The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance.

Autor: Wijers M; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Zanoni P; Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland., Liv N; Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., Vos DY; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Jäckstein MY; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Smit M; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Wilbrink S; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Wolters JC; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., van der Veen YT; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Huijkman N; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Dekker D; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Kloosterhuis N; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., van Dijk TH; Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Billadeau DD; Department of Immunology and Biochemistry, Division of Oncology Research, Mayo Clinic, Rochester, New York, USA., Kuipers F; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.; Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., Klumperman J; Section Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands., von Eckardstein A; Institute for Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland; Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland., Kuivenhoven JA; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands., van de Sluis B; Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2019 Jun 06; Vol. 4 (11). Date of Electronic Publication: 2019 Jun 06 (Print Publication: 2019).
DOI: 10.1172/jci.insight.126462
Abstrakt: 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 LDLR 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: MEDLINE