Human CETP adenoviral particles

The evolutionary conserved Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is one of the key multiprotein complexes that promotes endosomal recycling of transmembrane proteins. Defects in WASH components are associated with inherited developmental and neurological disorders in humans. Here, researchers show that in chow-fed mice, hepatic ablation of the WASH component Washc1 increases plasma cholesterol concentrations in both LDL and HDL without affecting liver cholesterol content, hepatic cholesterol synthesis, biliary cholesterol excretion, or hepatic bile acid metabolism. Increased plasma LDL cholesterol was associated with decreased levels of hepatocyte surface LDL receptor (LDLR) and LDLR-related protein LRP1. Hepatic WASH ablation also reduced surface levels of class B type I scavenger receptors and concomitantly reduced selective uptake of HDL cholesterol into the liver. Furthermore, WASHC1 deficiency increased LDLR proteolysis by LDLR-induced degraders but did not affect proprotein convertase subtilisin/kexin type 9-mediated LDLR degradation. Together, these findings indicate that the WASH complex is a regulator of LDL and HDL metabolism and provide in vivo evidence for endosomal trafficking of scavenger receptor class B type I in hepatocytes.

Unlike humans, mice do not express cholesteryl ester transfer protein (CETP), which esterifies HDL-C to TG in very low-density lipoprotein (VLDL) and LDL. Therefore, cholesterol in mouse plasma is primarily present in HDL rather than LDL. To further evaluate the effect of hepatic Washc1 deficiency on plasma LDL and HDL-C levels in mice with a more human-like lipoprotein profile, Washc1ΔHep and WT mice were injected with adenovirus expressing human CETP (Ad-CETP). Similar hepatic levels of human CETP expression were observed in Washc1ΔHep and WT mice (Figure 1A). Ectopic expression of CETP reduced TC levels in mice compared to mice that did not express CETP, but TC levels were significantly higher in Washc1ΔHep mice expressing CETP compared to WT mice (Figure 1B). Hepatic expression of human CETP resulted in a shift in cholesterol from HDL to LDL in both Washc1ΔHep and WT mice (Figure 1C). However, Washc1ΔHep mice had increased levels of LDL-C, HDL-C, and apolipoproteins ApoB, Apo-AI, and ApoE compared with WT mice (Figure 1C and D). CETP expression normalized the increase in HDL particles in Washc1ΔHep mice compared with Washc1ΔHep mice that did not express CETP (Figure 1C), a phenomenon also seen in SR-B1-deficient mice.

Figure 1. Hepatic WASHC1 deficiency results in increased plasma LDL-C and HDL-C in mice expressing CETP. (Wijers M, et al., 2019)