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 Grove

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 2013

Fingerprint

Macaca mulatta
Insulin Resistance
Antibodies
Body Weight Changes
Fc Receptors
p38 Mitogen-Activated Protein Kinases
Antigen-Antibody Complex
Primates
Blood Vessels
Rodentia
Atherosclerosis
Anti-Inflammatory Agents
Cardiovascular Diseases
Phosphorylation
oxidized low density lipoprotein
Cytokines
Diet
Inflammation
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques. / Li, Shijie; Kievit, Paul; Robertson, Anna Karin; Kolumam, Ganesh; Li, Xiumin; von Wachenfeldt, Karin; Valfridsson, Christine; Bullens, Sherry; Messaoudi, Ilhem; Bader, Lindsay; Cowan, Kyra J.; Kamath, Amrita; van Bruggen, Nicholas; Bunting, Stuart; Frendéus, Björn; Grove, Kevin.

In: Molecular Metabolism, Vol. 2, No. 3, 08.2013, p. 256-269.

Research output: Contribution to journalArticle

Li, S, Kievit, P, Robertson, AK, Kolumam, G, Li, X, von Wachenfeldt, K, Valfridsson, C, Bullens, S, Messaoudi, I, Bader, L, Cowan, KJ, Kamath, A, van Bruggen, N, Bunting, S, Frendéus, B & Grove, K 2013, 'Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques', Molecular Metabolism, vol. 2, no. 3, pp. 256-269. https://doi.org/10.1016/j.molmet.2013.06.001
Li, Shijie ; Kievit, Paul ; Robertson, Anna Karin ; Kolumam, Ganesh ; Li, Xiumin ; von Wachenfeldt, Karin ; Valfridsson, Christine ; Bullens, Sherry ; Messaoudi, Ilhem ; Bader, Lindsay ; Cowan, Kyra J. ; Kamath, Amrita ; van Bruggen, Nicholas ; Bunting, Stuart ; Frendéus, Björn ; Grove, Kevin. / Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques. In: Molecular Metabolism. 2013 ; Vol. 2, No. 3. pp. 256-269.
@article{f352f8b0a8454edeb16cfd3fb85eab60,
title = "Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques",
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.",
keywords = "Atherosclerosis, Diabetes, Inflammation, Nonhuman primate, Obesity, Ox-LDL",
author = "Shijie Li and Paul Kievit and Robertson, {Anna Karin} and Ganesh Kolumam and Xiumin Li and {von Wachenfeldt}, Karin and Christine Valfridsson and Sherry Bullens and Ilhem Messaoudi and Lindsay Bader and Cowan, {Kyra J.} and Amrita Kamath and {van Bruggen}, Nicholas and Stuart Bunting and Bj{\"o}rn Frend{\'e}us and Kevin Grove",
year = "2013",
month = "8",
doi = "10.1016/j.molmet.2013.06.001",
language = "English (US)",
volume = "2",
pages = "256--269",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
number = "3",

}

TY - JOUR

T1 - Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques

AU - Li, Shijie

AU - Kievit, Paul

AU - Robertson, Anna Karin

AU - Kolumam, Ganesh

AU - Li, Xiumin

AU - von Wachenfeldt, Karin

AU - Valfridsson, Christine

AU - Bullens, Sherry

AU - Messaoudi, Ilhem

AU - Bader, Lindsay

AU - Cowan, Kyra J.

AU - Kamath, Amrita

AU - van Bruggen, Nicholas

AU - Bunting, Stuart

AU - Frendéus, Björn

AU - Grove, Kevin

PY - 2013/8

Y1 - 2013/8

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Diabetes

KW - Inflammation

KW - Nonhuman primate

KW - Obesity

KW - Ox-LDL

UR - http://www.scopus.com/inward/record.url?scp=84883245665&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84883245665&partnerID=8YFLogxK

U2 - 10.1016/j.molmet.2013.06.001

DO - 10.1016/j.molmet.2013.06.001

M3 - Article

VL - 2

SP - 256

EP - 269

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

IS - 3

ER -