TY - JOUR AU - Wijers, Melinde AU - Zanoni, Paolo AU - Liv, Nalan AU - Vos, Dyonne Y. AU - Jäckstein, 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 T1 - The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance PY - 2019/06/08/ 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.126462 VL - 4 IS - 11 UR - https://doi.org/10.1172/jci.insight.126462 PB - The American Society for Clinical Investigation ER -