Reduced VLDL clearance in ApoeNpc1 mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels

6533b7d2fe1ef96bd125f6c5

RESEARCH PRODUCT

Reduced VLDL clearance in ApoeNpc1 mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels

David Masson Scott Sayers Minako Ishibashi Alan R. Tall Nan Wang Marit Westerterp Rong Li Carrie L. Welch

subject

Apolipoprotein E receptor Cholesterol VLDL LDL/metabolism Macrophages Peritoneal/cytology Biochemistry Mice Endocrinology hemic and lymphatic diseases Receptors Orphan Nuclear Receptors/genetics polycyclic compounds nuclear receptor Cells Cultured Research Articles Liver X Receptors Mice Knockout Cultured Sterol Regulatory Element Binding Protein 2/genetics lipoprotein Serine Endopeptidases Intracellular Signaling Peptides and Proteins Lamin Type A Orphan Nuclear Receptors Triglycerides/blood Cholesterol Liver Proteins/genetics Kexin lipids (amino acids peptides and proteins)Proprotein Convertases Proprotein Convertase 9 Sterol Regulatory Element Binding Protein 1 Niemann-Pick disease Sterol Regulatory Element Binding Protein 2 medicine.medical_specialty Cells Knockout Ubiquitin-Protein Ligases Receptors LDL/metabolism Serine Endopeptidases/genetics QD415-436 Biology Cholesterol/blood digestive system Apolipoproteins E Liver/physiology Sterol Regulatory Element Binding Protein 1/genetics Niemann-Pick C1 Protein Internal medicine medicine Animals Peritoneal/cytology Cholesterol VLDL/metabolism Ubiquitin-Protein Ligases/genetics Liver X receptor Triglycerides Macrophages PCSK9 Proteins nutritional and metabolic diseases VLDL/metabolism Lamin Type A/metabolism Cell Biology Sterol regulatory element-binding protein Endocrinology Receptors LDL LDL receptor Macrophages Peritoneal Sterol regulatory element-binding protein 2 atherosclerosis Apolipoproteins E/genetics Lipoprotein

description

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.

year	journal	country	edition	language
2010-09-01	Journal of Lipid Research

https://doi.org/10.1194/jlr.m006163