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Nutrients 2016, 8(4), 215; doi:10.3390/nu8040215

Glutamine Modulates Macrophage Lipotoxicity

1
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA
2
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
3
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
*
Author to whom correspondence should be addressed.
Received: 17 February 2016 / Revised: 24 March 2016 / Accepted: 6 April 2016 / Published: 12 April 2016
(This article belongs to the Special Issue Diet and Metabolic Dysfunction)
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Abstract

Obesity and diabetes are associated with excessive inflammation and impaired wound healing. Increasing evidence suggests that macrophage dysfunction is responsible for these inflammatory defects. In the setting of excess nutrients, particularly dietary saturated fatty acids (SFAs), activated macrophages develop lysosome dysfunction, which triggers activation of the NLRP3 inflammasome and cell death. The molecular pathways that connect lipid stress to lysosome pathology are not well understood, but may represent a viable target for therapy. Glutamine uptake is increased in activated macrophages leading us to hypothesize that in the context of excess lipids glutamine metabolism could overwhelm the mitochondria and promote the accumulation of toxic metabolites. To investigate this question we assessed macrophage lipotoxicity in the absence of glutamine using LPS-activated peritoneal macrophages exposed to the SFA palmitate. We found that glutamine deficiency reduced lipid induced lysosome dysfunction, inflammasome activation, and cell death. Under glutamine deficient conditions mTOR activation was decreased and autophagy was enhanced; however, autophagy was dispensable for the rescue phenotype. Rather, glutamine deficiency prevented the suppressive effect of the SFA palmitate on mitochondrial respiration and this phenotype was associated with protection from macrophage cell death. Together, these findings reveal that crosstalk between activation-induced metabolic reprogramming and the nutrient microenvironment can dramatically alter macrophage responses to inflammatory stimuli. View Full-Text
Keywords: lysosome; cell death; metabolism; inflammasome lysosome; cell death; metabolism; inflammasome
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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He, L.; Weber, K.J.; Schilling, J.D. Glutamine Modulates Macrophage Lipotoxicity. Nutrients 2016, 8, 215.

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