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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Bartuzi, P; Billadeau, DD; Favier, R; Rong, S; Dekker, D; Fedoseienko, A; Fieten, H; Wijers, M; Levels, JH; Huijkman, N; Kloosterhuis, N; van der Molen, H; Brufau, G; Groen, AK; Elliott, AM; Kuivenhoven, JA; Plecko, B; Grangl, G; McGaughran, J; Horton, JD; Burstein, E; Hofker, MH; van de Sluis, B.
CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL.
Nat Commun. 2016; 7(5):10961-10961
Doi: 10.1038/ncomms10961
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- Co-Autor*innen der Med Uni Graz
- Grangl Gernot
- Plecko Barbara
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- Abstract:
- The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1-deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC-associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking.
- Find related publications in this database (using NLM MeSH Indexing)
- Adaptor Proteins, Signal Transducing - genetics
- Adolescent -
- Adult -
- Animals -
- Animals, Genetically Modified -
- Child -
- Child, Preschool -
- Cholesterol, LDL - metabolism
- Chromatography, Liquid -
- Dogs -
- Endosomes - metabolism
- Female -
- Fluorescent Antibody Technique -
- HEK293 Cells -
- Humans -
- Hypercholesterolemia - genetics
- Immunoprecipitation -
- Liver - metabolism
- Male -
- Mice -
- Mice, Knockout -
- Microfilament Proteins - genetics
- Middle Aged -
- Mutation -
- Protein Transport - genetics
- Proteins - genetics
- Receptors, LDL - metabolism
- Transcriptome -
- Triglycerides - metabolism
- Young Adult -