title: Nicotinamide phosphoribosyltransferase and lipid accumulation in macrophages.
abstract: BACKGROUND
  Accumulation of modified low-density lipoprotein (LDL) in macrophages is a key event in all stages of atherogenesis. We have previously shown increased level of nicotinamide phosphoribosyltransferase (nampt) in symptomatic, compared to asymptomatic, atherosclerotic carotid lesions, primarily located to macrophages. Here we sought to investigate the regulation and effect of intracellular nampt in macrophages.
  
  
  METHODS
  The expression of nampt was assessed by real-time PCR in THP-1 cells that was exposed to different pro-atherogenic stimuli. The effect of nampt on lipid accumulation was examined in phorbol myristate acetate-differentiated THP-1 and in primary monocyte-derived macrophages.
  
  
  RESULTS
  Our main findings were: (1) Nampt is increased during macrophage differentiation. (2) Tumor necrosis factor (TNF)α, oxidized (ox)LDL, and hypoxia increased nampt expression in macrophages, with further enhancing effect when these stimuli were combined. The effect of hypoxia seems to involve hypoxia inducing factor 1α. (3) Silencing of nampt increased lipid accumulation in macrophages as shown by increased protein levels of the lipid droplet marker adipose differentiation-related protein (ADRP). (4) A specific inhibitor of nampt enzymatic activity, increased ADRP and cholesterol levels in oxLDL stimulated macrophages, and enhanced the binding of acetylated LDL in these cells. (5). Nampt inhibition decreased the relative amount of cholesterol efflux in oxLDL-exposed macrophages.
  
  
  CONCLUSIONS
  Our data suggest that the regulation of nampt in macrophages is linked to pro-atherogenic stimuli, potentially mediating counteracting effects on lipid accumulation and foam cell formation. These findings suggest a rather complex role of nampt in atherogenesis, potentially mediating both adaptive and maladaptive responses.
authors.affiliation: Research Institute for Internal Medicine, University Hospital Rikshospitalet, Oslo, Norway. tuvad@rr-research.no
authors.forename: Tuva
authors.initials: T
authors.lastname: Dahl
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.forename: Sverre
authors.initials: S
authors.lastname: Holm
authors.forename: Rolf
authors.initials: R
authors.lastname: Berge
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
mesh_terms: D000704:Analysis of Variance; D050197:Atherosclerosis / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D006801:Humans; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D014280:Triglycerides; D054409:Nicotinamide Phosphoribosyltransferase