uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Show others and affiliations
2010 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 30, no 8, 1614-1620 p.Article in journal (Refereed) Published
Abstract [en]


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.


 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=8.7×10−4 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.


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.

Place, publisher, year, edition, pages
2010. Vol. 30, no 8, 1614-1620 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-130558DOI: 10.1161/ATVBAHA.110.207191ISI: 000279886000021PubMedID: 20489167OAI: oai:DiVA.org:uu-130558DiVA: diva2:349899
Available from: 2010-09-09 Created: 2010-09-09 Last updated: 2012-07-12Bibliographically approved
In thesis
1. Genetic and Genomic Analysis of DNA Sequence Variation
Open this publication in new window or tab >>Genetic and Genomic Analysis of DNA Sequence Variation
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The studies in this thesis describe the application of genotyping and allele specific expression analysis to genetic studies. The role of the gene NPC1 in Triglyceride metabolism was explored in mouse models and in humans on the population level in study I. NPC1 was found to affect hepatic triglyceride metabolism, and to be relevant for controlling serum triglyceride levels in mice and potentially in humans. In study II the utility of the HapMap CEU samples was investigated for tagSNP selection in six European populations. The HapMap CEU was found to be representative for tagSNP selection in all populations while allele frequencies differed significantly in the sample from Kuusamo, Finland. In study III the power of Allele specific expression as a tool for the mapping of cis-regulatory variation was compared to standard eQTL analysis, ASE was found to be the more powerful type of analysis for a similar sample size. Finally ASE mapping was applied to regions reported to harbour long non-coding RNAs and associated SNPs were compared to published trait-associations. This revealed strong cis-regulatory SNPs of long non-coding RNAs with reported trait or disease associations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 702
SNP, NPC1, association study, allele specific expression, tagSNP, non-coding RNA
National Category
Medical Genetics
Research subject
Molecular Medicine
urn:nbn:se:uu:diva-158486 (URN)978-91-554-8156-8 (ISBN)
Public defence
2011-10-25, Enghoffsalen, Entrance 50, bottom floor, Uppsala University Hospital, Uppsala, 09:15 (English)
Available from: 2011-10-04 Created: 2011-09-08 Last updated: 2011-11-04

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Siegbahn, AgnetaWallentin, LarsSyvänen, Ann-Christine
By organisation
Molecular MedicineDepartment of Medical SciencesClinical ChemistryGeriatrics
In the same journal
Arteriosclerosis, Thrombosis and Vascular Biology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 175 hits
ReferencesLink to record
Permanent link

Direct link