Cell Reports (Oct 2015)

Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation

  • Vincent Sarrazy,
  • Sophie Sore,
  • Manon Viaud,
  • Guylène Rignol,
  • Marit Westerterp,
  • Franck Ceppo,
  • Jean-Francois Tanti,
  • Rodolphe Guinamard,
  • Emmanuel L. Gautier,
  • Laurent Yvan-Charvet

DOI
https://doi.org/10.1016/j.celrep.2015.08.068
Journal volume & issue
Vol. 13, no. 1
pp. 132 – 144

Abstract

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Enhanced glucose utilization can be visualized in atherosclerotic lesions and may reflect a high glycolytic rate in lesional macrophages, but its causative role in plaque progression remains unclear. We observe that the activity of the carbohydrate-responsive element binding protein ChREBP is rapidly downregulated upon TLR4 activation in macrophages. ChREBP inactivation refocuses cellular metabolism to a high redox state favoring enhanced inflammatory responses after TLR4 activation and increased cell death after TLR4 activation or oxidized LDL loading. Targeted deletion of ChREBP in bone marrow cells resulted in accelerated atherosclerosis progression in Ldlr−/− mice with increased monocytosis, lesional macrophage accumulation, and plaque necrosis. Thus, ChREBP-dependent macrophage metabolic reprogramming hinders plaque progression and establishes a causative role for leukocyte glucose metabolism in atherosclerosis.