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The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance
Melinde Wijers, … , Jan Albert Kuivenhoven, Bart van de Sluis
Melinde Wijers, … , Jan Albert Kuivenhoven, Bart van de Sluis
Published June 6, 2019
Citation Information: JCI Insight. 2019;4(11):e126462. https://doi.org/10.1172/jci.insight.126462.
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Research Article Hepatology Metabolism

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

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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.

Authors

Melinde Wijers, Paolo Zanoni, Nalan Liv, Dyonne Y. Vos, Michelle Y. Jäckstein, 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

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Figure 1

WASHC1 deficiency destabilizes the WASH complex and perturbs lysosomal structures in primary hepatocytes.

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WASHC1 deficiency destabilizes the WASH complex and perturbs lysosomal s...
(A) Protein expression of the WASH complex components in liver homogenates of WT and Washc1ΔHep mice as determined by immunoblotting. (B) Quantification of immunoblot results depicted in A. (C) EM images of WT and Washc1ΔHep livers. BC, bile canaliculus, ER, endoplasmic reticulum; LD, lipid droplet; Lys, lysosome; Mito, mitochondrion. (D) Quantification of WT (n = 57) and Washc1ΔHep (n = 63) lysosomal area in liver sections. (E) EM image depicting aberrant lysosomal structure in Washc1ΔHep hepatocyte. Inset shows magnified area with tubulated lysosomes. For visualization of lysosomal tubulation, lysosomal perimeters were selected using the Lasso tool in Adobe Photoshop and color was added to the selected organelles. Data are presented as the mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001 as determined by Student’s t test.

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