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

doi:10.1016/j.molmet.2013.06.001

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

Oregon National Primate Research Center

Research output: Contribution to journal › Article › peer-review

37 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 language	English (US)
Pages (from-to)	256-269
Number of pages	14
Journal	Molecular Metabolism
Volume	2
Issue number	3
DOIs	https://doi.org/10.1016/j.molmet.2013.06.001
State	Published - Aug 2013

Keywords

Atherosclerosis
Diabetes
Inflammation
Nonhuman primate
Obesity
Ox-LDL

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molmet.2013.06.001

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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

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, KL 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

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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 Grove, {Kevin L.}",

note = "Funding Information: This work was supported by a U.S. National Institutes of Health Grant , P51 OD011092 , and funding from Genentech, USA . We thank the Division of Comparative Medicine at the Oregon National Primate Research Center at OHSU for their excellent care of the animals. ",

year = "2013",

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doi = "10.1016/j.molmet.2013.06.001",

language = "English (US)",

volume = "2",

pages = "256--269",

journal = "Molecular Metabolism",

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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 L.

N1 - Funding Information: This work was supported by a U.S. National Institutes of Health Grant , P51 OD011092 , and funding from Genentech, USA . We thank the Division of Comparative Medicine at the Oregon National Primate Research Center at OHSU for their excellent care of the animals.

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

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

Abstract

Keywords

ASJC Scopus subject areas

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