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Jens Lagerstedt

Associate professor

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Postprandial apoE Isoform and Conformational Changes Associated with VLDL Lipolysis Products Modulate Monocyte Inflammation

Author

  • Laura J. den Hartigh
  • Robin Altman
  • Romobia Hutchinson
  • Jitka Petrlova
  • Madhu S. Budamagunta
  • Sarada D. Tetali
  • Jens Lagerstedt
  • John C. Voss
  • John C. Rutledge

Summary, in English

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. Methods and 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 TNF alpha 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. Conclusion: Postprandial apoE isoform and conformational changes associated with VLDL dramatically modulate vascular inflammation.

Department/s

  • Medical Protein Science
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2012

Language

English

Publication/Series

PLoS ONE

Volume

7

Issue

11

Document type

Journal article

Publisher

Public Library of Science

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Medical Protein Science

ISBN/ISSN/Other

  • ISSN: 1932-6203