title: Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sarrazy
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sore
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Viaud
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
authors.forename: Guylène
authors.initials: G
authors.lastname: Rignol
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Ceppo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Tanti
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, 06204 Nice, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Guinamard
authors.affiliation: 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.
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Yvan-Charvet
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D007249:Inflammation; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010084:Oxidation-Reduction; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008077:Lipoproteins, LDL; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D011973:Receptors, LDL; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D005947:Glucose