title: Postprandial apoE isoform and conformational changes associated with VLDL lipolysis products modulate monocyte inflammation.
abstract: OBJECTIVE
  Postprandial hyperlipemia, characterized by increased circulating very low-density lipoproteins (VLDL) and circulating lipopolysaccharide (LPS), has been proposed as a mechanism of vascular injury. Our goal was to examine the interactions between postprandial lipoproteins, LPS, and apoE3 and apoE4 on monocyte activation.
  
  
  RESULTS
  We showed that apoE3 complexed to phospholipid vesicles attenuates LPS-induced THP-1 monocyte cytokine expression, while apoE4 increases expression. ELISA revealed that apoE3 binds to LPS with higher affinity than apoE4. Electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels placed on specific amino acids of apoE3 showed that LPS interferes with conformational changes normally associated with lipid binding. Specifically, compared to apoE4, apoE bearing the E3-like R112→Ser mutation displays increased self association when exposed to LPS, consistent with a stronger apoE3-LPS interaction. Additionally, lipolysis of fasting VLDL from normal human donors attenuated LPS-induced TNFα secretion from monocytes to a greater extent than postprandial VLDL, an effect partially reversed by blocking apoE. This effect was reproduced using fasting VLDL lipolysis products from e3/e3 donors, but not from e4/e4 subjects, suggesting that apoE3 on fasting VLDL prevents LPS-induced inflammation more readily than apoE4.
  
  
  CONCLUSIONS
  Postprandial apoE isoform and conformational changes associated with VLDL dramatically modulate vascular inflammation.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of California Davis, Davis, California, United States of America. ljdenhartigh@gmail.com
authors.forename: Laura J
authors.initials: LJ
authors.lastname: den Hartigh
authors.forename: Robin
authors.initials: R
authors.lastname: Altman
authors.forename: Romobia
authors.initials: R
authors.lastname: Hutchinson
authors.forename: Jitka
authors.initials: J
authors.lastname: Petrlova
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Budamagunta
authors.forename: Sarada D
authors.initials: SD
authors.lastname: Tetali
authors.forename: Jens O
authors.initials: JO
authors.lastname: Lagerstedt
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
authors.forename: John C
authors.initials: JC
authors.lastname: Rutledge
mesh_terms: D000293:Adolescent; D000328:Adult; D053318:Apolipoprotein E3 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D053327:Apolipoprotein E4 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001057:Apolipoproteins E / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004578:Electron Spin Resonance Spectroscopy; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008066:Lipolysis / Q000187:drug effects*; D008070:Lipopolysaccharides; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008070:Lipopolysaccharides; D008079:Lipoproteins, VLDL; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha