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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 orcid 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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organization
publishing date
type
Contribution to journal
publication status
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
Lippincott Williams & Wilkins
external identifiers
  • wos:000279886000021
  • scopus:77955173643
  • pmid:20489167
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
2016-04-01 10:34:39
date last changed
2024-03-13 10:59:41
@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}},
  keywords     = {{lysosomal storage disease; lipid droplets; dyslipidemia; fatty liver; single-nucleotide polymorphism}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{230--1614}},
  publisher    = {{Lippincott Williams & Wilkins}},
  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}},
  doi          = {{10.1161/ATVBAHA.110.207191}},
  volume       = {{30}},
  year         = {{2010}},
}