The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance
| Autor: | Marieke Smit, Dyonne Y. Vos, Michelle Y. Jäckstein, Judith Klumperman, Folkert Kuipers, Daphne Dekker, Daniel D. Billadeau, Niels J. Kloosterhuis, Arnold von Eckardstein, Melinde Wijers, Nicolette C. A. Huijkman, Sanne Wilbrink, Bart van de Sluis, Paolo Zanoni, Jan Albert Kuivenhoven, Justina C. Wolters, Ydwine T. van der Veen, Nalan Liv, Theo H. van Dijk |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Cardiovascular Centre (CVC), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), University of Zurich, van de Sluis, Bart |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Male medicine.medical_specialty Vesicular Transport Proteins 610 Medicine & health Mice Transgenic 2700 General Medicine APOLIPOPROTEIN-E DEFICIENT MICE WASH complex 03 medical and health sciences chemistry.chemical_compound ESTER TRANSFER PROTEIN Mice 0302 clinical medicine High-density lipoprotein Internal medicine 540 Chemistry medicine Animals Scavenger receptor 10038 Institute of Clinical Chemistry Medicine(all) Chemistry Cholesterol Cholesterol HDL Microfilament Proteins SR-BI General Medicine Cholesterol LDL DEGRADATION Scavenger Receptors Class B LRP1 A-I Mice Inbred C57BL 030104 developmental biology Endocrinology TISSUE UPTAKE Liver 030220 oncology & carcinogenesis LDL receptor Kexin SELECTIVE UPTAKE lipids (amino acids peptides and proteins) Female HIGH-DENSITY-LIPOPROTEIN SCAVENGER RECEPTOR BI Research Article |
| Zdroj: | JCI Insight, 4(11):126462. AMER SOC CLINICAL INVESTIGATION INC JCI Insight, 4(11). The American Society for Clinical Investigation |
| ISSN: | 2379-3708 |
| Popis: | The evolutionary conserved Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is one of the crucial multiprotein complexes that facilitates endosomal recycling of transmembrane proteins. Defects in WASH components have been associated with inherited developmental and neurological disorders in humans. Here, we show that hepatic ablation of the WASH component Washc1 in chow-fed mice increases plasma concentrations of cholesterol in both LDLs and HDLs, without affecting hepatic cholesterol content, hepatic cholesterol synthesis, biliary cholesterol excretion, or hepatic bile acid metabolism. Elevated plasma LDL cholesterol was related to reduced hepatocytic surface levels of the LDL receptor (LDLR) and the LDLR-related protein LRP1. Hepatic WASH ablation also reduced the surface levels of scavenger receptor class B type I and, concomitantly, selective uptake of HDL cholesterol into the liver. Furthermore, we found that WASHC1 deficiency increases LDLR proteolysis by the inducible degrader of LDLR, but does not affect proprotein convertase subtilisin/kexin type 9-mediated LDLR degradation. Remarkably, however, loss of hepatic WASHC1 may sensitize LRP1 for proprotein convertase subtilisin/kexin type 9-induced degradation. Altogether, these findings identify the WASH complex as a regulator of LDL as well as HDL metabolism and provide in vivo evidence for endosomal trafficking of scavenger receptor class B type I in hepatocytes. |
| Databáze: | OpenAIRE |
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