Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques

Shijie Li, Paul Kievit, Anna Karin Robertson, Ganesh Kolumam, Xiumin Li, Karin von Wachenfeldt, Christine Valfridsson, Sherry Bullens, Ilhem Messaoudi, Lindsay Bader, Kyra J. Cowan, Amrita Kamath, Nicholas van Bruggen, Stuart Bunting, Björn Frendéus, Kevin L. Grove

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Oxidation of LDL (oxLDL) is a crucial step in the development of cardiovascular disease. Treatment with antibodies directed against oxLDL can reduce atherosclerosis in rodent models through unknown mechanisms. We demonstrate that through a novel mechanism of immune complex formation and Fc-γ receptor (FcγR) engagement, antibodies targeting oxLDL (MLDL1278a) are anti-inflammatory on innate immune cells via modulation of Syk, p38 MAPK phosphorylation and NFκB activity. Subsequent administration of MLDL1278a in diet-induced obese (DIO) nonhuman primates (NHP) resulted in a significant decrease in pro-inflammatory cytokines and improved overall immune cell function. Importantly, MLDL1278a treatment improved insulin sensitivity independent of body weight change. This study demonstrates a novel mechanism by which an anti-oxLDL antibody improves immune function and insulin sensitivity independent of internalization of oxLDL. This identifies MLDL1278a as a potential therapy for reducing vascular inflammation in diabetic conditions.

Original languageEnglish (US)
Pages (from-to)256-269
Number of pages14
JournalMolecular Metabolism
Volume2
Issue number3
DOIs
StatePublished - Aug 1 2013

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Keywords

  • Atherosclerosis
  • Diabetes
  • Inflammation
  • Nonhuman primate
  • Obesity
  • Ox-LDL

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Li, S., Kievit, P., Robertson, A. K., Kolumam, G., Li, X., von Wachenfeldt, K., Valfridsson, C., Bullens, S., Messaoudi, I., Bader, L., Cowan, K. J., Kamath, A., van Bruggen, N., Bunting, S., Frendéus, B., & Grove, K. L. (2013). Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques. Molecular Metabolism, 2(3), 256-269. https://doi.org/10.1016/j.molmet.2013.06.001