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.
Highlights
Niemann-Pick type C1 (NPC1) promotes the transport of LDL receptor (LDL-R)-derived cholesterol from late endosomes/lysosomes to other cellular compartments
In VLDL separated from plasma by ultracentrifugation, both apoB100 and apoB48 levels were markedly increased in ApoeϪ/ϪNpc1Ϫ/Ϫ mice, and apoB48 was predominant in both strains (Fig. 1E)
We have shown that ApoeϪ/ϪNpc1Ϫ/Ϫ mice exhibited elevated cholesterol levels but reduced TG levels in both plasma and liver compared with ApoeϪ/Ϫ controls
Summary
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. We demonstrate that NPC1 deficiency has a major impact on VLDL metabolism in Apoe؊/؊ mice through modulation of hepatic LDL-R protein levels. Reduced VLDL clearance in Apoe؊؊/؊؊Npc1؊؊/؊؊ mice is associated with increased Pcsk and Idol expression and decreased hepatic LDL-receptor levels. Since NPC1-deficient cells (fibroblasts and macrophages) fail to deliver LDL-derived free cholesterol to mitochondria and ER [3], they have impaired synthesis of endogenous liver X receptor (LXR) ligands, such as 25-hydroxycholesterol (25-OHC) and 27hydroxycholesterol (27-OHC), and LXR target genes are downregulated [4,5,6]. The current study was undertaken to investigate the mechanism underlying the increase of VLDL and IDL/LDL cholesterol concentrations in ApoeϪ/ϪNpc1Ϫ/Ϫ mice
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