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Cell Rep. 2015 Oct 6;13(1):132-144. doi: 10.1016/j.celrep.2015.08.068. Epub 2015 Sep 24.

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

Author information

1
Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
2
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
3
Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Pierre and Marie Curie University Paris 6, ICAN Institute of Cardiometabolism and Nutrition, 75006 Paris, France.
4
Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France. Electronic address: laurent.yvan-charvet@unice.fr.

Abstract

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.

PMID:
26411684
DOI:
10.1016/j.celrep.2015.08.068
[Indexed for MEDLINE]
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