Reduced VLDL clearance in Apoe-/- Npc1-/- mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels

Abstract

Niemann-Pick type C1 (NPC1) promotes the transport of LDL receptor (LDL-R)-derived cholesterol from late endosomes/lysosomes to other cellular compartments. NPC1-deficient cells showed impaired regulation of liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP) target genes. We observed that Apoe-/- Npc1-/- mice displayed a marked increase in total plasma cholesterol mainly due to increased VLDL, reflecting decreased clearance. Although nuclear SREBP-2 and Ldlr mRNA levels were increased in Apoe-/- Npc1-/- liver, LDL-R protein levels were decreased in association with marked induction of proprotein convertase subtilisin/kexin type 9 ( Pcsk9) and inducible degrader of the LDL-R ( Idol), both known to promote proteolytic degradation of LDL-R. While Pcsk9 is known to be an SREBP-2 target, marked upregulation of IDOL in Apoe-/- Npc1-/- liver was unexpected. However, several other LXR target genes also increased in Apoe-/- Npc1-/- liver, suggesting increased synthesis of endogenous LXR ligands secondary to activation of sterol biosynthesis. In conclusion, we demonstrate that NPC1 deficiency has a major impact on VLDL metabolism in Apoe-/- mice through modulation of hepatic LDL-R protein levels. In contrast to modest induction of hepatic IDOL with synthetic LXR ligands, a striking upregulation of IDOL in Apoe -/- Npc1-/- mice could indicate a role of endogenous LXR ligands in regulation of hepatic IDOL. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.