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PLoS One. 2014 Aug 20;9(8):e104925. doi: 10.1371/journal.pone.0104925. eCollection 2014.

Sox17 regulates liver lipid metabolism and adaptation to fasting.

Author information

1
Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille University, UM2, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France; Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France.
2
Université de Bourgogne, Laboratoire BioPeroxIL, EA7270, Dijon, France.
3
University of Texas Southwestern Medical Center, Center for Genetics of Host Defense, Dallas, Texas, United States of America.
4
Institut National de la Santé et de la Recherche Médicale (INSERM), Aix-Marseille University, UMR_S 1090, TGML/TAGC, Marseille, France.
5
Department of Veterinary Anatomy, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
6
Institut Pasteur de Lille, INSERM U1011, Université de Lille 2, EGID, Lille, France.

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.

PMID:
25141153
PMCID:
PMC4139292
DOI:
10.1371/journal.pone.0104925
[Indexed for MEDLINE]
Free PMC Article

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