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.
JCI Insight : https://insight.jci.org/articles/view/126462
Two professors nominated by the University of Groningen have been awarded Royal Decorations on Tuesday 26 April. Professor K.U. Loos is appointed Knight of the Order of the Netherlands Lion. She received this honour from Mayor K. Schuiling at...
Cisca Wijmenga treedt per 1 september 2023 toe tot de Raad van Toezicht van de Hanzehogeschool.
The Board of the University of Groningen has taken note of the Letter to the House of Representatives regarding internationalization in higher education, sent to the House on Friday 21 April by the Minister of Education, Culture and Science Robbert...
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