1. Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network.
- Author
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Reardon CA, Lingaraju A, Schoenfelt KQ, Zhou G, Cui C, Jacobs-El H, Babenko I, Hoofnagle A, Czyz D, Shuman H, Vaisar T, and Becker L
- Subjects
- Animals, Atherosclerosis genetics, Cholesterol metabolism, Foam Cells metabolism, Gene Expression Regulation, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells metabolism, Receptors, Interferon metabolism, Receptors, LDL deficiency, Receptors, LDL metabolism, Interferon gamma Receptor, Atherosclerosis metabolism, Atherosclerosis pathology, Insulin Resistance, Interferon-gamma metabolism, Macrophages metabolism, Obesity metabolism, Obesity pathology
- Abstract
Type 2 diabetes (T2D) is associated with increased risk for atherosclerosis; however, the mechanisms underlying this relationship are poorly understood. Macrophages, which are activated in T2D and causatively linked to atherogenesis, are an attractive mechanistic link. Here, we use proteomics to show that diet-induced obesity and insulin resistance (obesity/IR) modulate a pro-atherogenic "macrophage-sterol-responsive-network" (MSRN), which, in turn, predisposes macrophages to cholesterol accumulation. We identify IFNγ as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation and show that obesity/IR primes T cells to increase IFNγ production. Accordingly, myeloid cell-specific deletion of the IFNγ receptor (Ifngr1-/-) restores MSRN proteins, attenuates macrophage cholesterol accumulation and atherogenesis, and uncouples the strong relationship between hyperinsulinemia and aortic root lesion size in hypercholesterolemic Ldlr-/- mice with obesity/IR, but does not affect these parameters in Ldlr-/- mice without obesity/IR. Collectively, our findings identify an IFNγ-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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