Glutamine Modulates Macrophage Lipotoxicity
AbstractObesity 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
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He, L.; Weber, K.J.; Schilling, J.D. Glutamine Modulates Macrophage Lipotoxicity. Nutrients 2016, 8, 215.
He L, Weber KJ, Schilling JD. Glutamine Modulates Macrophage Lipotoxicity. Nutrients. 2016; 8(4):215.Chicago/Turabian Style
He, Li; Weber, Kassandra J.; Schilling, Joel D. 2016. "Glutamine Modulates Macrophage Lipotoxicity." Nutrients 8, no. 4: 215.
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