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

Melinde Wijers, Paolo Zanoni, Nalan Liv, Dionne Y. Vos, Michelle Y. Jackstein, Marieke Smit, Sanne Wilbrink, Justina C. Wolters, Ydwine T. van der Veen, Nicolette Huijkman, Daphne Dekker, Niels Kloosterhuis, Theo H. van Dijk, Daniel D. Billadeau, Folkert Kuipers, Judith Klumperman, Arnold von Eckardstein, Jan Albert Kuivenhoven, Bart van de Sluis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number126462
Number of pages16
JournalJCI Insight
Volume4
Issue number11
DOIs
Publication statusPublished - 6-Jun-2019

Keywords

  • HIGH-DENSITY-LIPOPROTEIN
  • ESTER TRANSFER PROTEIN
  • SCAVENGER RECEPTOR BI
  • SR-BI
  • APOLIPOPROTEIN-E
  • SELECTIVE UPTAKE
  • DEFICIENT MICE
  • TISSUE UPTAKE
  • A-I
  • DEGRADATION

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