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Inflammation modulates human HDL composition and function in vivo

  • Author Footnotes
    1 Both authors contributed equally.
    Margarita de la Llera Moya
    Footnotes
    1 Both authors contributed equally.
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Author Footnotes
    1 Both authors contributed equally.
    Fiona C. McGillicuddy
    Footnotes
    1 Both authors contributed equally.
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Nutrigenomics Research Group, UCD Conway Institute, School of Public Health & Population Science, University College Dublin, Dublin 4, Ireland
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  • Christine C. Hinkle
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Michael Byrne
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Michelle R. Joshi
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Vihn Nguyen
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Jennifer Tabita-Martinez
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Megan L. Wolfe
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Karen Badellino
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Leticia Pruscino
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Nehal N. Mehta
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
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  • Bela F. Asztalos
    Affiliations
    Lipid Metabolism at Human Nutrition Research Center at Tufts University, Boston, MA, USA
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  • Muredach P. Reilly
    Correspondence
    Corresponding author at: Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, 11-136 TRC Building 421, 3400 Civic Center Blvd., Philadelphia, PA 19104-6160, USA. Tel.: +1 215 573 1214; fax: +1 215 573 2094.
    Affiliations
    Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Search for articles by this author
  • Author Footnotes
    1 Both authors contributed equally.

      Abstract

      Objectives

      Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans.

      Methods and results

      We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-β1a HDL particles determined by 2-D gel electrophoresis (−32.2 ± 9.3% at 24 h, p < 0.05) as well as small (−23.0 ± 5.1%, p < 0.01, at 24 h) and medium (−57.6 ± 8.0% at 16 h, p < 0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (∼36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (−20.8 ± 3.4% at 24 h, p < 0.01) and cholesterol ester transfer protein mass (−22.2 ± 6.8% at 24 h, p < 0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models.

      Conclusions

      These data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels.

      Highlights

      • Endotoxin challenge in humans results in marked alterations in HDL particle composition with reduced phospholipids and increased serum amyloid A but without significant change in cholesterol of apo-AI.
      • Endotoxin induced selective remodeling of HDL particles with induction of specific HDL lipases and reductions in CETP mass and LCAT activity.
      • HDL efflux function was reduced after endotoxin challenge with reduced capacity of particles to mediate efflux via ABCA1 and SR-BI cholesterol transporter pathways; reduced efflux correlated with alterations in HDL composition and reduction in specific HDL sub-populations.
      • Overall, these data support the concept that atherogenic HDL dysfunction and impaired RCT occur in human inflammatory syndromes, independent of significant change in plasma HDL-C levels.

      Keywords

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