Sox17 regulates liver lipid metabolism and adaptation to fasting

Samuel Rommelaere, Virginie Millet, Thien Phong Vu Manh, Thomas Gensollen, Pierre Andreoletti, Mustapha Cherkaoui-Malki, Christophe Bourges, Bertrand Escalière, Xin Du, Yu Xia, Jean Imbert, Bruce Beutler, Yoshiakira Kanai, Bernard Malissen, Marie Malissen, Anne Tailleux, Bart Staels, Franck Galland, Philippe Naquet

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9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere104925
JournalPloS one
Volume9
Issue number8
DOIs
StatePublished - Aug 20 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Rommelaere, S., Millet, V., Vu Manh, T. P., 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. (2014). Sox17 regulates liver lipid metabolism and adaptation to fasting. PloS one, 9(8), [e104925]. https://doi.org/10.1371/journal.pone.0104925