglycerides Adaptor Proteins Signal Transducing transgenic Cholesterol Tumor Suppressor Proteins Cholesterol LDL Cytoskeletal Proteins HEK293 Cells 030104 developmental biology WASH COMPLEX Receptors LDL chemistry LDL receptor atherosclerosis Carrier Proteins Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] Gene Deletion 030217 neurology & neurosurgery Lipoprotein |
| Zdroj: | Circulation research, 122(12), 1648-1660. LIPPINCOTT WILLIAMS & WILKINS Circulation Research, 122, 12, pp. 1648-1660 Circulation Research, 122(12), 1648-1660 Circulation Research, 122, 1648-1660 Circ. Res. 122, 1648-1660 (2018) Circulation research, 122(12), 1648-1660. Lippincott Williams and Wilkins |
| ISSN: | 0009-7330 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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