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Obesity and Insulin Resistance Promote Atherosclerosis through an IFN?-Regulated Macrophage Protein Network.


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 IFN? as the mediator of obesity/IR-induced MSRN dysregulation and increased macrophage cholesterol accumulation and show that obesity/IR primes T cells to increase IFN? production. Accordingly, myeloid cell-specific deletion of the IFN? 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 IFN?-macrophage pathway as a mechanistic link between obesity/IR and accelerated atherogenesis.

SUBMITTER: Reardon CA 

PROVIDER: S-EPMC6082182 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Obesity and Insulin Resistance Promote Atherosclerosis through an IFNγ-Regulated Macrophage Protein Network.

Reardon Catherine A CA   Lingaraju Amulya A   Schoenfelt Kelly Q KQ   Zhou Guolin G   Cui Chang C   Jacobs-El Hannah H   Babenko Ilona I   Hoofnagle Andrew A   Czyz Daniel D   Shuman Howard H   Vaisar Tomas T   Becker Lev L  

Cell reports 20180601 10


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 accumul  ...[more]

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