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  • Uronen, Riikka-Liisa (author)

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

  • Article/chapterEnglish2010

Publisher, publication year, extent ...

  • 2010

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:477b0776-1be4-4bd1-838a-1ac86cbfd315
  • https://lup.lub.lu.se/record/1657700URI
  • https://doi.org/10.1161/ATVBAHA.110.207191DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-130558URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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.)

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Lundmark, PerUppsala universitet,Molekylär medicin(Swepub:uu)pelun425 (author)
  • Orho-Melander, MarjuLund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups(Swepub:lu)endo-mor (author)
  • Jauhiainen, Matti (author)
  • Larsson, KristinaUppsala universitet,Molekylär medicin (author)
  • Siegbahn, AgnetaUppsala universitet,Institutionen för medicinska vetenskaper,Koagulation(Swepub:uu)agsie424 (author)
  • Wallentin, LarsUppsala universitet,Klinisk kemi(Swepub:uu)larswall (author)
  • Zethelius, BjörnUppsala universitet,Geriatrik(Swepub:uu)bjorzeth (author)
  • Melander, OlleLund University,Lunds universitet,Kardiovaskulär forskning - hypertoni,Forskargrupper vid Lunds universitet,Cardiovascular Research - Hypertension,Lund University Research Groups(Swepub:lu)endo-ome (author)
  • Syvänen, Ann-ChristineUppsala universitet,Molekylär medicin(Swepub:uu)anncsyva (author)
  • Ikonen, Elina (author)
  • Uppsala universitetMolekylär medicin (creator_code:org_t)

Related titles

  • In:Arteriosclerosis, Thrombosis and Vascular Biology30:8, s. 230-16141524-46361079-5642

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