Skip to ContentSkip to Navigation
About usMedical SciencesResearchPediatrics
University Medical Center Groningen

New Key Publication: The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance.

08 June 2019

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 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.

  • Wijers M
  • Zanoni P
  • Liv N
  • Vos DY
  • Jäckstein MY
  • Smit M
  • Wilbrink S
  • Wolters JC
  • van der Veen YT
  • Huijkman N
  • Dekker D
  • Kloosterhuis N
  • van Dijk TH
  • Billadeau DD
  • Kuipers F
  • Klumperman J
  • von Eckardstein A
  • Kuivenhoven JA
  • van de Sluis B

JCI Insight : https://insight.jci.org/articles/view/126462

Last modified:08 June 2019 1.25 p.m.

More news

  • 23 August 2019

    Opening Academisch Jaar 2019-20 in teken van data

    De officiële opening van het 406e Academisch Jaar van de Rijksuniversiteit Groningen is op maandagmiddag 2 september 2019 in de Martinikerk. Rector Magnificus Cisca Wijmenga leidt voor het eerst de feestelijke ceremonie. Deze vindt plaats van 16.00...

  • 13 August 2019

    Eat, sleep, recycle

    The 51st edition of KEI week is devoted to the theme of sustainability. On Monday 12 August, around 6,000 KEI participants and KEI leaders were handed cloth bags instead of plastic ones and a KEI wristband with a chip enabling digital payments. A vegetarian...

  • 12 August 2019

    Cold winters not caused by Arctic climate change

    Recent studies into the relationship between decreases in sea ice in the Arctic and ice-cold winters in the mid-latitudes, like the Polar Vortex cold waves in North America, seem to suggest that such a connection does indeed exist. However, the mechanisms...