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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apolipoproteins E* / genetics
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Apolipoproteins E* / metabolism
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Cells, Cultured
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Cholesterol / blood
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Cholesterol, VLDL / metabolism*
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Intracellular Signaling Peptides and Proteins
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Lamin Type A / metabolism
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Liver / physiology*
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Liver X Receptors
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Macrophages, Peritoneal / cytology
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Knockout
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Niemann-Pick C1 Protein
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Orphan Nuclear Receptors / genetics
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Orphan Nuclear Receptors / metabolism
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Proprotein Convertase 9
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Proprotein Convertases
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Proteins* / genetics
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Proteins* / metabolism
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Receptors, LDL / metabolism*
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Sterol Regulatory Element Binding Protein 2 / genetics
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Sterol Regulatory Element Binding Protein 2 / metabolism
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Triglycerides / blood
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Apolipoproteins E
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Cholesterol, VLDL
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Intracellular Signaling Peptides and Proteins
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Lamin Type A
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Liver X Receptors
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Niemann-Pick C1 Protein
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Npc1 protein, mouse
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Orphan Nuclear Receptors
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Proteins
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Receptors, LDL
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Triglycerides
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Cholesterol
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Mylip protein, mouse
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Ubiquitin-Protein Ligases
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Pcsk9 protein, mouse
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Proprotein Convertase 9
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Proprotein Convertases
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Serine Endopeptidases