title: Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels.
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.
  
  
  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.
authors.affiliation: Institute of Biomedicine/Anatomy, University of Helsinki, Finland.
authors.forename: Riikka-Liisa
authors.initials: RL
authors.lastname: Uronen
authors.forename: Per
authors.initials: P
authors.lastname: Lundmark
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Kristina
authors.initials: K
authors.lastname: Larsson
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.forename: Björn
authors.initials: B
authors.lastname: Zethelius
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
mesh_terms: D019342:Acetic Acid / Q000378:metabolism; D000368:Aged; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002784:Cholesterol / Q000096:biosynthesis*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D014280:Triglycerides; D019301:Oleic Acid; D002784:Cholesterol; D019342:Acetic Acid