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.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Atherosclerosis / genetics
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Atherosclerosis / immunology*
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / immunology
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Bone Marrow Cells / pathology
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Female
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Gene Expression Regulation
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Glucose / metabolism
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Glycolysis / genetics
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Humans
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Inflammation
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Lipoproteins, LDL / pharmacology
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Macrophage Activation / drug effects
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Macrophages / drug effects
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Macrophages / immunology*
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Macrophages / pathology
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Mice
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Mice, Knockout
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Nuclear Proteins / metabolism
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Oxidation-Reduction
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Plaque, Atherosclerotic / genetics
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Plaque, Atherosclerotic / immunology*
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Plaque, Atherosclerotic / metabolism
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Plaque, Atherosclerotic / pathology
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Primary Cell Culture
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Receptors, LDL / deficiency
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Receptors, LDL / genetics
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Receptors, LDL / immunology*
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Signal Transduction
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism
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Transcription Factors / genetics
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Transcription Factors / immunology*
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Transcription Factors / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Lipoproteins, LDL
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Mlxipl protein, mouse
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Nuclear Proteins
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Receptors, LDL
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Transcription Factors
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oxidized low density lipoprotein
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Glucose