Fiche publication
Date publication
août 2014
Journal
PloS one
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ANDREOLETTI Pierre
,
Pr CHERKAOUI-MALKI Mustapha
Tous les auteurs :
Rommelaere S, Millet V, Vu Manh TP, Gensollen T, Andreoletti P, Cherkaoui-Malki M, Bourges C, Escalière B, Du X, Xia Y, Imbert J, Beutler B, Kanai Y, Malissen B, Malissen M, Tailleux A, Staels B, Galland F, Naquet P
Lien Pubmed
Résumé
Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.
Mots clés
Adaptation, Physiological, physiology, Amidohydrolases, blood, Animals, Fasting, blood, GPI-Linked Proteins, blood, HMGB Proteins, genetics, Lipid Metabolism, genetics, Liver, metabolism, Mice, Mice, Transgenic, PPAR alpha, genetics, SOX9 Transcription Factor, genetics, SOXF Transcription Factors, genetics, Transcriptome
Référence
PLoS One. 2014 08 20;9(8):e104925
