Publication: Sox17 regulates liver lipid metabolism and adaptation to fasting.

Publié dans: PLoS One 2014 ; 9(8): e104925

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

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.

Lien vers Pubmed [PMID] – 25141153

Lien vers le DOI – 10.1371/journal.pone.0104925