title: 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.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY, USA. ishibashiminako@gmail.com
authors.forename: Minako
authors.initials: M
authors.lastname: Ishibashi
authors.forename: David
authors.initials: D
authors.lastname: Masson
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Scott
authors.initials: S
authors.lastname: Sayers
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Welch
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D015243:Cholesterol, VLDL / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A / Q000378:metabolism; D008099:Liver / Q000502:physiology*; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D000071518:Liver X Receptors; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D057093:Orphan Nuclear Receptors; D011506:Proteins; D011973:Receptors, LDL; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D002784:Cholesterol; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases