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Niemann-Pick C1 Modulates Hepatic Triglyceride Metabolism and Its Genetic Variation Contributes to Serum Triglyceride Levels

Uronen, Riikka-Liisa; Lundmark, Per; Orho-Melander, Marju LU ; Jauhiainen, Matti; Larsson, Kristina; Siegbahn, Agneta; Wallentin, Lars; Zethelius, Bjorn; Melander, Olle LU and Syvanen, Ann-Christine, et al. (2010) In Arteriosclerosis, Thrombosis and Vascular Biology 30(8). p.230-1614
Abstract
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 [H-3] oleic acid and [H-3] acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [H-3] carbons into cholesterol was increased. Inhibition of cholesterol synthesis... (More)
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 [H-3] oleic acid and [H-3] acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [H-3] 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. Conclusion-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. (Arterioscler Thromb Vasc Biol. 2010;30:1614-1620.) (Less)
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published
subject
keywords
lysosomal storage disease, lipid droplets, dyslipidemia, fatty liver, single-nucleotide polymorphism
in
Arteriosclerosis, Thrombosis and Vascular Biology
volume
30
issue
8
pages
230 - 1614
publisher
American Heart Association
external identifiers
  • wos:000279886000021
  • scopus:77955173643
ISSN
1524-4636
DOI
10.1161/ATVBAHA.110.207191
language
English
LU publication?
yes
id
477b0776-1be4-4bd1-838a-1ac86cbfd315 (old id 1657700)
date added to LUP
2010-08-24 13:12:21
date last changed
2018-05-29 09:24:09
@article{477b0776-1be4-4bd1-838a-1ac86cbfd315,
  abstract     = {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 [H-3] oleic acid and [H-3] acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [H-3] 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. Conclusion-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. (Arterioscler Thromb Vasc Biol. 2010;30:1614-1620.)},
  author       = {Uronen, Riikka-Liisa and Lundmark, Per and Orho-Melander, Marju and Jauhiainen, Matti and Larsson, Kristina and Siegbahn, Agneta and Wallentin, Lars and Zethelius, Bjorn and Melander, Olle and Syvanen, Ann-Christine and Ikonen, Elina},
  issn         = {1524-4636},
  keyword      = {lysosomal storage disease,lipid droplets,dyslipidemia,fatty liver,single-nucleotide polymorphism},
  language     = {eng},
  number       = {8},
  pages        = {230--1614},
  publisher    = {American Heart Association},
  series       = {Arteriosclerosis, Thrombosis and Vascular Biology},
  title        = {Niemann-Pick C1 Modulates Hepatic Triglyceride Metabolism and Its Genetic Variation Contributes to Serum Triglyceride Levels},
  url          = {http://dx.doi.org/10.1161/ATVBAHA.110.207191},
  volume       = {30},
  year         = {2010},
}