Identification of GCN2 as new redox regulator for oxidative stress prevention in vivo.
Constitution of oxidative defense systems and, correspondingly, oxidative stress prevention are highly dependent on amino acid supply. In vitro, experiments have demonstrated that amino acid availability participates to the homeostasis of reactive oxygen species. However the molecular mechanisms involved in the maintenance of redox homeostasis responsive to circulating amino acid levels remain unclear. As GCN2 is a protein kinase considered to be an important sensor for amino acids availability and a potential regulator of redox homeostasis, we hypothesized that this kinase can modulate redox homeostasis in vivo, in response to an amino acid-imbalanced diet. We investigated the response of GCN2+/+ and GCN2-/- mice to a long-term (24 weeks) leucine-imbalanced diet (EDΔLeu). In order to evaluate the oxidation level in each group of mice, we determined the degree of protein oxidation in the liver. Interestingly, GCN2-/- mice exhibited an increase in protein carbonylation, a marker of oxidative stress, in response to the EDΔLeu diet. These data correlate with a decrease in hepatic GPX1 expression, a major antioxidant enzyme, and a decrease in total GPX activity in the liver. Our results suggest that GCN2 and its downstream signaling pathway have an important role in the protection against oxidative injuries induced by an amino acid-imbalanced diet, and that it can play a critical role in the prevention of oxidative damage.
Unité de Nutrition Humaine, UMR 1019, INRA de Theix, 63122 Saint Genès Champanelle, France.
Cédric
C
Chaveroux
Sarah
S
Lambert-Langlais
Laurent
L
Parry
Valérie
V
Carraro
Céline
C
Jousse
Anne-Catherine
AC
Maurin
Alain
A
Bruhat
Geoffroy
G
Marceau
Vincent
V
Sapin
Julien
J
Averous
Pierre
P
Fafournoux
D000818:Animals; D004032:Diet; D007930:Leucine / Q000172:deficiency; D008099:Liver / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D007930:Leucine