Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels
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
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=8.7×10−4 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.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-130558DOI: 10.1161/ATVBAHA.110.207191ISI: 000279886000021PubMedID: 20489167OAI: oai:DiVA.org:uu-130558DiVA: diva2:349899