title: Activation of peroxisome proliferator-activated receptor δ inhibits human macrophage foam cell formation and the inflammatory response induced by very low-density lipoprotein.
abstract: OBJECTIVE
  Hypertriglyceridemia is an important risk factor for cardiovascular disease. Elevated plasma very low-density lipoprotein (VLDL) puts insulin-resistant patients at risk for atherosclerosis. VLDL readily induces macrophage lipid accumulation and inflammatory responses, for which targeted therapeutic strategies remain elusive. We examined the ability of VLDL to induce macrophage foam cells and the inflammatory response and sought to define the cell signaling cascades involved. We further examined the potential of peroxisome proliferator-activated receptor (PPAR) δ activation to attenuate both VLDL-stimulated lipid accumulation and cytokine expression.
  
  
  RESULTS
  THP-1 macrophages exposed to VLDL displayed significant triglyceride accumulation, which was attenuated by PPARδ activation. PPARδ agonists stimulated a transcriptional program resulting in inhibition of lipoprotein lipase activity, activation of fatty acid uptake, and enhanced β-oxidation. VLDL-treated macrophages significantly increased the expression of activator protein 1 associated cytokines interleukin-1β, macrophage inflammatory protein 1α, and intercellular adhesion molecule-1. VLDL treatment significantly increased the phosphorylation of both extracellular signal-related kinase 1 and 2 and p38. VLDL reduced AKT phosphorylation as well as its downstream effector forkhead box protein O1, concomitant with increased nuclear forkhead box protein O1. Cells treated with PPARδ agonists were completely resistant to VLDL-induced expression of inflammatory cytokines, mediated by normalization of mitogen-activated protein kinase (MAPK)(erk) and AKT/forkhead box protein O1 signaling.
  
  
  CONCLUSIONS
  The combined PPARδ-mediated reductions of lipid accumulation and inflammatory cytokine expression suggest a novel macrophage-targeted therapeutic option in treating atherosclerosis.
authors.affiliation: Vascular Biology, Robarts Research Institute, Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Lazar A
authors.initials: LA
authors.lastname: Bojic
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Sawyez
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Edwards
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008079:Lipoproteins, VLDL / Q000009:adverse effects* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
chemical_list: D016207:Cytokines; D005227:Fatty Acids; D008024:Ligands; D008079:Lipoproteins, VLDL; D047494:PPAR delta; D014280:Triglycerides; D020929:Mitogen-Activated Protein Kinase Kinases