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

• Published in: Molecular metabolism (Germany) Vol. 2; no. 3; pp. 256 - 269
• Main Authors: 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 L
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.08.2013; Elsevier
• Subjects: Atherosclerosis; Diabetes; Endocrinology & Metabolism; Inflammation; Nonhuman primate; Obesity; Original; ox-LDL; Obesity; ox-LDL; Inflammation; Diabetes; Nonhuman primate; Atherosclerosis
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2013.06.001

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.