TY - JOUR
T1 - The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance
AU - Wijers, Melinde
AU - Zanoni, Paolo
AU - Liv, Nalan
AU - Vos, Dionne Y.
AU - Jackstein, Michelle Y.
AU - Smit, Marieke
AU - Wilbrink, Sanne
AU - Wolters, Justina C.
AU - van der Veen, Ydwine T.
AU - Huijkman, Nicolette
AU - Dekker, Daphne
AU - Kloosterhuis, Niels
AU - van Dijk, Theo H.
AU - Billadeau, Daniel D.
AU - Kuipers, Folkert
AU - Klumperman, Judith
AU - von Eckardstein, Arnold
AU - Kuivenhoven, Jan Albert
AU - van de Sluis, Bart
PY - 2019/6/6
Y1 - 2019/6/6
N2 - 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.
AB - 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.
KW - HIGH-DENSITY-LIPOPROTEIN
KW - ESTER TRANSFER PROTEIN
KW - SCAVENGER RECEPTOR BI
KW - SR-BI
KW - APOLIPOPROTEIN-E
KW - SELECTIVE UPTAKE
KW - DEFICIENT MICE
KW - TISSUE UPTAKE
KW - A-I
KW - DEGRADATION
U2 - 10.1172/jci.insight.126462
DO - 10.1172/jci.insight.126462
M3 - Article
SN - 2379-3708
VL - 4
JO - JCI Insight
JF - JCI Insight
IS - 11
M1 - 126462
ER -