| Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels. | |
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MedLine Citation:
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PMID: 20489167 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels. METHODS AND RESULTS: In Npc1(-/-) mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1(-/-) mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1(-/-) mouse serum and hepatocytes. In Npc1(-/-) hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1(-/-) hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7 x 10(-4) for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals. CONCLUSIONS: This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans. |
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Authors:
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Riikka-Liisa Uronen; Per Lundmark; Marju Orho-Melander; Matti Jauhiainen; Kristina Larsson; Agneta Siegbahn; Lars Wallentin; Björn Zethelius; Olle Melander; Ann-Christine Syvänen; Elina Ikonen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-20 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 30 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-07-15 Completed Date: 2010-08-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1614-20 Citation Subset: IM |
Affiliation:
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Institute of Biomedicine/Anatomy, University of Helsinki, Finland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetic Acid
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metabolism Aged Animals Carrier Proteins / genetics* Cholesterol / biosynthesis* Cohort Studies Female Gene Frequency Genetic Predisposition to Disease Hepatocytes / metabolism* Humans Liver / metabolism* Male Membrane Glycoproteins / genetics* Mice Mice, Inbred BALB C Mice, Knockout Niemann-Pick Disease, Type C / genetics*, metabolism Oleic Acid / metabolism Phenotype Polymorphism, Single Nucleotide* Proteins / genetics*, metabolism Time Factors Triglycerides / blood* |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/Membrane Glycoproteins; 0/NPC1 protein, human; 0/Npc1 protein, mouse; 0/Proteins; 0/Triglycerides; 112-80-1/Oleic Acid; 57-88-5/Cholesterol; 64-19-7/Acetic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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